Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA; Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
Dev Biol. 2013 Oct 15;382(2):375-84. doi: 10.1016/j.ydbio.2013.08.021. Epub 2013 Aug 29.
Members of the bone morphogenetic protein (BMP) superfamily, including transforming growth factor-betas (TGFβ), regulate multiple aspects of chondrogenesis. Smad7 is an intracellular inhibitor of BMP and TGFβ signaling. Studies in which Smad7 was overexpressed in chondrocytes demonstrated that Smad7 can impact chondrogenesis by inhibiting BMP signaling. However, whether Smad7 is actually required for endochondral ossification in vivo is unclear. Moreover, whether Smad7 regulates TGFβ in addition to BMP signaling in developing cartilage is unknown. In this study, we found that Smad7 is required for both axial and appendicular skeletal development. Loss of Smad7 led to impairment of the cell cycle in chondrocytes and to defects in terminal maturation. This phenotype was attributed to upregulation of both BMP and TGFβ signaling in Smad7 mutant growth plates. Moreover, Smad7-/- mice develop hypocellular cores in the medial growth plates, associated with elevated HIF1α levels, cell death, and intracellular retention of types II and X collagen. Thus, Smad7 may be required to mediate cell stress responses in the growth plate during development.
骨形态发生蛋白（BMP）超家族成员，包括转化生长因子-β（TGFβ），调节软骨生成的多个方面。Smad7 是 BMP 和 TGFβ 信号的细胞内抑制剂。在软骨细胞中过表达 Smad7 的研究表明，Smad7 通过抑制 BMP 信号来影响软骨生成。然而，Smad7 是否在体内对于软骨内骨化实际上是必需的尚不清楚。此外，Smad7 是否除了在发育中的软骨中调节 BMP 信号外还调节 TGFβ信号也是未知的。在这项研究中，我们发现 Smad7 对于轴性和附肢骨骼发育都是必需的。Smad7 的缺失导致软骨细胞中细胞周期受损，并导致终末成熟缺陷。这种表型归因于 Smad7 突变生长板中 BMP 和 TGFβ 信号的上调。此外，Smad7-/-小鼠在中侧生长板中发育出细胞稀少的核心，与 HIF1α 水平升高、细胞死亡和 II 型和 X 型胶原的细胞内滞留有关。因此，Smad7 可能需要在发育过程中在生长板中介导细胞应激反应。
