Nutt (2014)). They are present throughout the epidermis of skin, where dendritic cells, and by cytokines secreted by the cells. These cytokines
they were first described, but are most clearly identifiable in the stratum not only help activate the T cell but can also direct the nature of the
spinosum. They have an irregular nucleus and a clear cytoplasm, and T-cell response (e.g. Th1 or Th2). Appropriate T cells are thus activated
contain characteristic elongated membranous vesicles (Birbeck gran- to proliferate and are primed for carrying out their immunological
ules). Langerhans cells endocytose and process antigens, undergoing a functions. Once primed, T cells can then be stimulated by any APC,
process of maturation from antigen-capturing to antigen-presenting including macrophages and B cells.
cells that express high levels of MHC class I and II molecules,
co-stimulatory molecules and adhesion molecules. They migrate to Follicular dendritic cells
lymph nodes to activate T lymphocytes.
Follicular dendritic cells (FDCs; Fig. 4.15) are a non-migratory popula-
Interdigitating dendritic cells
tion of cells found in the follicles of secondary lymphoid tissues, where
they attract and interact with B cells. Unlike other dendritic cells, FDCs
Immature dendritic cells are found all over the body, including periph- are not haemopoietic in origin but are probably derived from the
eral blood, and function in antigen-processing and immune surveil- stromal cells of lymphoid tissues. They are unable to endocytose and
lance. Mature dendritic cells are present in T-cell-rich areas of secondary process antigen, and they lack MHC class II molecules. However, Fc
lymphoid tissue (paracortical areas of lymph nodes, interfollicular areas receptors and complement receptors CD21 and CD35 on FDCs allow
of MALT, peri-arteriolar sheaths of splenic white pulp), where they are the cells to bind immune complexes to their surface for subsequent
frequently referred to as interdigitating dendritic cells. Within the sec- presentation, as unprocessed antigen, to germinal centre B cells. Interac-
ondary lymphoid tissues, they are involved in the presentation to T tions between B cells, CD4 helper T cells and FDCs in the germinal


lymphocytes of antigens associated with either MHC class I (CD8 T centres are important in the selection of high-affinity B cells and their
cells) or MHC class II (CD4 T cells) molecules. Naïve T cells can only maturation to either plasma cells or memory B lymphocytes (Liu 2001).
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81
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Functional anatomy of the CHAPTER
5
musculoskeletal system
The musculoskeletal system consists of the specialized connective common proteoglycan molecule, aggrecan, forms huge molecular ag
tissues of the articulated bony skeleton and the skeletal muscles that gregates with other proteoglycans and with hyaluronan (see Fig. 5.1).
act across the articulations. All the specialized cells of the musculoskel
etal system (bone, cartilage, muscle, tendon) are related members of the Cartilage cells
connective tissue family and are derived from mesenchymal stem cells.
The cells of cartilage are chondroblasts and chondrocytes. Chondro
CARTILAGE blasts are actively dividing cells, often flattened and irregular in shape,
and are abundant in growing tissue where they synthesize the extracel
lular matrix (Fig. 5.2). Small projections arising from the cell mem
Cartilage is the fetal precursor tissue in the development of many bones. brane (Fig. 5.3) can form gap junctions with adjacent cells (Bruehlmann
In the adult skeleton it persists at almost all joints between bones and et al 2002), but these junctions may be lost when interstitial growth
in structures that must be deformable as well as strong, e.g. in the res causes greater cell separation. As chondroblasts mature and lose the
piratory tract. ability to divide, they develop into the larger but metabolically less
active chondrocytes. These ovalshaped cells form sparse populations
that maintain the extensive matrix of adult cartilage. The name ‘chondro
MICROSTRUCTURE OF CARTILAGE
cyte’ is commonly employed, as it is here, to denote all of the cartilage
Cartilage is a pliant, loadbearing connective tissue, covered by a fibrous
perichondrium except at its junctions with bones and over the articular
surfaces of synovial joints. It has a capacity for rapid interstitial and Proteoglycan Type II
complex collagen fibrils
appositional growth in young and growing tissues. Three types of car
tilage (hyaline cartilage, white fibrocartilage and yellow elastic cartilage)
can be distinguished on the basis of the composition and structure of
their extracellular matrices, but many features of the cells and matrix


are common to all three types, and these features will be considered
first.
Extracellular matrix
The matrix is mostly comprised of collagen and, in some cases, elastic
fibres, embedded in a highly hydrated proteoglycan gel (Fig. 5.1). Large
proteoglycan molecules have numerous side chains of glycosaminogly
cans (GAGs), carbohydrates with remarkable waterbinding properties.
A preponderance of fixed negative charges on the surface of GAGs
strongly attract polarized water molecules, causing wet cartilage to swell
until restricted by tension in the collagen network, or by external
loading. In this way, cartilage develops a compressive turgor that enables
it to distribute loading evenly on to subchondral bone, rather like a
water bed. Effectively, water is held in place by proteoglycans, which are
themselves held in place by the collagen network. Other constituents
of cartilage include dissolved salts, noncollagenous proteins, and
glycoproteins.
Collagens are described on page 38. Most fibrous tissues contain
collagen type I, which forms large fibres with a wavy ‘crimped’ structure;
however, this type of collagen is only found in cartilage in the outer
layers of the perichondrium and in white fibrocartilage. More typical of Proteoglycan
cartilage is collagen type II, which forms very thin fibrils dispersed monomer
between the proteoglycan molecules so that they do not clump together
to form larger fibres. Collagen type II fibrils are often less than 50 nm Large
proteoglycan
in diameter and are too small to be seen by light microscopy. Trans complex
mission electron microscopy reveals that they have a characteristic
crossbanding (65 nm periodicity) and are interwoven to create a three
dimensional meshwork. The collagen network varies in different types
of cartilage and with age. The length of collagen fibrils and fibres in Hyaluronan
cartilage is unknown, but even relatively short fibrils can reinforce the
matrix by interacting physically and chemically with each other, and Core protein
with other matrix constituents including proteoglycans (Hukins and Glycosaminoglycan
chain
Aspden 1985), reflecting the fact that the term collagen means ‘glue
maker’.


Collagen type II is found in the notochord, the nucleus pulposus of Fig. 5.1 The fine structural organization of hyaline cartilage matrix. Large
an intervertebral disc, the vitreous body of the eye, and the primary proteoglycan complexes and type II collagen fibres (cross-banded and of
corneal stroma. different diameters) are depicted. Proteoglycan complexes bind to the
Cartilage proteoglycans are similar to those found in general, i.e. surface of these fibres via their monomeric side chains and link them
nonspecialized, connective tissue. The most common GAG side chains together. The arrangement of glycosaminoglycans and core protein of the
in cartilage are chondroitin sulphate and keratan sulphate. The most proteoglycan monomer is illustrated in the expansion.


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
82
1
noiTCEs
B C
Cc
P Cb
M B
C
M
B C
A B
Fig. 5.2 Sections through hyaline cartilage. A, A low-power view of human rib, showing perichondrium (P), young chondroblasts (Cb) embedded in
pale-staining interterritorial matrix, and mature chondrocytes (Cc) embedded in the basophilic interterritorial matrix (centre and right). B, Higher
magnification of hyaline cartilage in human bronchial wall, showing isogenous groups of chondrocytes (C). Note the more deeply stained basophilic
zones (B) (rich in acidic proteoglycans) around the cell clusters, with older, paler-staining matrix (M) between clusters. (B, Courtesy of Mr Peter Helliwell
and the late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
Collagen is synthesized within the rough endoplasmic reticulum in
the same way as it is in fibroblasts. Polypeptide chains are assembled
into triple helices, and some carbohydrate is added. After transport to
the Golgi apparatus, where further glycosylation occurs, the resulting
procollagen molecules are secreted into the extracellular space. Termi
nal registration peptides are cleaved from their ends, forming tropocol
lagen molecules, and the final assembly into collagen fibrils takes
place. Core proteins of the proteoglycan complexes are also synthe
sized in the rough endoplasmic reticulum and addition of GAG chains
begins; the process is completed in the Golgi complex. Hyaluronan,
which lacks a protein core, is synthesized by enzymes on the surface of
the chondrocyte; it is not modified postsynthetically, and is extruded
directly into the matrix without passing through the endoplasmic
reticulum.
Matrix turnover is much slower in cartilage than in more metaboli
cally active tissues. Collagen turnover is particularly slow, leaving it
vulnerable to the slow process of nonenzymatic glycation, which
makes the tissue yellow, stiff and vulnerable to injury (DeGroot et al


2004). Proteoglycans are turned over faster than collagen, with an esti
mated turnover time of 5 years for adult humans.
Cartilage is often described as avascular. Certainly, the ability of the
matrix to deform under load makes it difficult for hollow blood vessels
to persist in the tissue beyond early childhood, but a limited vascular
Fig. 5.3 An electron micrograph of chondroblasts in rabbit femoral supply is often found on the cartilage surface, from where it can revas
condylar cartilage. The central cell has an active euchromatic nucleus cularize the tissue following injury or degeneration. Metabolite trans
with a prominent nucleolus, and its cytoplasm contains concentric
port to cartilage cells is mostly by the process of diffusion down a
cisternae of rough endoplasmic reticulum, scattered mitochondria,
concentration gradient from the cartilage surface, although fluid
lysosomes and glycogen aggregates. The plasma membrane bears
‘pumping’ as a result of changing mechanical loading can contribute
numerous short filopodia which project into the surrounding matrix. The
under certain circumstances. Metabolite transport severely limits cell
latter shows a delicate feltwork of collagen fibrils within finely granular
density and metabolic rate in the adult, and this in turn restricts carti
interfibrillary material. No pericellular lacuna is present; the matrix
lage thickness to a few millimetres (Junger et al 2009). Cartilage cells
separates the central chondroblast from the cytoplasm of two adjacent
situated further than this from a nutrient vessel do not survive, and their
chondroblasts (left, and crescentic profile). (Preparation courtesy of Susan
Smith, Department of Anatomy, GKT School of Medicine, London.) surrounding matrix typically becomes calcified. In the larger cartilages,
and during the rapid growth of some fetal cartilages, vascular cartilage
canals penetrate the tissue at intervals, providing an additional source
of nutrients. In some cases these canals are temporary structures but
cells embedded in an extensive matrix. Chondrocytes are normally in
others persist throughout life.
close contact with their dense matrix (see Fig. 5.3); however, artefacts
of tissue processing can sometimes give the illusion of an empty space
Hyaline cartilage
or ‘lacuna’ surrounding each cell or group of cells in histological sec


tions. One or more chondrocytes can form a chondron, which consists
of the cells and their pericellular matrix (see Fig. 5.2B), surrounded by Hyaline (glassy) cartilage has a homogeneous, opalescent appearance,
a protective basket of collagen (Roberts et al 1991, Youn et al 2006). sometimes appearing bluish. It is firm and smooth to the touch and
Chondrocytes synthesize and secrete all of the major components shows considerable deformability. The size, shape and arrangement of
of the cartilage matrix, and their ultrastructure is typical of cells that are cells vary at different sites and with age. Chondrocytes are flat near the
active in making and secreting proteins. The nucleus is round or oval, surface perichondrium, and rounded or angular deeper in the tissue
appears euchromatic and possesses one or more nucleoli. The cyto (see Fig. 5.2A). Groups of two or more cells frequently form a cell nest
plasm is filled with rough endoplasmic reticulum, transport vesicles and (isogenous cell group) surrounded by a basket of fine collagen fibrils
Golgi complexes, and contains many mitochondria and frequent lyso (see Fig. 5.2B). Within such a chondron, daughter cells of a common
somes, together with numerous glycogen granules, intermediate fila chondroblast often meet at a straight line. The pericellular matrix
ments (vimentin) and pigment granules. When these cells mature to closest to the cells is typically lacking in collagen fibrils, but rich in
the relatively inactive chondrocyte stage, the nucleus becomes hetero proteoglycans that can exhibit basophilic and metachromatic staining.
chromatic, the nucleolus smaller, and the protein synthetic machinery More distant and older interterritorial matrix appears paler and is
much reduced; the cells may also accumulate large lipid droplets. mostly collagen type II (75% of dry weight) and proteoglycans (22%).


Cartilage
83
5
RETPAHC
Cartilage zone
Articular surface
Collagen fibrils
Superficial or
tangential
Middle or
Chondrocyte
intermediate
Deep or
radial
Tide mark
Calcified
Subchondral
bone
Fig. 5.4 Articular cartilage from the anterior region of the lateral femoral
condyle of a young adult human female. Three-dimensional digital 1mm
volumetric fluorescence imaging of serially sectioned, eosin-Y and
Fig. 5.5 Articular cartilage is not homogenous: the various zones are
acridine orange-stained tissue. Articular surface (top), articular cartilage
different in terms of cell size and shape, and the orientation of the
and subchondral bone (below). Note the changes in size and spatial
collagen fibril network.
distribution of articular chondrocytes through the thickness of the
cartilage. (Courtesy of Professor Robert L. Sah, Drs Won C. Bae, Kyle D.
Jadin, Benjamin L. Wong, Kelvin W. Li and Mrs Barbara L. Schumacher, (Properties of the articular surface are described below under ‘Synovial
Department of Bioengineering and Whitaker Institute of Biomedical joints’, p. 97.) Deeper within the tangential zone, the collagen fibrils
Engineering, University of California, San Diego.) increase in diameter and density, and gradually merge with the transi
tional (or intermediate) zone. Here, the chondrocytes are large and
After adolescence, hyaline cartilage may become calcified as part of rounded, and surrounded by collagen fibrils in a range of oblique ori
the normal process of bone development, or as an agerelated, degen entations. Deeper still, in the radial zone, the cells are often disposed
erative change. In costal cartilage, the matrix tends to fibrous striation, in vertical columns, interspersed with vertical collagen fibrils. The
especially in old age when cellularity diminishes. The xiphoid process matrix in this zone contains collagen types IX and XI, as well as collagen
and the cartilages of the nose, larynx and trachea (excepting the elastic II. An undulating band known as the tidemark indicates the start of the


cartilaginous epiglottis and corniculate cartilages) resemble costal car deepest zone, the zone of calcified cartilage, which has mechanical
tilage in microstructure. Hyaline cartilage is the prototypical form, but properties intermediate between cartilage and bone. This calcified zone
it varies more with age and location than either elastic or fibrocartilage. is keyed into the subchondral bone by fine ridges and interdigitations,
Its regenerative capacity following injury is poor. which serve to prevent shearing (gliding) movements between cartilage
Articular cartilage, which covers the articular surfaces of synovial and bone. With age, articular cartilage thins by upward advancement of
joints, is a specialized hyaline cartilage that lacks a perichondrium (Fig. the tidemark, and gradual replacement of calcified cartilage by bone.
5.4). The synovial membrane overlaps and then merges into its struc Cells of articular cartilage are capable of cell division, but mitosis is
ture circumferentially (see Fig. 5.32). The thickness of articular cartilage rarely observed in adult tissue and cartilage damage is not repaired.
varies from 1 to 7 mm (typically 2 mm) in different joints, and decreases Superficial cells are lost progressively from normal young joint surfaces,
from middle to old age. Thickness does not increase in response to to be replaced by cells from deeper layers. Agerelated reductions in cell
increased mechanical loading, at least in adults, although matrix com number and activity, and biochemical changes in the extracellular
position and stiffness can adapt somewhat (Gahunia and Pritzker matrix, particularly affect the superficial zone of articular cartilage,
2012). Central regions tend to be thickest on convex osseous surfaces, increasing the risk of mechanical failure and of osteoarthritis (Lotz and
and thinnest on concave surfaces. Loeser 2012).
Articular cartilage provides an extremely smooth, firm yet deform Articular cartilage derives nutrients by diffusion from vessels of the
able layer that increases the contact area between bones and thereby synovial membrane, synovial fluid and hypochondral vessels of an
reduces contact stress (see Fig. 5.61). Microscopic undulations on the adjacent medullary cavity, some capillaries from which penetrate and


cartilage surface help to trap synovial fluid between the articulating occasionally traverse the calcified cartilage zone. The contributions from
bones (see Fig. 5.60) and enable fluidfilm lubrication to reduce fric these sources are uncertain and may change with age. Small molecules
tion and wear. Articular cartilage is generally too thin and stiff to be a freely traverse articular cartilage, with diffusion coefficients about half
good shock absorber, although shock absorption may be significant those in aqueous solution. Larger molecules have diffusion coefficients
where there are multiple cartilagecovered surfaces, as in the carpus and inversely related to their molecular size. The permeability of cartilage
tarsus. to large molecules is greatly affected by variations in its GAG (and hence
Adult articular cartilage shows a structural zonation defined by its water) content: a threefold increase in GAGs increases the diffusion
network of fine collagen type II fibrils (Fig. 5.5). Embedded in the deep coefficient 100fold.
calcified zone, fibrils rise vertically through the radial zone towards the Cartilaginous growth plates (see below under ‘Bone’) are also com
cartilage surface, where they appear to reorientate to run parallel to the posed of hyaline cartilage, and there are similarities between active
surface in the tangential zone. These collagen arcades can be visualized growth plates and growing articular cartilage on the epiphyses of long
using phasecontrast microscopy (Thambyah and Broom 2007) but it bones. In both cases, chondrocytes undergo a sequence of cell divisions
is likely that each arcade represents numerous discrete fibrils rather than and hypertrophy (with cells forming into columns) followed by cell
a single fibre. Their threedimensional orientation can be appreciated death, and ossification by invading osteoblasts.
by repeatedly piercing the cartilage surface with a needle; this creates a
Fibrocartilage
series of permanent elongated splits in the surface, which can be stained
by Indian ink. The resulting split line pattern (Meachim et al 1974)
reveals the predominant directions of collagen bundles in the cartilage Fibrocartilage is a dense, whitish tissue with a distinct fibrous texture.
tangential zone, which may be related to internal lines of tension gener It forms the intervertebral discs of the spine and menisci of the knee,


ated during joint movement. as well as smaller structures such as the glenoid and acetabular labra,
Each zone of articular cartilage (see Fig. 5.5) has a distinct cell mor and the lining of bony grooves for tendons. It forms a versatile and
phology and matrix composition. The tangential (or superficial) zone tough material that combines considerable tensile strength with the
has relatively small, elongated cells orientated parallel to the surface. ability to resist high compressive forces and to distribute them evenly


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
84
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Fig. 5.6 White fibrocartilage in a late human fetal intervertebral disc. Fig. 5.7 Elastic cartilage, stained to demonstrate elastin fibres (blue–
Chondroblasts lie between coarse collagen type I fibres (blue) derived black). Chondroblasts and larger chondrocytes are embedded in the
from the anulus fibrosus. Mallory’s triple stain. matrix, which also contains collagen type II fibres.
on to underlying bone (Adams et al 2013). Histologically, fibrocartilage sation foreshadows that of the future cartilage. They also become
is intermediate between dense fibrous connective tissues such as tendon rounded, with prominent round or oval nuclei and a low cytoplasm:
and ligaments, and hyaline cartilage. In some structures such as interver nucleus ratio. Each cell differentiates into a chondroblast as it secretes
tebral discs, matrix composition and cell types vary from one location a basophilic halo of matrix, composed of a delicate network of fine type
to another, reflecting varying mechanical properties. II collagen fibrils, type IX collagen and proteoglycan core protein. At
Regions of fibrocartilage that are loaded predominantly in tension some sites, continued secretion of matrix separates the cells, producing
consist of large crimped fibres of collagen type I embedded in a hydrated typical hyaline cartilage. Elsewhere, many cells become fibroblasts; col
proteoglycan gel. Cells are rounded in young tissue (Fig. 5.6), but lagen synthesis predominates and chondroblastic activity appears only
become elongated and fibroblastlike with age. They may be linked by in isolated groups or rows of cells that become surrounded by dense
gap junctions (Bruehlmann et al 2002). Those regions that are loaded bundles of collagen fibres to form white fibrocartilage. In yet other sites,
predominantly in compression appear more homogeneous, contain a the matrix of early cellular cartilage is permeated first by anastomosing
high proportion of fine collagen type II fibrils in an abundant proteo oxytalan fibres, and later by elastin fibres. In all cases, developing car


glycan gel, and contain rounded, chondrocytelike cells. Fibrocartilage tilage is surrounded by condensed mesenchyme, which differentiates
could therefore be regarded as a mingling of two types of tissue rather into a bilaminar perichondrium. The cells of the outer layer become
than a separate type of cartilage. However, no other tissue combines fibroblasts and secrete a dense collagenous matrix lined externally by
high proportions of proteoglycans with collagen type I, suggesting that vascular mesenchyme. The cells of the inner layer contain differentiated,
fibrocartilage should be regarded as a distinct class of connective tissue. but mainly resting, chondroblasts or prechondroblasts.
The articular surfaces of bones that ossify in mesenchymal mem Cartilage grows by interstitial and appositional mechanisms. Inter
branes (e.g. squamous temporal, mandible and clavicle) are covered by stitial growth is the result of continued mitosis of early chondroblasts
white fibrocartilage. The deep layers, adjacent to hypochondral bone, throughout the tissue mass and is obvious only in young cartilage,
resemble calcified regions of the radial zone of hyaline articular carti where plasticity of the matrix permits continued expansion. When a
lage. The superficial zone contains dense parallel bundles of thick col chondroblast divides, its descendants temporarily occupy the same
lagen fibres, interspersed with typical dense connective tissue fibroblasts chondron. They are soon separated by a thin septum of secreted matrix,
and little ground substance. Fibre bundles in adjacent layers alternate which thickens and further separates the daughter cells. Continuing
in direction, as they do in the cornea. A transitional zone of irregular division produces isogenous groups. Appositional growth is the result
bundles of coarse collagen and active fibroblasts separates the superfi of continued proliferation of the cells that form the internal, chondro
cial and deep layers. The fibroblasts are probably involved in elabora genic layer of the perichondrium. Newly formed chondroblasts secrete
tion of proteoglycans and collagen, and may also constitute a germinal matrix around themselves, creating superficial lacunae beneath the peri
zone for deeper cartilage. Fibre diameters and types may differ at dif chondrium. This continuing process adds additional surface, while the


ferent sites according to the functional load. entrapped cells participate in interstitial growth. Apposition is thought
to be most prevalent in mature cartilages, but interstitial growth must
Elastic cartilage persist for long periods in growthplate cartilage. Relatively little is
known about the factors that determine the overall shape of cartilage
structures.
Elastic cartilage occurs in the external ear, corniculate cartilages, epiglot
tis and apices of the arytenoids. Like hyaline cartilage, it contains typical
chondrocytes, either singly or in small groups, surrounded by a matrix
BONE
rich in type II collagen fibrils. However, the more distant interterritorial
matrix is pervaded by very fine yellow elastic fibres (Fig. 5.7) containing
the protein elastin, which show no periodic banding structure under Bone is a strong and rigid connective tissue that has evolved to enable
the electron microscope (as collagen fibrils do). A structure is termed fast terrestrial locomotion. Its strength provides support and protection
‘elastic’ if it returns to its original shape when loaded and then unloaded; for the body, while its rigidity enables it to create precisely shaped
elastic fibres (and cartilage) have the special property of being able to articular surfaces that do not distort under load, and ensures that force
do this even after being subjected to deformations greater than 15%, ful muscle contractions result in rapid limb movements rather than
which would damage collagen fibres. This characteristic is termed elastic bending of bones. Unlike cartilage, bone is a highly vascular tissue with
recoil. Most sites in which elastic cartilage occurs have vibrational func a high cell density; high cellularity enables it to adapt to changing
tions, such as laryngeal soundwave production, or the collection and mechanical demands, and to regenerate following injury.
transmission of sound waves in the ear. Elastic cartilage is resistant to
degeneration, and its capacity for limited regeneration following trau
matic injury can be appreciated from the distorted repair of a cauli MACROSCOPIC ANATOMY OF BONE
flower ear, as seen in participants of some contact sports.
Macroscopically, living bone is white. Its texture is either dense like
ivory (compact bone) or honeycombed by large cavities (trabecular,


DEVELOPMENT AND GROWTH OF CARTILAGE cancellous or spongy bone), where the bony element is reduced to a
latticework of bars and plates known collectively as trabeculae (Figs
Cartilage is usually formed in embryonic mesenchyme. Mesenchymal 5.8–5.9). Compact bone is usually limited to the outer shell or cortex
cells proliferate and become tightly packed; the shape of their conden of mature bones, where it is important in determining their strength


Bone
85
5
RETPAHC
and providing rigid articular surfaces. Cortical thickness and architec
ture vary between and within bones, and generally decrease with age in
CC adults. Trabecular bone provides support to the cortex while minimiz
ing weight. The presence of a large central medullary canal in long
bones also helps to reduce their weight. Spaces within bones provide
convenient and secure locations for the storage of haemopoietic tissues
and fat. Bone forms a reservoir of metabolic calcium (99% of body
calcium is in the bony skeleton) and of phosphate, which is under
hormonal and cytokine control.
The proportions of compact to cancellous bone vary between and
within bones. Generally, a thick cortex is required to provide strength
in bending, e.g. in the middiaphysis of a long bone (see Fig. 5.20).
Trabecular bone provides strength in compression and so is abundant
in the epiphyses of long bones, and in the vertebral bodies of the spine.
In flat bones such as the ribs, the interior is uniformly cancellous, and
compact bone forms the surface. Internal cavities are usually filled with
marrow, either red haemopoietic or yellow adipose, according to age
CC and site. However, in some bones of the skull, notably the mastoid
process of the temporal bone and the paranasal sinuses of the frontal,
maxilla, sphenoid and ethmoid bones, many of the internal cavities are
Fig. 5.8 A vertical section 2 cm below the anterosuperior border of the
filled with air, i.e. they are variably pneumatized.
iliac crest (female, 42 years). The cancellous bone consists of intersecting
Bones vary not only in their primary shape but also in lesser surface
curved plates and struts. Osteonal (Haversian) canals can just be seen in
details (secondary markings), which appear mainly in postnatal life.
the two cortices (C) at this magnification.
Most bones display features such as elevations and depressions (fossae),
smooth areas and rough ridges. Some articular surfaces are called fossae
Fig. 5.9 Trabecular (e.g. the glenoid fossa); lengthy depressions are grooves or sulci (e.g.


bone at different sites the humeral bicipital sulcus); a notch is an incisura; and an actual gap
in the proximal part of
is a hiatus. A large projection is termed a process or, if elongated and
the same human femur.
slender or pointed, a spine. A curved process is a hamulus or cornu (e.g.
All fields are shown
the pterygoid hamuli of the sphenoid bone and the cornua of the
at the same scale.
hyoid). A rounded projection is a tuberosity or tubercle, and occasion
A, Subcapital part of
ally a trochanter. Long elevations are crests, or lines if they are less
the neck. B, Greater
developed; crests are wider and present boundary edges or lips. An
trochanter. C, Rim of
epicondyle is a projection close to a condyle and is usually a site where
the articular surface
of the head. Note the the common tendon of a superficial muscle group or the collateral liga
wide variation in ment of the adjacent joint is attached. The terms protuberance, promi
thickness, orientation nence, eminence and torus are less often applied to certain bony
and spacing of the projections. The expanded proximal ends of many long bones are often
trabeculae. (Original termed the ‘head’ or caput (e.g. humerus, femur, radius). A hole in a
photographs from bone is a foramen and becomes a canal when lengthy. Large holes may
Whitehouse WJ, Dyson be called apertures or, if covered largely by connective tissue, fenestrae.
A ED 1974 Scanning Clefts in or between bones are fissures. A lamina is a thin plate; larger
electron microscope laminae may be called squamae (e.g. the temporal squama). Large areas
studies of trabecular on many bones are featureless and as smooth as articular surfaces, from
bone in the proximal which they differ by being pierced by visible vascular foramina.
end of the human Tendons are usually attached at roughened bone surfaces. Wherever
femur. J Anat 118:
any aggregation of collagen in a muscle reaches bone, surface irregulari
417–414, by permission
ties correspond in form and extent to the pattern of tendinous fibres.
from Blackwell


Such markings are almost always elevated above the general surface, as
Publishing.)
if ossification advanced into the collagen bundles from periosteal bone.
How such secondary markings are induced is uncertain but they may
result from the continued incorporation of new collagen fibres into the
bone, perhaps necessary for minor functional adjustment. There is evi
dence that their prominence may be related to the power of the muscles
involved, and they increase with advancing years as if the pull of
muscles and ligaments exercised a cumulative effect over a limited area.
Surface markings delineate the shape of attached connective tissue
structures, e.g. an obvious tendon, intramuscular tendon or septum,
aponeurosis, or tendinous fibres mediating what is otherwise a direct
B muscular attachment. These markings may be facets, ridges, nodules,
rough areas or complex mixtures; they afford accurate indications of
the junctions of bone with muscles, tendons, ligaments or articular
capsules.
Muscle fibres do not attach directly to periosteum or bone. Force
transmission is through the connective tissue that encapsulates (epimy
sium) and pervades (perimysium and endomysium) all muscles. These
two forms of attachment of muscles, which are at the extremes of a
range of admixtures, differ in the density of collagen fibres between
muscle and bone. Where collagen is visibly concentrated, markings
appear on the bone surface. In contrast, the multitude of microscopic
connective tissue ties of direct attachment that occur over a larger area
do not visibly mark the bone, and so it appears smooth to unaided
vision and touch.
Many bones articulate with their neighbours at synovial joints. Small
articular surfaces are termed facets or foveae; larger, knuckleshaped
surfaces are condyles; a trochlea is grooved like a pulley. Articular sur
faces are smooth and covered by articular cartilage, which means that
C they lack the vascular foramina typical of the surfaces of most other
bones.


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
86
1
noiTCEs
Bone minerals
Approximately 60–70% of bone dry weight is made up of inorganic
mineral salts in the form of microcrystalline hydroxyapatite (Ca
10
(PO) (OH)). The microcrystals confer hardness and much of the
4 6 2
rigidity of bone, and are the main reason why bone is easily seen on
radiographs. (Bone must be 50% mineralized to be visible on radio
graphs produced with a standard Xray unit.) Bone mineral also has
an important carbonate content, and a lower Ca/P ratio than pure
hydroxyapatite, together with a small amount of calcium phosphate.
Bone crystals are extremely small (which gives them a high surface:volume
ratio). They take the form of thin plates or leaflike structures; the largest
are 150 nm long × 80 nm wide × 5 nm thick, although most are half that
size. Up to twothirds of the mineral content of bone is thought to be
located within collagen fibrils, where the crystals are packed closely
together, with their long axes nearly parallel to the fibrils; crystal forma
tion is probably initiated in the gaps between individual collagen mol
ecules. Narrow spaces between the crystals contain water and organic
macromolecules. The mineral substances of bone are mostly acid
soluble. If they are removed, using calcium chelators such as citrates or
Fig. 5.10 A scanning electron micrograph of collagen fibres on the
ethylene diamine tetraacetic acid (EDTA), the bone retains its shape
surface of human trabecular bone. Note the branching fibres (female,
2 months, sixth rib). but becomes highly flexible.
The major ions in bone mineral include calcium, phosphate,
hydroxyl and carbonate. Less numerous ions are citrate, magnesium,
sodium, potassium, fluoride, chloride, iron, zinc, copper, aluminium,
MICROSTRUCTURE OF BONE lead, strontium, silicon and boron, many of which are present only in
trace quantities. Fluoride ions can substitute for hydroxyl ions, and
carbonate can substitute for either hydroxyl or phosphate groups.
Bone contains a mineralized collagenous extracellular matrix surround


‘Group IIA cations’, such as radium, strontium and lead, all readily
ing a range of specialized cells including osteoblasts, osteocytes and
substitute for calcium and are therefore known as boneseeking cations.
osteoclasts. Periosteum, endosteum and marrow are closely associated
tissues. All of these components will be described first individually, and Since they can be either radioactive or chemically toxic, their presence
then their overall organization will be considered. in bone, where they may be close to haemopoietic bone marrow, may
cause illness and characteristic appearances on Xrays.
Bone organic matrix Mineralization of newly synthesized osteoid is a gradual process that
slows over time; it typically reaches 70–80% in 3 weeks. Immature
woven bone mineralizes faster and so may be distinguished from adja
Approximately 10–20% of bone mass is water. A significant proportion
cent lamellar bone by its higher degree of mineralization. In cortical
(30–40%) of the remaining dry weight is made up of the organic com
bone, lamellae mostly take the form of cylindrical osteons (see Fig.
ponent of the extracellular matrix. Approximately 30% of this organic
5.16). These structures mineralize from inside to out, so that the con
matrix is collagen; the remainder includes various noncollagenous
centration of mineral is highest in the older, more peripheral, lamellae.
proteins, glycoproteins and carbohydrates. The proportions of these
Although new osteons are less mineralized than old ones, they may
components vary with age, location and metabolic status.
show one or more highly mineralized ‘arrest lines’ within their walls.
Most of the collagen in bone is an ordered branching network of
Mineral distribution is most uniform in established, highly mineralized
type I fibres (Fig 5.10). Although type I collagen fibres are found in
osteons. Overall, mineralization increases with age, even though bone
most connective tissues, their molecular structure in bone is atypical:
mass decreases.
internal crosslinking between component fibrils is stronger and chemi
cally more inert, and transverse spacings between collagen molecules
Osteoblasts
within each fibril are larger, allowing more space for the deposition of
minerals. A small amount of type V collagen is also present, probably


to help regulate fibrillogenesis. Collagen fibres contribute greatly to the Osteoblasts are derived from osteoprogenitor (stem) cells of mesenchy
cohesive mechanical strength of bone, and also to its toughness (which mal origin present in bone marrow and other connective tissues. They
is reflected in the energy required to break a bone). proliferate and differentiate into osteoblasts prior to bone formation,
Collagen is synthesized in bone by osteoblasts. Newly secreted mol stimulated by bone morphogenetic proteins (BMPs). A layer of osteo
ecules of tropocollagen lose part of their nonhelical terminal regions, blasts covers the forming surfaces of growing or remodelling bone (Fig.
thus allowing them to polymerize in the extracellular matrix to form 5.11). In relatively quiescent adult bone, they appear to be present
fibrils, which then associate to form fibres. These structures are stabi mostly on endosteal rather than periosteal surfaces, but they also occur
lized by various crosslinks, which increase in number and strength as deep within compact bone wherever osteons are being remodelled.
the tissue matures. In primary bone, collagen fibres form a complex Osteoblasts are responsible for the synthesis, deposition and minerali
interwoven meshwork that incorporates other organic molecules; this zation of the bone matrix, which they secrete. Once embedded in the
‘osteoid’ material is then mineralized to form woven (nonlamellar) matrix, they become osteocytes.
bone. In time, primary bone is almost entirely replaced by regular Osteoblasts are basophilic, roughly cuboidal mononuclear cells
laminar arrays of nearly parallel collagen fibres, which form the basis 15–30 µm across. They contain prominent bundles of actin, myosin
of lamellar bone (Currey 2002). Partially mineralized collagen net and other cytoskeletal proteins associated with the maintenance of cell
works can be seen within osteoid on the outer and internal surfaces of shape, attachment and motility. Their plasma membranes display many
bone, and in the endosteal linings of vascular canals. Collagen fibres extensions, some of which contact neighbouring osteoblasts and
from the periosteum are incorporated in cortical bone (extrinsic fibres) embedded osteocytes at intercellular gap junctions. This arrangement


and anchor this fibrocellular layer at its surface. Terminal collagen fibres facilitates coordination of the activities of groups of cells, e.g. in the
of tendons and ligaments are incorporated deep into the matrix of corti formation of large domains of parallel collagen fibres.
cal bone. They may be interrupted by new osteons during cortical drift Ultrastructurally, osteoblasts are typical proteinsecreting cells. They
(modelling) and turnover (remodelling), and remain as islands of inter synthesize and secrete collagens and a number of glycoproteins. Osteo
stitial lamellae or even trabeculae. calcin is required for bone mineralization, binds hydroxyapatite and
Bone organic matrix includes small amounts of various macromol calcium, and is used as a marker of new bone formation. Osteonectin
ecules attached to collagen fibres and surrounding bone crystals. They is a phosphorylated glycoprotein that binds strongly to hydroxyapatite
are secreted by osteoblasts and young osteocytes, and include osteonec and collagen; it may play a role in initiating crystallization and may be
tin, osteocalcin, the bone proteoglycans biglycan and decorin, the bone a cell adhesion factor. RANKL is the cell surface ligand for RANK (recep
sialoproteins osteopontin and thrombospondin, many growth factors tor for activation of nuclear factor kappa B), an osteoclast progenitor
including transforming growth factor beta (TGFβ), proteases and pro receptor (see below). Osteoprotegerin is a soluble, highaffinity decoy
tease inhibitors, often in a latent form. The functions of some of these ligand for RANKL, which restricts osteoclast differentiation. Biglycan
molecules are described with osteoblasts (see below). and decorin are bone proteoglycans that attract water; decorin also


Bone
87
5
RETPAHC
Fig. 5.12 Osteocyte lacunae shown at high magnification in a dry ground
section of lamellar bone. The territories of three osteocytes are shown.
Their branching dendrites contact those of neighbouring cells via the
canaliculi seen here within the bone matrix. Several other osteocyte
lacunae are present, out of the focal plane in this section, and tangential
Fig. 5.11 Bone cells actively remodelling alveolar bone to accommodate
to the osteon axis.
a developing tooth. Large multicellular osteoclasts (white arrow) are
actively resorbing bone on one surface, while a layer of osteoblasts (black
arrow) is depositing osteoid on another. Osteoblasts that have become
trapped in the matrix to form osteocytes are shown in the centre (white
arrowhead). (Image courtesy of Prof. Tim Arnett, University College
London.)
binds the growth factor TGFβ. The bone sialoproteins, osteopontin
and thrombospondin, mediate osteoclast adhesion to bone surfaces by
binding to osteoclast integrins. In addition, osteoblasts secrete latent
proteases and growth factors including BMPs and TGFβ (which is also
secreted by osteoclasts and which may be a coupling factor for stimulat
ing new bone formation at resorption sites).
Although extracellular fluid is generally supersaturated with respect
to the basic calcium phosphates, mineralization does not occur in most
tissues. In bone, osteoblasts secrete osteocalcin (binds calcium at levels
sufficient to concentrate the ion locally) and contain membranebound
vesicles full of alkaline phosphatase (cleaves phosphate ions from Fig. 5.13 Human parietal bone (male neonate) showing primary osteonal
various molecules to elevate concentrations locally) and pyrophos bone (grey) and woven bone (white) containing many connecting
phatase (degrades inhibitory pyrophosphate in the extracellular fluid). osteocyte lacunae (black). Internal resorption of the bone has produced
The vesicles bud off from the osteoblast surface into newly formed large, irregular dark spaces (trabecularization).
osteoid, where they initiate hydroxyapatite crystal formation. Some


alkaline phosphatase reaches the blood circulation, where it can be
detected in conditions of rapid bone formation or turnover. Osteocytes in woven bone are larger and more irregular in shape (Fig.
Osteoblasts also play a key role in the hormonal regulation of bone 5.13). Numerous fine branching processes containing bundles of
resorption. They express receptors for parathyroid hormone (PTH), microfilaments and some smooth endoplasmic reticulum emerge from
1,25dihydroxy vitamin D (calcitriol) and other promoters of bone each cell body. At their distal tips, these processes form gap junctions
3
resorption. When activated, osteoblasts promote osteoclast differentia with the processes of adjacent cells (osteocytes, osteoblasts and bone
tion via PTHactivated expression of cell surface RANKL, which binds lining cells) so that they are in electrical and metabolic continuity.
to RANK on immature osteoclasts, establishes cell–cell contact and Extracellular fluid fills the small, variable spaces between osteocyte
triggers contactdependent osteoclast differentiation. In the presence of cell bodies and their rigid lacunae, which may be lined by a variable
PTH, osteoblasts also downregulate secretion of osteoprotegerin, a (0.2–2 µm) layer of unmineralized organic matrix. The same fluid fills
soluble decoy ligand with higher affinity for RANKL. In conditions the narrow channels or canaliculi that surround the long processes of
favouring bone deposition, secreted osteoprotegerin blocks RANKL the osteocytes. Approximately 0.25–0.5 µm wide, the canaliculi provide
binding to RANK, restricting the number of mature osteoclasts. a route for the diffusion of nutrients, gases and waste products between
Bonelining cells are flattened epitheliallike cells that cover the free osteocytes and blood vessels. Canaliculi do not usually extend through
surfaces of adult bone not undergoing active deposition or resorption. and beyond the reversal line surrounding each osteon and so do not
Generally considered to be quiescent osteoblasts or osteoprogenitor communicate with neighbouring systems.
cells, they line the periosteal surface and the vascular canals within In wellvascularized bone, osteocytes are longlived cells that actively


osteons, and form the outer boundary of the marrow tissue on the maintain the bone matrix. The average lifespan of an osteocyte varies
endosteal surface of marrow cavities. with the metabolic activity of the bone and the likelihood that it will
be remodelled, but is measured in years. Old osteocytes may retract
Osteocytes their processes from the canaliculi; when they die, their lacunae
and canaliculi may become plugged with cell debris and minerals,
which hinders diffusion through the bone. Dead osteocytes occur com
Osteocytes are the major cell type of mature bone and are distributed
monly in interstitial bone (between osteons) and in central regions of
throughout its matrix, interconnected by numerous dendritic processes
trabecular bone that escape surface remodelling. They are particularly
to form a complex cellular network (Fig. 5.12). They are derived from
noticeable by the second and third decades. Bones that experience little
osteoblasts that have become enclosed within their rigid matrix (see
turnover, e.g. the auditory ossicles, are most likely to contain aged
Fig. 5.11) and so have lost the ability to divide or to secrete new matrix.
osteocytes and have low osteocyte viability. Osteocyte death leads to
(The rigidity of mineralized bone matrix prevents interstitial growth, so
matrix resorption by osteoclast activity. Osteocytes themselves are often
that new bone must always be deposited on preexisting surfaces.)
mineralized.
Osteocytes retain contact with each other and with cells at the surfaces
of bone (osteoblasts and bonelining cells) throughout their lifespan.
Osteoclasts
Mature, relatively inactive osteocytes have an ellipsoid cell body with
their longest axis (approximately 25 µm) parallel to the surrounding
lamellae. The rather narrow rim of cytoplasm is faintly basophilic, Osteoclasts are large (diameters of 40 µm or more) polymorphic cells
contains relatively few organelles and surrounds an oval nucleus. containing up to 20 oval, closely packed nuclei (see Fig. 5.11). They lie


FunCTionAl AnATomy oF THE musCuloskElETAl sysTEm
88
1
noiTCEs
OO
OO
MM
Fig. 5.14 A scanning electron micrograph of a neonatal rabbit osteoclast
actively resorbing bone in vitro from the surface of sperm whale dentine.
(Courtesy of Professor Alan Boyde, Queen Mary University of London,
London, UK.)
in close contact with the bone surface in resorption bays (Howship’s
lacunae). Their cytoplasm contains numerous mitochondria and vacu
oles, many of which are acid phosphatasepositive lysosomes. Rough
endoplasmic reticulum is relatively sparse but the Golgi complex is Fig. 5.15 An electron micrograph of woven bone from a failed fracture of
human distal tibia. Two osteoblasts (O) lie on the free surface (top). Newly
extensive. The cytoplasm also contains numerous coated transport vesi
synthesized collagenous osteoid matrix (M) is seen in the centre field,
cles and microtubule arrays involved in vesicle transport between the
with a mineralization front (electron-dense area) below (arrows). (Courtesy
Golgi stacks and the cell’s ruffled border (the highly infolded region of
of Dr Bart Wagner, Histopathology Department, Sheffield Teaching
plasma membrane of an active osteoclast at a site of bone resorption).
Hospitals, UK.)
A welldefined zone of actin filaments and associated proteins occurs
beneath the ruffled border around the circumference of a resorption
bay, in a region termed the sealing zone.
Functionally, osteoclasts are responsible for the local removal of required to propagate cracks that are sufficiently extensive to fracture
bone during bone growth and remodelling (Fig. 5.14). They dissolve the bone.
bone minerals by proton release to create an acidic local environment, Each lamella consists of a sheet of mineralized matrix containing
and they remove organic matrix by secreting lysosomal (cathepsin K) collagen fibres of similar orientation locally, running in branching
and nonlysosomal (e.g. collagenase) enzymes. Osteoclasts are stimu bundles 2–3 µm thick and often extending the full width of a lamella.


lated to resorb bone by signals from local cells (including osteoblasts, The orientation of collagen fibres and crystals differs between 0° and
macrophages and lymphocytes) and by bloodborne factors such as 90° in adjacent lamellae, as may be demonstrated by polarized light
PTH and 1,25dihydroxy vitamin D (calcitriol). Calcitonin, produced microscopy (see Fig. 5.18). At the borders of lamellae, packing of col
3
by C cells of the thyroid follicle, reduces osteoclast activity. lagen fibres into bundles is less perfect and intermediate and random
Osteoclasts differentiate from myeloid stem cells via macrophage orientations of collagen predominate.
colonyforming units. Differentiation is primarily regulated by two
cytokines: macrophagecolony stimulating factor, secreted by osteob Cortical bone
lasts, and RANKL, expressed by osteoblasts (see above). The mononu
clear precursors fuse to form terminally differentiated multinuclear The cylindrical structural units that comprise most cortical bone are
osteoclasts (Väänänen and LaitalaLeinonen 2008). Osteoclast differen termed Haversian systems or osteons (Fig. 5.17). Osteons usually lie
tiation inhibitors are potential therapeutic agents for bone loss parallel with each other (Fig. 5.18); in long bones, they lie parallel with
associated disorders, e.g. osteoporosis, rheumatoid arthritis, Paget’s the long axis of the bone. Adjacent osteons may encroach on one
disease, periodontal disease and osteosarcoma. another because they are usually formed at different times, during suc
cessive periods of bone remodelling. Irregular gaps between osteons are
Woven and lamellar bone
filled with interstitial lamellae (see Fig. 5.17A), which are the fragmen
tary remains of older osteons and circumferential lamellae. Osteons
The mechanical properties of bone depend not only on matrix compo may be spiral or they may branch, and some end blindly. They are
sition, as described above, but also on the manner in which the matrix round or ellipsoidal in crosssection. The main direction of collagen


constituents are organized. Woven bone and lamellar bone represent fibres within osteons varies: in the shaft of long bones, fibres are more
two quite distinct types of organization. longitudinal at sites that are subjected mainly to tension, and more
In woven (or bundle) bone, the collagen fibres and bone crystals are oblique at sites subjected mostly to compression. Peripheral lamellae
irregularly arranged. The diameters of the fibres vary, so that fine and of osteons contain more transverse fibres.
coarse fibres intermingle, producing the appearance of the warp and It has been estimated that there are 21 million osteons in a typical
weft of a woven fabric. Woven bone is typical of young fetal bones, but adult skeleton. Their diameter varies from 100 to 400 µm, and they
is also seen in adults during excessively rapid bone remodelling and usually contain 5–20 lamellae. Each osteon is permeated by the canal
during fracture repair (Fig. 5.15). It is formed by highly active osteo iculi of its resident osteocytes, which form pathways for the diffusion
blasts during development, and is stimulated in the adult by fracture, of metabolites between osteocytes and blood vessels. The maximum
growth factors or prostaglandin E. diameter of an osteon ensures that no osteocyte is more than 200 µm
2
Lamellar bone, which makes up almost all of an adult skeleton, is from a blood vessel, a distance that may be a limiting factor in their
more organized and is produced more slowly. The precise arrangement survival.
of lamellae (bone layers) varies from site to site. In trabeculae and the The central Haversian canals of osteons vary in size, with a mean
outer (periosteal) and inner (endosteal) surfaces of cortical bone, a few diameter of 50 µm; those near the marrow cavity are somewhat larger.
lamellae form continuous circumferential layers that are more or less Each canal contains one or two capillaries lined by fenestrated endothe
parallel to the bony surfaces. However, in more central regions of corti lium and surrounded by a basal lamina, which also encloses typical
cal bone, the lamellae are arranged in concentric cylinders around pericytes. They usually contain a few unmyelinated and occasional


neurovascular channels called Haversian canals (Fig. 5.16). This inter myelinated axons. The bony surfaces of osteonic canals are perforated
connecting, threedimensional, laminated construction increases the by the openings of osteocyte canaliculi and are lined by collagen fibres.
toughness of lamellar bone because the interfaces between lamellae are Haversian canals communicate with each other and directly or indi
effective in stopping the growth of cracks; more energy is therefore rectly with the marrow cavity via vascular (nutrient) channels called


Bone
89
5
RETPAHC
Outer circumferential
lamellae
Osteon
Interstitial lamellae
Inner circumferential
lamellae
Haversian canal
Periosteum
Osteocyte lacuna
Canaliculi
Volkmann’s canal
Medullary trabecular bone
Osteon
Fig. 5.16 The main features of the microstructure of mature lamellar bone. Areas of compact and trabecular (cancellous) bone are included. Note the
general construction of the osteons; distribution of the osteocyte lacunae; Haversian canals and their contents; resorption spaces; and different views of
the structural basis of bone lamellation.
Volkmann’s canals, which run obliquely or at right angles to the long bone tissue. It is absent from articular surfaces, and from the points of
axes of the osteons (see Fig. 5.18). The majority of these channels insertion of tendons and ligaments (entheses) (see Fig. 5.51). The peri
appear to branch and anastomose, but some join large vascular connec osteum is highly active during fetal development, when it generates
tions with vessels in the periosteum and the medullary cavity. osteoblasts for the appositional growth of bone. These cells form a layer,
Osteons are distinguished from their neighbours by a cement line 2–3 cells deep, between the fibrous periosteum and new woven bone
that contains little or no collagen, and is strongly basophilic because it matrix. Osteoprogenitor cells within the mature periosteum are indis
has a high content of glycoproteins and proteoglycans. Cement lines tinguishable morphologically from fibroblasts. Periosteum is important
are also known as reversal lines because they mark the limit of bone in the repair of fractures; where it is absent (e.g. within the joint capsule
erosion prior to the formation of a new osteon. Canaliculi occasionally of the femoral neck) fractures are slow to heal.
pass through cement lines, and so provide a route for exchange be Quiescent osteoblasts and osteoprogenitor cells act as the principal


tween interstitial bone lamellae and vascular channels within osteons. reservoir of new boneforming cells for remodelling or repair on the
Basophilic resting lines can occur in the absence of erosion; they indi endosteal surfaces of resting adult bone. Bone endosteum is likely to
cate where bony growth has been interrupted and then resumed. be important in calcium homeostasis because it provides a total surface
area of approximately 7.5 m2. It is formed by flattened osteoblast pre
Trabecular bone cursor cells and reticular (type III collagen) fibres, and lines all the
internal cavities of bone, including the Haversian canals. It overlies the
endosteal circumferential lamellae and encloses the medullary cavity.
The organization of trabecular bone (also known as cancellous or
spongy bone) is basically lamellar, as shown most clearly under polar
ized light (Fig. 5.19). Trabeculae take the form of branching bars and
curved plates of varying width, length and thickness (50−400 µm) (see NEUROVASCULAR SUPPLY OF BONE
Fig. 5.9). They are covered in endosteal tissue because they are adjacent
to marrow cavities. Thick trabeculae and regions close to compact bone Vascular supply
may contain small osteons, but blood vessels do not otherwise lie
within trabeculae; osteocytes therefore rely on canalicular diffusion The osseous circulation supplies bone tissue, marrow, perichondrium,
from adjacent medullary vessels. In young bone, calcified cartilage may epiphysial cartilages in young bones, and, in part, articular cartilages.
occur in the cores of trabeculae, but this is generally replaced by bone The vascular supply of a long bone depends on several points of inflow
during subsequent remodelling. that feed complex and regionally variable sinusoidal networks within
the bone. The sinusoids drain to venous channels that leave through all
Periosteum, endosteum and bone marrow
surfaces that are not covered by articular cartilage. The flow of blood
through cortical bone in the shafts of long bones is mainly centrifugal
The outer surface of bone is covered by a condensed collagenous layer, (Fig. 5.20).


the periosteum. The inner surface is lined by a thinner, more cellular One or two main diaphysial nutrient arteries enter the shaft ob
endosteum. Osteoprogenitor cells, osteoblasts, osteoclasts and other liquely through nutrient foramina, which lead into nutrient canals.
cells important in the turnover and homeostasis of bone tissue lie in Their sites of entry and angulation are almost constant and characteristi
these layers. cally directed away from the dominant growing epiphysis. Nutrient
The periosteum is tethered to underlying bone by thick collagen arteries do not branch in their canals but divide into ascending and
fibres (Sharpey’s fibres), which penetrate deep into the outer cortical descending branches in the medullary cavity; these approach the


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A
A
B
B
Fig. 5.17 A, Osteons in a dry ground transverse section of bone.
Fig. 5.19 Trabecular bone in a bone marrow sample taken from the
Concentric lamellae surround the central Haversian canal of each
human posterior iliac crest. A, Irregular trabeculae of bone, surrounded by
complete osteon; they contain the dark lacunae of osteocytes and the
bone marrow haemopoietic and adipose tissue (haematoxylin and eosin
canaliculi, which are occupied in life by their dendrites. These canaliculi
stain). B, The same field viewed under polarized light, demonstrating
interconnect with canaliculi of osteocytes in adjacent lamellae. Incomplete
lamellar, non-osteonic bone with lamellae orientated in different directions
(interstitial) lamellae (e.g. centre field) are the remnants of osteons
in different regions. Osteocytes are just visible, embedded in the solid
remodelled by osteoclast erosion. B, A high-power view of osteocytes
matrix. (Courtesy of Mr Peter Helliwell and the late Dr Joseph Mathew,
within lamellae; a Haversian canal is seen on the right. (B, Photograph by
Department of Histopathology, Royal Cornwall Hospitals Trust, UK.)
Sarah-Jane Smith.)
Within bone, the arteries are unusual in consisting of endothelium with
only a thin layer of supportive connective tissue. The epiphysial and
metaphysial arterial supply is richer than the diaphysial supply.
H
Medullary arteries in the shaft give off centripetal branches, which
feed a hexagonal mesh of medullary sinusoids that drain into a wide,
V thinwalled central venous sinus. They also possess cortical branches,
which pass through endosteal canals to feed fenestrated capillaries in
H Haversian systems. The central sinus drains into veins that retrace the
paths of nutrient arteries, sometimes piercing the shaft elsewhere as
independent emissary veins. Cortical capillaries follow the pattern of
Haversian canals, and are mainly longitudinal with oblique connec
V


tions via Volkmann’s canals (see Fig. 5.18). At bone surfaces, cortical
capillaries make capillary and venous connections with periosteal plex
V
uses (see Fig. 5.20) formed by arteries from neighbouring muscles that
contribute vascular arcades with longitudinal links to the fibrous peri
osteum. A capillary network permeates the deeper, osteogenic perios
H
teum from this external plexus. At muscular attachments, periosteal and
Fig. 5.18 Osteons in a dry ground longitudinal section of bone. The muscular plexuses are confluent and the cortical capillaries then drain
central Haversian canals (H; tubular structures, mainly dark) show into interfascicular venules.
transverse nutrient canals (Volkmann’s canals, V), which form bridges In addition to the centrifugal supply of cortical bone, there is an
between adjacent osteons and their blood vessels. appreciable centripetal arterial flow to outer cortical zones from perios
teal vessels. The large nutrient arteries of epiphyses form many intraos
epiphyses, dividing repeatedly into smaller helical branches close to the seous anastomoses, their branches passing towards the articular surfaces
endosteal surface. The endosteal vessels are vulnerable during surgical within the trabecular spaces of the bone. Near the articular cartilages,
operations, such as intramedullary nailing, which involve passing metal these form serial anastomotic arcades (e.g. there are three or four in the
implants into the medullary canal. Near the epiphyses, diaphysial femoral head), which give off endarterial loops. The latter often pierce
vessels are joined by terminal branches of numerous metaphysial and the thin hypochondral compact bone to enter, and sometimes traverse,
epiphysial arteries (see Fig. 5.20). The former are direct branches of the calcified zone of articular cartilage, before returning to the epiphy
neighbouring systemic vessels; the latter come from periarticular vas sial venous sinusoids.
cular arcades formed on nonarticular bone surfaces. Numerous vascu In immature long bones, the supply is similar but the epiphysis is


lar foramina penetrate bones near their ends, often at fairly specific a discrete vascular zone. Epiphysial and metaphysial arteries enter
sites; some are occupied by arteries but most contain thinwalled veins. on both sides of the growth cartilage and rarely, if ever, anastomose.


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Endosteal
vessels
Epiphysis
Metaphysis
Diaphysis
Periosteal vessels
Tendon
Muscular vessels
Fig. 5.20 The main features of the blood supply of a long bone. Note the contrasting supplies of the diaphysis, metaphysis and epiphysis, and their
connections with periosteal, endosteal, muscular and peri-articular vessels. The expansion shows part of the diaphysis in more detail. The marrow cavity
contains a large central venous sinus, a dense network of medullary sinusoids, and longitudinal medullary arteries and their circumferential rami.
Longitudinally oblique transcortical capillaries emerge through minute ‘cornet-shaped’ foramina to become confluent with the periosteal capillaries and
venules. The obliquity of the cortical capillaries is emphasized for clarity. Not to scale.
Growth cartilages are probably supplied from both sources, and from unmyelinated axons accompany nutrient vessels into bone and marrow,
an anastomotic collar in the adjoining periosteum. Occasionally, carti and lie in the perivascular spaces of Haversian canals. Osteoblasts
lage canals are incorporated into a growth plate. Metaphysial bone is possess receptors for several neuropeptides found in these nerves,
nourished by terminal branches of metaphysial arteries and by primary including neuropeptide Y, calcitonin generelated peptide, vasoactive
nutrient arteries of the shaft, which form terminal blindended sprouts intestinal peptide and substance P, indicating that bone has a complex
or sinusoidal loops in the zone of advancing ossification. Young peri autonomic and sensory innervation.
osteum is more vascular; its vessels communicate more freely with those
of the shaft than their adult counterparts and give off more metaphysial
branches. DEVELOPMENT AND GROWTH OF BONE
Large, irregular bones such as the scapula and innominate not only
receive a periosteal supply but are also often supplied by large nutrient Some of the bones in the skull are laid down within a fibrocellular
arteries that penetrate directly into their cancellous bone, the two mesenchymal membrane, by a process known as intramembranous


systems anastomosing freely. Short bones receive numerous fine vessels ossification. Most bones are formed by a process of endochondral ossi
that supply their compact and cancellous bone and medullary cavities fication, in which preformed cartilage templates (models) define their
from the periosteum. Arteries enter vertebrae close to the base of their initial shapes and positions, and the cartilage is replaced by bone in an
transverse processes (see Fig. 43.20). Each vertebral medullary cavity ordered sequence.
drains to two large basivertebral veins, which converge to a foramen
on the posterior surface of the vertebral body (see Fig. 43.21). Flatter Intramembranous ossification
cranial bones are supplied by numerous periosteal or mucoperiosteal
vessels. Large, thinwalled veins run tortuously in cancellous bone.
Intramembranous ossification is the direct formation of bone (mem
Lymphatic vessels accompany periosteal plexuses but have not been
brane bone) within highly vascular sheets or ‘membranes’ of condensed
convincingly demonstrated in bone.
primitive mesenchyme. At centres of ossification, mesenchymal stem
cells differentiate into osteoprogenitor cells, which proliferate around
Innervation
the branches of a capillary network, forming incomplete layers of
osteoblasts in contact with the primitive bone matrix. The cells are
Nerves are most numerous in the articular extremities of long bones, polarized, and secrete osteoid only from the surface that faces away
vertebrae and larger flat bones, and in periosteum. Fine myelinated and from the blood vessels. The earliest crystals appear in association with


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Fig. 5.21 A, A section of a human fetal hand
showing cartilaginous models of the carpal bones
and the primary ossification centres, which display
varying stages of maturity, in the metacarpals and
phalanges. Note that none of the carpal elements
shows any evidence of ossification. B, A higher-
power view of an early primary ossification centre.
The cartilage cells in the shaft have hypertrophied
and this region is surrounded by a delicate tube or
collar of subperiosteal bone (red). (Photograph by
Kevin Fitzpatrick on behalf of GKT School of
Medicine, London.)
A B
extracellular matrix vesicles produced by the osteoblasts. Crystal forma
tion subsequently extends into collagen fibrils in the surrounding G
matrix, producing an early labyrinth of woven bone, the primary spon
giosa. As layers of calcifying matrix are added to the early trabeculae,
osteoblasts become enclosed within primitive lacunae. These new
H
osteocytes retain intercellular contact by means of their fine cytoplasmic
processes (dendrites) and, as these elongate, matrix condenses around
them to form canaliculi.
As matrix secretion and calcification proceed, trabeculae thicken and
vascular spaces become narrower. Where bone remains trabecular, the O
process slows and the spaces between trabeculae become occupied by
haemopoietic tissue. Where compact bone is forming, trabeculae con
tinue to thicken and vascular spaces continue to narrow. Meanwhile,
the collagen fibres of the matrix, secreted on the walls of the narrowing
spaces between trabeculae, become organized as parallel, longitudinal
or spiral bundles, and the cells they enclose occupy concentric sequen R
tial rows. These irregular, interconnected masses of compact bone each
have a central canal and are called primary osteons (primary Haversian
systems). They are later eroded, together with the intervening woven
bone, and replaced by generations of mature (secondary) osteons.
Fig. 5.22 The sequence of cellular events in endochondral ossification.


While these changes are occurring, mesenchyme condenses on the This low-magnification micrograph shows the primary ossification centre
outer surface to form a fibrovascular periosteum. Bone is laid down in a human fetal bone. See Figure 5.24 for further details. Abbreviations;
increasingly by new osteoblasts, which differentiate from osteoprogeni G, growth zone; H, hypertrophic zone; O, ossification zone; R, remodelling
tor cells in the deeper layers of the periosteum. Modelling of the zone.
growing bone is achieved by varying rates of resorption and deposition
at different sites.
ing from chondrocytes in the proliferation zone are most evident in the
Endochondral ossification
intercolumnar regions, where they appear to initiate crystal formation.
At the same time, cells in the deep layer of perichondrium around the
The hyaline cartilage model that forms during embryogenesis is a mini centre of the cartilage model differentiate into osteoblasts and form a
ature template of the bone that will subsequently develop. It becomes peripheral layer of bone. Initially, this periosteal collar, formed by
surrounded by a condensed, vascular mesenchyme or perichondrium, intramembranous ossification within the perichondrium, is a thin
which resembles the mesenchymal ‘membrane’ in which intramembra walled tube that encloses and supports the central shaft (see Figs 5.21–
nous ossification occurs. Its deeper layers contain osteoprogenitor cells. 5.22). As it increases in diameter, it also extends towards both ends of
The first appearance of a centre of primary ossification (Fig. 5.21) the shaft.
occurs when chondroblasts deep in the centre of the primitive shaft The periosteal collar, which overlies the calcified cartilaginous walls
enlarge greatly, and their cytoplasm becomes vacuolated and accumu of degenerate chondrocyte lacunae, is invaded from the deep layers of
lates glycogen. The intervening matrix is compressed into thin, often the periosteum (formerly perichondrium) by osteogenic buds. These
perforated, septa. The cells degenerate and may die, leaving enlarged are blindended capillary sprouts that are accompanied by osteopro


and sometimes confluent lacunae (primary areolae) whose thin walls genitor cells and osteoclasts. The latter excavate newly formed bone to
become calcified during the final stages (Fig. 5.22). Type X collagen is reach adjacent calcified cartilage, where they continue to erode the walls
produced in the hypertrophic zone of cartilage. Matrix vesicles originat of primary chondrocyte lacunae (Figs 5.23–5.24). This process leads to


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Fig. 5.24 Endochondral ossification in human fetal bone. Spicules of
Fig. 5.23 An Alcian-blue periodic acid–Schiff (PAS)-stained section of
cartilaginous remnants (pale blue) serve as surfaces for the deposition of
human fetal femur showing the hypertrophy and palisading of cartilage
osteoid (dark blue), shown in the upper half of the field. Mineralized,
cells as the ossifying (mineralizing) front of an early primary centre of
woven bone is stained red. Three large multinucleate osteoclasts (arrows)
ossification is approached (below). Lacunae are enlarged, and matrix
are seen centre right, further eroding cartilage and remodelling the
partitions are reduced in width and exhibit increased staining density
developing bone. Blood sinusoids and haemopoietic tissue (below) fill the
following cartilage calcification. (Courtesy of Mr Peter Helliwell and the
spaces between areas of ossification. Heidenhain’s azan trichrome
late Dr Joseph Mathew, Department of Histopathology, Royal Cornwall
preparation.
Hospitals Trust, UK.)
A CartilageBHypertrophy C Calcification of D Invasion of E Primary bone laid down F Continued growth of cartilage of G Cessation of cartilage growth and complete
template of central cells matrix in primary primary centre on calcified cartilage epiphysial plate and epiphysis; ossification of epiphysial plate (fusion of the
ossification centre by vascular remnants; secondary centre proliferation of red bone marrow epiphysis). Replacement of red bone marrow with
and formation of osteogenic buds of ossification appears yellow, adipose marrow in most adult long bones
periosteal collar of and becomes vascularized
bone
Growth
Transformation
Ossification
Remodelling
Growth: Cell division
Interstitial and appositional growth
Cell columns (palisades)
Transformation: Cell hypertrophy
Calcification of matrix
Ossification: Chondrolysis
Vascularization
Osteogenesis
Remodelling: Erosion and deposition
Fig. 5.25 The stages of endochondral ossification in a long bone.
their fusion into larger, irregular communicating spaces, secondary of dynamic change from cartilage to bone persists until longitudinal


areolae, which fill with embryonic medullary tissue (vascular mesen growth of the bone ceases.
chyme, osteoblasts and osteoclasts, haemopoietic and marrow stromal Expansion of the cartilaginous extremity (usually an epiphysis; see
cells, etc.). Osteoblasts attach themselves to the delicate residual walls Fig 5.20) keeps pace with the growth of the rest of the bone by both
of calcified cartilage and lay down osteoid, which rapidly becomes appositional and interstitial growth. The growth zone expands in all
confluent, forming a continuous lining of bone. Further layers of bone dimensions. Lateral growth of a developing long bone is caused by
are added, enclosing young osteocytes in lacunae and narrowing the occasional transverse mitosis in its chondrocytes, and by appositional
perivascular spaces. Bone deposition on the more central calcified car growth as a result of matrix deposition by cells from the perichondrial
tilage ceases as the formation of subperiosteal bone continues. collar or ring at this level. The future growth plate therefore expands in
Osteoclastic erosion of the early bone spicules then creates a primi concert with the shaft and adjacent future epiphysis. A zone of relatively
tive medullary cavity in which only a few trabeculae, composed of bone quiescent chondrocytes (the resting zone) lies on the side of the plate
with central cores of calcified cartilage (see Fig. 5.23), remain to support closest to the epiphysis. An actively mitotic zone of cells faces towards
the developing marrow tissues. These trabeculae soon become remod the shaft of the bone; the more frequent divisions in the long axis of
elled and replaced by more mature bone or by marrow. Meanwhile, the bone soon create numerous longitudinal columns (palisades) of
new, adjacent, cartilaginous regions undergo similar changes. Since discshaped chondrocytes, each in a flattened lacuna (see Fig. 5.25).
these are most advanced centrally, and the epiphyses remain cartilagi Proliferation and column formation occur in this zone of cartilage
nous, the intermediate zones exhibit a temporospatial sequence of growth (the proliferative zone), and its continued longitudinal intersti


changes when viewed in longitudinal section (Fig. 5.25). This region tial expansion provides the basic mode of elongation of a bone.


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The columns of cells show increasing maturity towards the centre of tion of osteoprogenitor cells at sutures; periosteal bone is mainly added
the shaft, as their chondrocytes increase in size and accumulate glyco externally and eroded internally, but not at uniform rates or at all times.
gen. In the hypertrophic zone, energy metabolism is depressed at the The rate of formation increases with radial distance from the centre of
level of the mineralizing front (see Fig. 5.23). The lacunae are now ossification (in this case, the future parietal eminence). Bone formation
separated by transverse and longitudinal walls, and the latter are may also occur endocranially as well as ectocranially, so changing the
impregnated with apatite crystals in what has become the zone of calci curvature of the bone. The relative positions of the original centres of
fied cartilage (or ossification zone; see Fig. 5.22). The calcified partitions ossification change in three dimensions as the skull bones thicken and
enter the zone of bone formation and are invaded by vascular mesen grow at the sutures and as the vault of the skull expands to accommo
chyme containing osteoblasts, osteoclasts, etc. The partitions, especially date the growth of the brain. Development of the outer and inner corti
the transverse ones, are then partly eroded while osteoid deposition, cal plates is accompanied by internal development of trabeculae and
bone formation and osteocyte enclosure occur on the surfaces of the marrow spaces.
longitudinal walls. Lysis of calcified partitions is mediated by osteoclast Long bones increase in length mainly by endochondral ossification
action, aided by cells associated with the terminal buds of vascular at the epiphysial growth plates. Simultaneous increase in width occurs
sinusoids that occupy, and come into close contact with, each incom by subperiosteal deposition and endosteal erosion. Growth at different
plete columnar trabecular framework. locations can occur at different rates, or even be replaced by resorption,
Continuing cell division in the growth zone adds to the epiphysial resulting in a change in the shape of a bone. This explains how, for


ends of cell columns, and the bone grows in length as this sequence of example, the tibia changes its crosssectional shape from tubular to
changes proceeds away from the diaphysial centre. The bone also grows triangular. Similarly, the waisted contours of metaphyses are preserved
in diameter as further subperiosteal bone deposition occurs near the by differential rates of periosteal erosion and endosteal deposition, as
epiphyses, and its medullary cavity enlarges transversely and longitudi metaphysial bone becomes diaphysial in position. The junction between
nally. Internal erosion and remodelling of the newly formed bone tissue a field of resorption and one of deposition on the surface of a growing
continues. bone is called a surface reversal line. The relative position of such a line
Growth continues in this way for many months or years in different may remain stable over long periods of growth and shape change.
bones, but eventually one or more secondary centres of ossification Lamellar bone forms and is remodelled at variable rates throughout
usually appear in the cartilaginous extremities. Initially, these epiphysial adult life (see below).
centres (or the ends of bones that lack epiphyses) do not display cell Normal development and maintenance of bone requires adequate
columns. Instead, isogenous cell groups hypertrophy, with matrix cal intake and absorption of calcium, phosphorus and vitamins A, C and
cification, and are then invaded by osteogenic vascular mesenchyme, D, and a balance between growth hormone (GH, somatotropin),
sometimes from cartilage canals. Bone is formed on calcified cartilage, thyroid hormones, oestrogens and androgens. Other biological influ
as described above. As an epiphysis enlarges, its cartilaginous periphery ences include prostaglandins and glucocorticoids. Vigorous mechanical
(perichondrium) also forms a zone of proliferation in which cell loading is important for the maintenance of adequate bone mass. Pro
columns are organized radially; hypertrophy, calcification, erosion and longed deficiency in any of these factors can lead to loss of bone tissue
ossification occur at increasing depths from the surface. The early (osteopaenia); if bone loss is severe (osteoporosis), it can lead to frac
osseous epiphysis is thus surrounded by a superficial growth cartilage, ture and deformity.


and the growth plate adjacent to the metaphysis soon becomes the most Vitamin D influences intestinal transport of calcium and phosphate,
active region. and therefore affects circulatory calcium levels. In adults, prolonged
As a bone reaches maturity, epiphysial and metaphysial ossification deficiency (with or without low intake) produces bones that contain
processes gradually encroach upon the growth plate from either side; regions of deformable, uncalcified osteoid (osteomalacia). During
when they meet, bony fusion of the epiphysis occurs and longitudinal growth, vitamin D deficiency can lead to severe disturbance of growth
growth of the bone ceases. The events that take place during fusion are cartilages and ossification, such as reductions of regular columnar
broadly as follows. As growth ceases, the cartilaginous plate becomes organization in growth plates, and failure of cartilage calcification even
quiescent and gradually thins; proliferation, palisading and hypertro though chondrocytes proliferate. Growth plates also become thicker
phy of chondrocytes stop, and the cells form short, irregular, conical and irregular, as exemplified in classic rickets or juvenile osteomalacia.
masses. Patchy calcification is accompanied by resorption of calcified In rickets, the uncalcified or poorly calcified cartilaginous trabeculae are
cartilage and some of the adjacent metaphysial bone, forming resorp only partially eroded; osteoblasts secrete layers of osteoid but these fail
tion channels that are invaded by vascular mesenchyme. to ossify in the metaphysial region, and ultimately gravity deforms these
Some endothelial sprouts pierce the thin plate of cartilage, and the softened bones.
metaphysial and epiphysial vessels unite. Ossification around these Vitamin C is essential for the adequate synthesis of collagen and
vessels spreads into the intervening zones and results in fusion of epi matrix proteoglycans in connective tissues. When vitamin C is deficient,
physis and metaphysis. This bone is visible in radiographs as a radio growth plates become thin, ossification almost stops, and metaphysial
dense epiphysial line (a term that is also used to describe the level of trabeculae and cortical bone are reduced in thickness, causing fragility


the perichondrial collar or ring around the growth cartilage of imma and delayed healing of fractures.
ture bones, or the surface junction between epiphysis and metaphysis Vitamin A is necessary for normal growth and for a correct balance
in a mature bone). In smaller epiphyses, which unite earlier, there is between deposition and removal of bone. Deficiency retards growth as
usually one initial eccentric area of fusion, and thinning of the residual a result of the failure of internal erosion and remodelling, particularly
cartilaginous plate. The original sites of fusion are subsequently resorbed in the cranial base. Foramina are narrowed, sometimes causing pressure
and replaced by new bone. Medullary tissue extends into the whole atrophy of the nerves that pass through them. The cranial cavity and
cartilaginous plate until union is complete and no epiphysial ‘scar’ spinal canal may fail to expand at the same rate as the developing
persists. In larger epiphyses, which unite later, similar processes also central nervous system, impairing nervous function. Conversely, excess
involve multiple perforations in growth plates, and islands of epiphysial vitamin A stimulates vascular erosion of growth cartilages, which
bone often persist as epiphysial scars. Calcified cartilage coated by bone become thin or totally lost, and longitudinal growth ceases. Retinoic
forms the epiphysial scar, and is also found below articular cartilage. It acid, a vitamin A derivative, is involved in pattern formation in limb
has been called metaplastic bone, a term also applied to sites of attach buds and in the differentiation of osteoblasts.
ments of tendons, ligaments and other dense connective tissues to Balanced endocrine functions are also essential to normal bone
bone. maturation, and disturbances in this balance may have profound
The cartilaginous surfaces of epiphyses that form synovial joints effects. In addition to its role in calcium metabolism, excess parathyroid
remain unossified, but the typical sequence of cartilaginous zones per hormone (primary hyperparathyroidism) stimulates unchecked osteo
sists in them throughout life. A similar developmental sequence occurs clastic erosion of bone, particularly subperiosteally and later endo
at synchondroses, except that the proliferative rates of chondrocytes and steally (osteitis fibrosa cystica). Growth hormone is required for normal


the replacement of cartilage by bone are similar, although not identical, interstitial proliferation in growth cartilages, ensuring normal increase
on either side of the synchondrosis. in stature. Termination of normal growth is imperfectly understood, but
may involve a fall in hormone production or in the sensitivity of chon
Postnatal growth and maintenance of bone
droblasts to insulinlike growth factors regulated by GH. Reduction of
GH production in the young leads to quiescence and thinning of
Modelling, by which is meant changes in general shape, occurs in all growth plates and hence pituitary dwarfism. Conversely, continued
growing bones. The process has been studied mainly in cranial and long hypersecretion in the immature leads to gigantism, and in the adult
bones with expanded extremities. results in thickening of bones by subperiosteal deposition; the mandi
A bone such as the parietal thickens and expands, but decreases in ble, hands and feet are the most affected, a condition known as
curvature, during growth. Accretion continues at its edges by prolifera acromegaly.