Role of chemerin/CMKLR1 signaling in adipogenesis and osteoblastogenesis of bone marrow stem cells.
Maintenance of healthy bone mass requires a well-coordinated balance between the ongoing processes of bone formation and bone resorption. Bone-forming osteoblasts derive from resident adult stem cells within bone marrow called bone marrow stromal cells (BMSCs). These BMSCs are multipotent and also can give rise to adipocytes, which do not contribute directly to bone formation but may influence bone remodeling through the release of bioactive signaling molecules. Chemerin is a novel adipocyte-derived signaling molecule that promotes adipocyte differentiation. In this study we examined the role of chemerin and the cognate receptors CMKLR1 and CCRL2 as determinants of osteoblast and adipocyte differentiation of the preosteoblast 7F2 cell line and of primary BMSCs. Expression and secretion of chemerin increased dramatically with adipocyte differentiation of these cells. Functionally, knockdown of chemerin or CMKLR1 expression using RNA interference abrogated adipocyte differentiation, clonal expansion, and basal proliferation of BMSCs. In contrast, knockdown of either gene was associated with increased osteoblast marker gene expression and mineralization in response to osteoblastogenic stimuli. Forced expression of the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) induced chemerin expression and partially rescued the loss of adipogenesis associated with chemerin or CMKLR1 knockdown in BMSCs. Taken together, these data support a novel role for chemerin/CMKLR1 signaling in regulating adipogenesis and osteoblastogenesis of bone marrow-derived precursor cells. These data reveal a potential role for this signaling pathway as a modulator of bone mass.
Muruganandan
Shanmugam
S
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Roman
Alexandra A
AA
Sinal
Christopher J
CJ
D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D054388:Receptors, CCR; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C486456:CMKLR1 protein, mouse; C111851:Ccrl2 protein, mouse; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D054388:Receptors, CCR; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; C523686:chemerin protein, mouse