Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
J Bone Miner Res. 2010 Feb;25(2):222-34. doi: 10.1359/jbmr.091106.
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.
维持健康的骨量需要成骨和骨吸收这两个持续进行的过程之间达到良好的协调平衡。成骨细胞来源于骨髓中被称为骨髓基质细胞（BMSCs）的常驻成人干细胞。这些 BMSCs 具有多能性，也可以分化为脂肪细胞，脂肪细胞不会直接参与骨形成，但可能通过释放生物活性信号分子影响骨重塑。趋化素是一种新的脂肪细胞衍生的信号分子，可促进脂肪细胞分化。在这项研究中，我们研究了趋化素及其同源受体 CMKLR1 和 CCRL2 作为前成骨细胞 7F2 细胞系和原代 BMSCs 中成骨细胞和脂肪细胞分化的决定因素的作用。这些细胞的脂肪细胞分化过程中，趋化素的表达和分泌显著增加。功能上，使用 RNA 干扰技术敲低趋化素或 CMKLR1 的表达会阻断 BMSCs 的脂肪细胞分化、克隆扩增和基础增殖。相比之下，敲低任何一个基因都与成骨细胞标志物基因表达增加和对成骨细胞刺激的矿化有关。过表达脂肪生成转录因子过氧化物酶体增殖物激活受体γ（PPARγ）诱导趋化素表达，并部分挽救了与 BMSCs 中趋化素或 CMKLR1 敲低相关的脂肪生成丧失。总之，这些数据支持趋化素/CMKLR1 信号在调节骨髓来源前体细胞的脂肪生成和成骨生成中的新作用。这些数据揭示了该信号通路作为骨量调节剂的潜在作用。
