| Chemerin,a secreted protein encoded by Rarres2 gene,which is mainly produced by adipocytes and hepatocytes,and plays a role in local and distant organs by endocrine or paracrine,including chemotaxis,proinflammation,angiogenesis and calcium mobilization.Chemerin initially synthesized the precursor with 183 amino acids,and then 20 amino at N-terminal were truncated to form inactive precursor（chemerin-s163）and released to the extracellular or circulating.5-9 amino at C-terminal were cleaved by plasminogen,elastase or cathepsin G,and formed various isomers with different affinity with CMKLR1（chemerin-K158,-S157,-F156,etc.）.Chemerin has three receptors:chemokine like receptor 1（CMKLR1）,G-protein coupled receptor 1（Gpr1）,and c-c-motif chemokine receptor like 2（CCRL2）.In obesity,the serum chemerin level increased,suggesting that chemerin may have the function of coupling obesity with obesity related metabolic diseases,such as fatty liver,cardiovascular disease and bone disease,as well as other adipokines（such as leptin,adiponectin,etc.）.Therefore,elucidating the role of chemerin in bone metabolism may provide a basis for preventing and treating obesity related bone diseases.Epidemiological studies reported that chemerin was associated with osteoporosis.Some studies found circulating chemerin was elevated in osteoporotic patients,while others indicated that circulating chemerin was decreased in postmenopausal osteoporotic women than non-osteoporotic postomenopausal women.In vitro studies found that chemerin knockdown promoted the osteogenic differentiation of mesenchymal stem cells and inhibited the differentiation of adipogenesis.However,the role and mechanism of chemerin in bone metabolism in vivo are not clear.In this study,we observed the association between chemerin and osteogenic genes in bone tissue;and chemerin knockout(Rarres2-/-)and Ap2-driven adiocyte specific overexpression（TG）mice were constructed to observe the effect of chemerin on bone metabolism and explore its potential mechanism.We found that in high-fat diet（HFD）mice,serum chemerin level increased,while bone marrow chemerin level decreased;Meanwhile,the expression of chemerin gene in bone tissue was positively correlated with the osteogenic marker genes（Alp,Runx,Osterix,Ocn,Opn,etc.）in wild type mice.To further study the role of chemerin in bone metabolism,μCT showed that the bone mass of Rarres2-/-mice decreased,while TG mice increased;Calcein labeled bone formation assay showed that bone formation decreased in Rarres2-/-mice,but increased in TG mice.In addition,we also observed that the expression of chemerin gene was also gradually up regulated with the increase of the osteogenic marker genes during osteogenic differentiation of bone marrow mesenchymal stem cells（BMSCs）.Furthermore,the BMSCs from Rarres2-/-mice showed a decreased osteogenic differentiation,while that from TG was increased.Mechanistically,it is reported that chemerin/CMKLR1 signal mainly affects Erk,p38 and Akt signals in the cells.However,we found that chemerin positively regulated Akt signals in bone tissue and BMSCs,rather than Erk and p38 signals.In addition,we further confirmed chemerin promoted osteogenic differentiation of BMSCs via Akt/Gsk3β/β-catenin axis.Moreover,Akt inhibitor（MK2206）can block the osteogenic differentiation,osteogenic genes expression and active-β-catenin induced by chemerin.In conclusion,our results show that chemerin promotes BMSCs osteogenic differentiation and osteogenesis in mice.Chemerin may be a new strategy for osteoporosis treatment.,... |
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