BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells via Interaction with Acvr2b
BMP3 Suppresses Osteoblast Differentiation of Bone Marrow Stromal Cells via Interaction with Acvr2b
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DOI：
10.1210/me.2011-1168
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发表时间：
2012-01-01
影响因子：
--
通讯作者：
Rosen, Vicki
中科院分区：
文献类型：
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作者：
Kokabu, Shoichiro;Gamer, Laura;Rosen, Vicki
增强骨形态发生蛋白(BMP)信号可在多种以骨修复为靶点的环境中增加骨形成。然而，BMP在维持成人骨量中的作用还不是很清楚。在小鼠体内靶向破坏BMP3导致骨小梁形成增加，而转基因BMP3在骨骼细胞中的过表达导致自发性骨折，这与BMP3在骨量调节中具有负面作用一致。在这里，我们研究了BMP3在成人骨骼中作为BMP信号媒介的重要性。我们发现成骨细胞和骨细胞是成人骨中BMP3的来源。利用原代骨髓基质细胞的体外培养，我们发现BMP3的过表达抑制了OBL的分化，而BMP3的缺失则增加了集落形成单位成纤维细胞和集落形成单位OBL。BMP3能够影响OBL的分化是由于它与激活素受体2b(Acvr2b)的相互作用，因为骨髓基质细胞内源性Acvr2b被敲除后，BMP3对OBL分化的抑制作用减弱。这些发现最符合这样一个模型，即由成熟的骨细胞产生的BMP3通过骨骼前体细胞中的Acvr2b减少BMP信号，限制它们分化为成熟的OBL。我们的数据进一步支持了内源性BMPs在调节成人骨量方面具有生理作用的观点。(分子内分泌学26：87-94,2012)
Enhancing bone morphogenetic protein (BMP) signaling increases bone formation in a variety of settings that target bone repair. However, the role of BMP in the maintenance of adult bone mass is not well understood. Targeted disruption of BMP3 in mice results in increased trabecular bone formation, whereas transgenic overexpression of BMP3 in skeletal cells leads to spontaneous fracture, consistent with BMP3 having a negative role in bone mass regulation. Here we investigate the importance of BMP3 as a mediator of BMP signaling in the adult skeleton. We find that osteoblasts (OBL) and osteocytes are the source of BMP3 in adult bone. Using in vitro cultures of primary bone marrow stromal cells, we show that overexpression of BMP3 suppresses OBL differentiation, whereas loss of BMP3 increases colony-forming unit fibroblasts and colony-forming unit OBL. The ability of BMP3 to affect OBL differentiation is due to its interaction with activin receptor type 2b (Acvr2b) because knockdown of endogenous Acvr2b in bone marrow stromal cells reduces the suppressive effect of BMP3 on OBL differentiation. These findings best fit a model in which BMP3, produced by mature bone cells, acts to reduce BMP signaling through Acvr2b in skeletal progenitor cells, limiting their differentiation to mature OBL. Our data further support the idea that endogenous BMPs have a physiological role in regulating adult bone mass. (Molecular Endocrinology 26: 87-94, 2012)