we suggest that bmp-9 has a regenerative role in the human liver . in favor of its establishment in diss s spaces and
supported additionally by presence of bmp-9 s receptors on the surface of human hepatocytes , we have reason to believe that bmp-9 exerts the same effects on hepatocytes themselves . our hypothesis is additionally based on the fact that rhbmp-9 binds to human hepatoma cells and stimulates their dna synthesis .
properties that bmp-9 exerts locally and systemically resemble physiological effects of insulin [ 46 ] , especially in protecting peripheral tissues in states of hyperglycemia such as diabetes .
bone morphogenetic proteins ( bmps ) are members of transforming growth factor beta ( tgf- ) a superfamily of cytokines that regulate cell growth and , differentiation during embryogenesis .
some bmps , such are bmp-2/4,-3 , -5 , -6 and -7 , justify their name as they regulate skeletal tissue formation and repair [ 710 ] .
bmp-2 is supplementally involved in formation of vascular calcifications , while bmp-7 deficiency plays a role in progression of chronic renal failure .
another tgf- superfamily member , growth differentiation factor 15 ( gdf-15 ) , although weak in osteogenic potential , has been implicated in playing an essential role in progression of congestive heart failure .
these facts open a new chapter on bmps and their role in pathogenesis of human non - skeletal diseases .
the mechanism of action of bone morphogenetic protein-7 ( bmp-7 ) is most likely the one understood the best .
accordingly , anti - inflammatory action on intestinal mucosal cells ( most likely suppressing interleukin-6 [ il-6 ] ) is shown .
two types of bmp receptors ( bmpr ) mediate activation of protein kinase and consecutive phosphorylation of amino - acids , phosphatidylinositol as 3-kinase and phospholipase c in insulin . the receptors are commonly composed of 2 transmembrane chains . the various combinations of types of chains can generate a broad range of effects in response to the same ligand .
phospholipase c generates inositol 1,4,5-triphosphate ( ip3 ) and diacylglycerol ( dag ) from phosphatidylinositol 4 , 5-biphosphate .
ip3 is a universal calcium - mobilized second messenger , while dag activates protein kinase c. both paths aim to increase ca influx and/or uptake .
second messengers  depicts the action of the bmp / bmpr system . just like other tissue - specific bmps ,
consequently , data suggest that bmp-9 is a potent alleviative of cartilage advance in vitro , and it has a significant role in forebrain embryogenesis , in cancer biology , in iron metabolism and in glucose homeostasis .
the first evidence of bmp-9 was found in the mouse liver , where it was expressed during embryonic development .
further investigations revealed that bmp-9 binds on human hepatoma cells and primary rat hepatocytes , inducing a proliferative response in both cell lines .
although bmp-9 was not detectable in rat hepatocytes , a high level of bmp-9 messenger rna is expressed in non - parenchymal cells of the liver ( ie , endothelial , kupffer , and stellate cells ) .
since cells of the hepatic reticuloendothelial system showed high binding affinity for bmp-9 , a possible autocrine - paracrine role is proposed for this morphogen in the liver .
this was supported by chen et al . , who found bmp-9 inhibits gluconeogenesis and activated expression of pivotal enzymes of lipid metabolism after a single subcutaneous injection of bmp-9 .
the hypoglycemic effect of bmp-9 was first established in transcription inhibition in rat hepatoma cells .
their effects , however , differ . while bmp-9 as potently as insulin regulates total glucose production , insulin s effect on gluconeogenesis is more potent .
bmp-9 has been demonstrated to improve glycemia in diabetic mice , which can be proven by in - situ exposition of hepatocytes to the combination of glucose and insulin and oral glucose in fasted rats , and is proposed as a candidate for the hepatic insulin - sensitizing substance ( hiss ) .
the process of hepatic regeneration has evoked wide interest since antiquity . despite many models of liver injury ( eg , ccl4 ) ,
hepatic regeneration has been witnessed in various species , but the exact mechanism and control over liver growth are unclear [ 2729 ] . it is proposed that regenerative capacities of the hepatocytes are dependent on the supply of oxygen and nutrients . the liver lobule is divided into 3 zones ( metabolic heterogeneity ) : zone i is the periportal part , which gets the maximum of oxygen and nutrients ; zone ii is the middle part of the liver lobule ; and zone iii surrounds the branches of hepatic vein and gets the minimum of oxygen and nutrients .
hepatocytes that are closer to the periportal zone have better regenerative abilities compared to those hepatocytes in the central zone . during liver regeneration ,
hepatocyte proliferation starts in the areas of the lobules surrounding the portal triads and then proceeds to the pericentral areas by 36 to 48 hours .
any explanation of this process has to take into account various blood - stream driven molecules : calcium , hepatocyte growth factor , epidermal growth factor , il-6 , transforming growth factor - alpha , and tumor necrosis factor - alpha .
insulin and norepinephrine , with limited effect on dna synthesis by themselves , are capable of altering growth factors induced liver regeneration .
the kinetics of both cell proliferation and the growth factors produced by proliferating hepatocytes suggest that hepatocytes provide the mitogenic stimuli leading to proliferation of the other cells . based on findings of the bmp-9 s expression in the human liver
, we hypothesize effects of bmp-9 to be dependent on blood supply ( cvijanovic et al . ) .
it is crucial to distinguish whether the localization of this protein is zone dependent ? if compared to the central zone , higher levels of the bmp-9 s expression in periportal hepatocytes would indicate its possible hepatoregenerative role .
thus , in orthopedics it needs to be applied in vast quantities , and in more adoptable quantities , it is active in soft - tissue locations - including the liver , nervous system and bone marrow .
is an extremely powerful tool that should help establishing possible therapeutic potential of bmp-9 in the treatment of type 2 diabetes .
the suggested work should expand our current understanding of bmps functions other than those concerning heading morphogenesis towards supporting tissue s formation [ 713 ] .
the effect of bmp-9 suggests its importance other than merely a bone formation inducer , most obviously in metabolism of carbohydrates , but nonetheless , fats .
such properties , in supporting tissues organization could reform the clinical management of many musculoskeletal disorders , and its capability in differentiation of many other tissues warrants its popularity and attractiveness .
precise determination of protein s expression is needed regarding zonal differences in normal and pathologically altered hepatocytes functions .
experimental study needs to be carried out in order to give rise to analysis of direct hepatoregenerative effect of bmp-9 .
therefore , our hypothesis predicts additional evidence to previously introduced ideas of bmp-9 as a local autocrine / paracrine factor in the liver or systemic protein with a possible effect on glucose sensitive peripheral tissues .
 summarybone morphogenetic protein-9 ( bmp-9 ) is a member of the transforming growth factor beta ( tgf- ) superfamily of cytokines , which regulate cell growth and differentiation during embryogenesis . 
 apart of that , the hypoglycemic potential of bmp-9 is of great interest . 
 it has been confirmed that bmp-9 , like insulin , improves glycemia in diabetic mice and regulates directional glucose metabolism in hepatocytes ; therefore it is proposed to be a candidate hepatic insulin - sensitizing substance ( hiss ) . in liver fibrosis , 
 due to the portocaval shunt , insulin bypasses the organ and the liver undergoes atrophy . 
 parenteral administration of insulin reverses atrophy by stimulating mitogenic activity of the hepatocytes . because bmp-9 has a signaling pathway similar to other bmps and insulin 
 , it is to be expected that bmp-9 has a certain regenerative role in the liver , supporting the above - mentioned is evidence of bmp-9 expression in diss s spaces and bmp-7 s mitogenic activity in mucosal cells . 
 however , further studies are needed to confirm the possible regenerative role of bmp-9 . 
Hypothesis
Evidence for the Hypothesis
Conclusions