Skeletal development is a highly sophisticated process in which the expression of a variety of growth factors, signaling molecules, and extracellular matrix proteins is spatially and temporally orchestrated. In the present study, we show that ADAM10, a transmembrane protease that is critically involved in the functional regulation of various membrane-bound molecules, plays an essential role in the longitudinal growth of long bones and in skeletal development. We found that mutant mice lacking ADAM10 in osteochondroprogenitors exhibited marked growth retardation and had shorter long bones than the control mice. Histomorphometric analysis revealed that the mutant mice had a shorter hypertrophic zone and that their hypertrophic chondrocytes were smaller in size than those of the control mice. Unexpectedly, we found that the mRNA expression of the chemokine CXCL12 and its receptor CXCR4 were significantly reduced in cartilage tissues lacking ADAM10. Further, exogenous supplementation of recombinant CXCL12 rescued the defect in the ADAM10-deficient growth plate in an ex vivo culture model. Taken together, our data show a previously unknown role for ADAM10 in skeletal development that involves its regulation of the CXCL12 and CXCR4 signaling pathway.

中文翻译：

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ADAM10对于小鼠的纵向骨骼生长必不可少

骨骼发育是一个高度复杂的过程，在这个过程中，各种生长因子、信号分子和细胞外基质蛋白的表达在空间和时间上都是协调一致的。在本研究中，我们表明 ADAM10 是一种跨膜蛋白酶，它与各种膜结合分子的功能调节密切相关，在长骨的纵向生长和骨骼发育中起着至关重要的作用。我们发现骨软骨祖细胞中缺乏 ADAM10 的突变小鼠表现出明显的生长迟缓，并且长骨比对照小鼠短。组织形态计量学分析显示，突变小鼠的肥大区较短，其肥大软骨细胞的尺寸小于对照小鼠。不料，我们发现在缺乏 ADAM10 的软骨组织中趋化因子 CXCL12 及其受体 CXCR4 的 mRNA 表达显着降低。此外，外源性补充重组 CXCL12 在体外培养模型中挽救了 ADAM10 缺陷生长板中的缺陷。总之，我们的数据显示了 ADAM10 在骨骼发育中的一个以前未知的作用，涉及其对 CXCL12 和 CXCR4 信号通路的调节。