Loss of BMPR2 leads to high bone mass due to increased osteoblast activity
Loss of BMPR2 leads to high bone mass due to increased osteoblast activity
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DOI：
10.1242/jcs.156737
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发表时间：
2015-04-01
影响因子：
4
通讯作者：
Rosen, Vicki
中科院分区：
文献类型：
--
作者：
Lowery, Jonathan W.;Intini, Giuseppe;Rosen, Vicki
骨形态发生蛋白（BMP）与激活素和TGF β信号传导的比例失衡越来越多地与人类疾病相关，但介导这种关系的机制仍不清楚。2型受体ACVR 2A和ACVR 2B结合BMP和激活素，但2型受体BMPR 2仅结合BMP，表明2型受体利用可能在介导这些途径的相互作用中起作用。我们在小鼠骨骼中测试了这一假设，在小鼠骨骼中，骨量受到BMP信号传导和激活素以及TGF β信号传导的双重调节。我们发现，在小鼠骨骼祖细胞（Bmpr 2-cKO小鼠）中删除Bmpr 2选择性地损害激活素信号传导，但对BMP信号传导没有影响，导致骨形成率增加和骨量增加。此外，激活素螯合对Bmpr 2-cKO小鼠的骨量没有影响，但增加了野生型小鼠的骨量。我们的研究结果提出了一种新的模型，其中BMPR 2的可用性增强了BMP和激活素之间的受体水平竞争，并且BMP对ACVR 2A和ACVR 2B的利用是以激活素为代价的。由于BMP和激活素通路调节是目前的治疗兴趣，我们的研究结果提供了重要的机制洞察这些途径之间的关系，在人类健康。
Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGF beta signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGF beta signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.