Arthritis and Tissue Degeneration Program, The Hospital for Special Surgery, New York, New York, USA.
Mol Cell Biol. 2013 Aug;33(16):3077-90. doi: 10.1128/MCB.00291-13. Epub 2013 Jun 3.
Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17ΔCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.
软骨内骨化是一个高度受调控的过程，依赖于发育中的生长板中细胞间的协调作用。本研究专注于理解细胞间相互作用的关键调节剂——膜锚定金属蛋白酶 ADAM17 在软骨内骨化中的作用。ADAM17 从细胞中释放生长因子、细胞因子和其他膜蛋白，对于表皮生长因子受体 (EGFR) 信号和肿瘤坏死因子α的加工至关重要。在这里，我们报告说，软骨细胞中缺乏 ADAM17 的小鼠 (A17ΔCh) 在生长板中有一个明显扩大的肥大软骨细胞区，并且长骨生长迟缓。这种异常是由最终分化的软骨细胞积累引起的，这些细胞产生钙化基质。破骨细胞或内皮细胞中 ADAM17 的失活不会影响肥大软骨细胞区，这表明 ADAM17 在生长板中的主要作用是在软骨细胞中。这一观点进一步得到了体外实验的支持，实验表明缺乏 Adam17 的原代软骨细胞的肥大分化增强。A17ΔCh 小鼠中肥大软骨细胞区的扩大类似于 EGFR 信号突变或其配体转化生长因子α (TGFα) 缺乏的小鼠中描述的情况，这表明 ADAM17 通过激活 TGFα/EGFR 信号轴来调节软骨细胞的终末分化在软骨内骨化过程中。
