chronic nonbacterial osteomyelitis ( cno ) ( omim number 259680 ) is an autoinflammatory , noninfectious disorder that affects the skeletal system and has first been described in 1972 .
an association with further autoimmune and autoinflammatory disorders such as pustolusis palmoplantaris , chronic inflammatory bowel disease ( ibd ) , psoriasis , c - anca positive vasculitis , takayasu 's arteriitis , and deficiency of il-1 receptor antagonist ( dira ) has been discussed [ 35 ] .
cno covers a wide clinical spectrum from non- or oligo - symptomatic monofocal bony lesions to its most severe form chronic recurring multifocal osteomyelitis ( crmo ) .
however , metaphyses of long bones are predominantly involved   with a predilection for the lower extremities ( distal femur , proximal tibia , distal tibia , and distal fibula ) , followed by the clavicle and spine .
systemic symptoms occur in a subset of patients and include low - grade fevers and malaise . even though scully et
2008 )   reported a predominance in females ( up to 85% ) , larger studies did not confirm this .
most research articles focus on clinical aspects of cno , and only few reports discuss putative pathomechanisms underlying this autoinflammatory disorder .
autoinflammatory diseases are rare disorders , characterized by recurrent episodes of fever and inflammation , and mostly affect joints , serosal surfaces , eyes and skin in the absence of high - titer autoantibodies , autoreactive t lymphocytes , and underlying infection . in 2006 ,
mcgonagle and mcdermott   suggested a clinical continuum with autoimmune disorders on the one , and autoinflammatory diseases on the other end of the spectrum .
disorders located towards the middle of the continuum exhibit features of both autoinflammatory as well as autoimmune diseases . according to this definition , cno has been classified as an autoinflammatory disorder . in cno
the diagnosis relies on clinical symptoms , systemic inflammation , and elevated acute phase proteins during attacks . in very few cases ,
underlying mutations in the relevant genes can be detected ( majeed syndrome , see below ) .
cno needs to be differentiated from infectious osteomyelitis , including mycobacterial infections , and malignant neoplasms .
laboratory and histopathological findings are nonspecific , with mildly elevated acute phase markers , and plasmacellular , granulocytic , and monocytic infiltrations respectively .
however in a substantial number of patients , systemic inflammatory signs ( such as low - grade fever and malaise and elevated acute phase proteins ) can not be found , even during attacks . in these cases ,
the diagnosis of cno can be made , combining clinical findings ( localized bone pain , swelling , and warmth in the affected areas ) and laboratory tests ( including testing for mycobacteria ) with radiographic techniques .
the presence of osteolytic lesions with surrounding sclerosis in x - ray imaging , supplemented by computerized tomography ( ct ) and/or magnetic resonance imaging ( mri ) , is usually helpful ( figure 1 ) .
silent asymptomatic lesions frequently appear on nuclear scans . even though cno has been treated with azithromycin   in the past , it does generally not respond to antibiotics .
treatment involves anti - inflammatory agents , including nsaids [ 13 , 15 , 16 ] and corticosteroids . in treatment
restistant cases , bisphosphonates   and biologicals , usually infliximab or etanercept ( blocking tumor necrosis factor- )   have been applied successfully , suggesting an involvement of tnf- in the pathophysiology of cno .
most cases are self - limiting and eventually resolve without major sequelae . however , a subset of patients exhibit severe and prolonged disease courses and are at risk of developing bone deformities that can be caused by premature closure of the epiphyses , and kyphoscoliosis as a result of vertebral involvement [ 4 , 6 , 19 ]
. disease onset at a young age and high numbers   of inflammatory bone lesions at disease onset seem to be predictive of poor outcomes [ 4 , 19 ] .
imbalances in cytokine expression can cause a disruption of immune homeostasis , resulting in increased or reduced inflammatory responses that in turn may cause susceptibility to infections or autoimmune disorders .
cytokine dysregulation can be caused on various levels , including ( 1 ) impaired transcription that can be caused by genomic variation and ( 2 ) epigenetic modifications .
genomic variations , including single - nucleotide polymorphisms ( snps ) , can influence gene expression by variable transcription factor binding or variation in genome organization .
epigenetic modifications alter chromatin accessibility for transcription factors and/or rna polymerases [ 21 , 22 ] .
posttranslational histone modifications influence the transcriptional activity of genes and serve as markers of epigenetic changes .
histone hypermethylation as repressing histone modification mediates dense packing of nucleosomes in transcriptionally silent , so - called  heterochromatic  regions .
however , convincing evidence for the involvement of this locus in the pathophysiology of cno is still lacking .
ferguson et al . [ 24 , 25 ] described homozygous mutations in the lpin2 gene , causing a syndromic autosomal recessive form of cno known as majeed syndrome .
the majeed syndrome 's classical triad includes early - onset crmo , congenital dyserythropoietic anemia and a neutrophilic dermatosis .
it is an extremely rare disease and has only been identified in three unrelated arabic families [ 14 , 26 ] .
bone lesions in majeed syndrome occur within the first two years of life , and the course is more aggressive then in cno , with more relapses .
lpin2 was mapped to chromosome 18p and found to be expressed in almost all tissues .
it shares a lipin domain with the human ortholog of murine lpin1 , which plays a role in fat metabolism . because of the dyserythropoesis in majeed syndrome
, it has been proposed that lpin2 could also play a role in mitosis , and that an impaired function may lead to abnormal mitosis in rapidly dividing cells , including the red blood cell lineage in the bone marrow .
it has further been hypothesised that mutations in lpin2 may play an etiologic role in psoriasis , since it localizes to a genomic region identified as a psoriasis susceptibility locus .
mutations in the pstpip2 gene have been described in the murine form of cno . to date , there are two murine cno models , both carrying mutations in the pstpip2 gene : ( 1 ) cmo mice [ 2629 ] and ( 2 ) lupo mice .
cmo ( chronic multifocal osteomyelitis ) mice have been reported to develop a phenotype that is similar to severe cases of human cno with multiple sites of inflammation . however , most cno patients present with less severe mono- or oligo - focal disease which does not completely resemble the disease in cmo mice that develop multifocal ( systemic ) inflammatory symptoms .
the disease is inherited in an autosomal recessive manner , and the cmo locus has been mapped to the murine chromosome 18 . within the refined region was the gene pstpip2 , which shares significant sequence homology to human pstpip1 .
expression patterns of murine pstpip2 , also called mayp ( macrophage actin - associated tyrosine - phosphorylated protein ) , are discussed controversially .
while pstpip2 mrna is ubiquitously expressed , western blot analysis revealed narrow protein expression patterns , with the highest pstpip2 expression in myeloid cells .
pstpip2 plays a role in cytoskeletal reorganization , and localizes to the cytosol as an f - actin associated phosphoprotein that interacts with pest - type protein tyrosine phosphatases ( ptp pest ) [ 31 , 32 ] .
mutations in the pstpip1 gene have been documented to cause the autoinflammatory papa syndrome ( pyogenic arthritis , pyoderma gangrenosum , and acne ) .
demonstrated that the pstpip1 mutations found in the autoinflammatory papa syndrome are in the putative coil - coil domain of pstpip1 , abolishing the capacity of pstpip1 to bind pest family ptps .
this alteration results in enhanced pstpip1 tyrosine phosphorylation and is accompanied by augmented binding of pstpip1 to pyrin via an sh3 domain , resulting in constitutive activation of nlrp3 , production of il-1 , and inflammation   ( figure 2 ) .
some similarities in the phenotypes of cmo mice and ( human ) papa patients may suggest an involvement of the same or similar immunologic pathways .
however , the absence of the sh3 domain in pstpip2 suggests that it does not bind pyrin directly .
classical  cno patients do not develop the characteristic pustulotic or pyogenic dermatitis that is seen in papa patients . even though cmo mice serve as an interesting model for bone inflammation , none of the reported cno patients   carry mutation in the pstpip1 and pstpip2 genes , except for several known polymorphisms .
the recent report of a condition , presenting with neonatal onset sterile multifocal osteomyelitis , periostosis , and pustulosis , that is caused by a deficiency of il-1 receptor antagonist ( dira ) , is of special interest . because of similar clinical , radiological and histological features of cno and dira , both disorders might share common or similar autoinflammatory processes .
however , in a recent study   a heterozygous missense mutation c.281g > t ( p.cys94phe ) could only be found in one patient with cno . in the other patients ,
another hint towards the understanding of genetic contributors to the pathophysiology of cno may be the clinical similarities of cno patients and patients with hypophosphatasia [ 37 , 38 ] .
hypophosphatasia is a rare defect of bone metabolism that is caused by a number of mutations in the gene encoding for the tissue - nonspecific alkaline phosphatase ( tnsalp ) on chromosome 1p36.1 .
the mode of inheritance is mostly autosomal - recessive [ 37 , 39 , 40 ] .
tnsalp mutations result in reduced enzyme activity and elevated concentrations of tnsalp substrates , including inorganic pyrophosphate , pyridoxal-50-phosphate and phosphoethanolamine [ 4143 ] .
it has been documented that pyrophosphate crystals stimulate the nlrp3 inflammasome resulting in interleukin-1 production . an inflammatory process secondary to the metabolic defect in hypophosphatasia involving the nlrp3 inflammasome
associations between cno and crohn 's disease , a multifactorial autoinflammatory disease , have been reported , morbach and colleagues   analyzed cno patients for nod2/card15 mutations .
in addition , susceptibility regions have been identified on chromosome 18 in two other diseases sharing similarities with cno : familial expansile osteolysis and familial paget 's disease of bone [ 26 , 46 , 47 ] .
the phenotypes of both diseases have been linked to mutations in the tnfrsf11a gene at 18q22.1 , which encodes the receptor activator of nuclear factor kappa b ( rank ) [ 46 , 47 ] .
recently , we reported an association of cno with il10 promoter polymorphisms [ 3 , 8 ] .
il-10 is an immune - regulatory cytokine that controls inflammation by limiting inflammatory cytokine expression and antigen presentation .
dysregulation in il-10 expression , sometimes caused by single - nucleotide polymorphisms ( snps ) in the il10 promoter have been associated to autoimmune and infectious diseases , such as sle , asthma , chronic viral diseases , rheumatoid arthritis as well as transplantation complications and cancer [ 4951 ] .
il10 promoter polymorphisms as an example for genomic variation , appear to play an important role in the interindividual variation of il-10 expression [ 8 , 52 ] .
the il10 promoter polymorphisms 1082g > a ( rs1800869 ) , 819c > t ( rs1800871 ) , and 592c > a ( rs1800872 ) are in tight linkage disequilibrium and form three well - defined or 
ata is associated with low , acc with intermediate , and gcc with high levels of il-10 expression [ 48 , 53 , 54 ] .
however , for the interindividual variability of il-10 expression , additional host factors seem to play an important role . as aforementioned ,
an association of il10 promoter polymorphisms with cno has been described , demonstrating an increased frequency of high il-10 expressing 1082g / g alleles , and resulting gcc haplotypes .
interestingly , monocytes from cno patients failed to produce il-10 in response to stimulation with lps .
this could be explained by ( 1 ) il10 promoter polymorphisms as part of larger haplotypes , extending several hundred kilobases over the entire cytokine cluster , develop cumulative effects in a genomic setting .
this hypothesis is supported by a recent study   that failed to find a link between il10 promoter snps and inflammatory bowel disease ( ibd ) , but showed an association between a snp 3 to the il10 gene and ulcerative colitis .
( 2 ) since it is known that il-10 mediates the proliferation of various lymphocytic tissues , including b cells , and enhances antibody production .
lymphocytes , but also plasma cells can be predominantly found in biopsies , taken from cno lesions . having the anti - inflammatory aspects of il-10 expression in mind , an association with gcc haplotypes could partly explain the lymphocyte expansion in affected tissues .
( 3 ) additional , namely , epigenetic mechanisms , could be involved in the dysregulation of cytokine expression in cno ( see below ) .
the expression of pro- and anti - inflammatory cytokines , including il-10 , is considered to be under epigenetic control .
zhang et al .   reported histone - phosphorylation within the il10 proximal promoter to be associated with transcription .
histone phosphorylation is particularly increased in regulatory regions that bind the transcription factor specificity protein 1 ( sp1 ) and 3 ( sp3 ) and mediate transcriptional activation in response to stimulation with lps [ 5861 ] .
since the proximal promoter region of il10 displays multiple gc rich sequences , which bind sp - family transcription factors , the binding of the transcriptional regulatory factor sp1 ( previously reported to play a role in the regulation of il-10 in monocytes and macrophages ) to the il10 promoter has been investigated .
a markedly reduced sp1 recruitment to the il10_636 sp1 element has been detected in monocytes from cno patients in response to lps stimulation .
this was accompanied with reduced histone h3 serine 10 phosphorylation ( h3s10p ) , an activating epigenetic mark .
these findings indicate ( 1 ) reduced sp1 recruitment and ( 2 ) attenuated h3s10 phosphorylation around the il10_636 element within the il10 promoter .
given that ( 1 ) lps stimulation induces map kinase ( mapk ) activation in monocytes and macrophages , including the p38 , the erks 1 and 2 , and the jnk mapk pathway , and ( 2 ) erks 1 and 2 are implicated in h3s10 phosphorylation , these reports could indicate a new pathophysiological mechanism in cno with impaired mapk signaling , resulting in reduced h3s10 phosphorylation , and sp1 recruitment to the il10 promoter and subsequently attenuated gene expression and immune homeostasis .
tnf- and il-1 are implicated in the pathophysiology of various autoimmune and autoinflammatory disorders , including cno , where it has been documented to be increased in inflammatory lesions . furthermore , clinical response to anti - tnf or il-1 receptor antagonist ( il-1ra ) anakinra treatment has been documented in cno ( summarized in ) .
however , it remains unclear whether increased tnf- and il-1 expression is the pathophysiological cause of cno or a downstream event in the disease .
the aforementioned reduced expression of il-10 in monocytes from cno patients may well contribute to a cytokine imbalance towards proinflammatory signals , including tnf-.
, they do not explain the pathophysiology of cno in the vast majority of cases .
mutations in the tnf and il1ra genes in humans and the pstpip2 gene in mice appear to be promising in the search for pathomechanisms in cno .
the most recently described pathophysiological mechanism in cno might involve impaired mapk signaling , reduced h3s10 phosphorylation , and attenuated sp1 recruitment to the il10 promoter that results in an impaired gene expression .
 chronic nonbacterial osteomyelitis ( cno ) with its most severe form chronic recurrent multifocal osteomyelitis ( crmo ) is a non - bacterial osteitis of yet unknown origin . 
 secondary to the absence of both high - titer autoantibodies and autoreactive t lymphocytes , and the association with other autoimmune diseases , it was recently reclassified as an autoinflammatory disorder of the musculoskeletal system . since its etiology is largely unknown , the diagnosis is based on clinical criteria , and treatment is empiric and not always successful . in this paper , we summarize recent advances in the understanding of possible etiopathogenetic mechanisms in cno . 
1. Introduction
2. Classification, Clinical Picture, Diagnosis, and Treatment
3. Putative Pathomechanisms
4. Conclusions