A SMOC2 variant inhibits BMP signaling by competitively binding to BMPR1B and causes growth plate defects
A SMOC2 variant inhibits BMP signaling by competitively binding to BMPR1B and causes growth plate defects
复制标题
SMOC2 变体通过竞争性结合 BMPR1B 抑制 BMP 信号传导并导致生长板缺陷
DOI：
10.1016/j.bone.2020.115686
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发表时间：
2021-01-01
期刊：
影响因子：
4.1
通讯作者：
Liu, Qiji
中科院分区：
文献类型：
--
作者：
Long, Feng;Shi, Hongbiao;Liu, Qiji
软骨内骨化是长骨形成的主要过程，软骨形成是这一过程的最后一步。一些研究表明，骨形态发生蛋白（BMP）是软骨形成所必需的，并调节多种生长板特征。异常的BMP途径导致生长板缺陷，导致骨软骨发育不良。SPARC相关的模块化钙结合2（SMOC 2）基因编码被认为是BMP信号传导的拮抗剂的细胞外蛋白。在这项研究中，我们通过敲入SMOC 2突变（c.1076 T > G）产生了一个小鼠模型，该模型显示出短肢侏儒症，胫骨生长板中的增殖区减少、紊乱和细胞减少，肥大区扩大。为了确定SMOC 2突变的潜在病理生理学机制，我们使用敲入小鼠来研究SMOC 2和BMP-SMAD 1/5/9信号通路在体内和体外的相互作用。最终，我们发现突变的SMOC 2不能与COL 9A 1和HSPG结合。此外，突变体SMOC 2通过竞争性结合BMPR 1B抑制BMP信号传导，这导致敲入小鼠的生长板缺陷和短肢侏儒症。
Endochondral ossification is the major process of long bone formation, and chondrogenesis is the final step of this process. Several studies have indicated that bone morphogenetic proteins (BMPs) are required for chondrogenesis and regulate multiple growth plate features. Abnormal BMP pathways lead to growth plate defects, resulting in osteochondrodysplasia. The SPARC-related modular calcium binding 2 (SMOC2) gene encodes an extracellular protein that is considered to be an antagonist of BMP signaling. In this study, we generated a mouse model by knocking-in the SMOC2 mutation (c.1076 T > G), which showed short-limbed dwarfism, reduced, disorganized, and hypocellular proliferative zones and expanded hypertrophic zones in tibial growth plates. To determine the underlying pathophysiological mechanism of SMOC2 mutation, we used knock-in mice to investigate the interaction between SMOC2 and the BMP-SMAD1/5/9 signaling pathway in vivo and in vitro. Eventually, we found that mutant SMOC2 could not bind to COL9A1 and HSPG. Furthermore, mutant SMOC2 inhibited BMP signaling by competitively binding to BMPR1B, which lead to defects in growth plates and short-limbed dwarfism in knock-in mice.