II型胶原蛋白通过促进整合素β1

肥大分化不仅是生长板软骨内骨化的终末过程，也是骨关节炎软骨的重要病理变化。II 型胶原蛋白 (COL2A1) 以前被认为只是软骨基质的一种结构成分，但最近发现它是一种细胞外信号分子，可以显着抑制软骨细胞肥大。然而，COL2A1 调节肥大分化的机制仍不清楚。在我们的研究中，一个Col2a1构建了p.Gly1170Ser突变小鼠模型，并在纯合子中证实了Col2a1的缺失。发现 Col2a1 的缺失会通过骨形态发生蛋白 (BMP)-SMAD1 途径加速软骨细胞肥大。在与 COL2A1 相互作用后，COL2A1 的主要受体整合素 β1 (ITGB1) 与 BMP 受体竞争结合 SMAD1，然后抑制 SMAD1 活化和核输入。COL2A1 还可以激活 ITGB1 诱导的 ERK1/2 磷酸化，并通过 ERK1/2-SMAD1 相互作用，进一步抑制 SMAD1 活化，从而抑制 BMP-SMAD1 介导的软骨细胞肥大。此外，COL2A1 表达下调，而软骨细胞肥大标志物和 BMP-SMAD1 信号活性在退行性人关节软骨中上调。

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Hypertrophic differentiation is not only the terminal process of endochondral ossification in the growth plate but is also an important pathological change in osteoarthritic cartilage. Collagen type II (COL2A1) was previously considered to be only a structural component of the cartilage matrix, but recently, it has been revealed to be an extracellular signaling molecule that can significantly suppress chondrocyte hypertrophy. However, the mechanisms by which COL2A1 regulates hypertrophic differentiation remain unclear. In our study, a Col2a1 p.Gly1170Ser mutant mouse model was constructed, and Col2a1 loss was demonstrated in homozygotes. Loss of Col2a1 was found to accelerate chondrocyte hypertrophy through the bone morphogenetic protein (BMP)-SMAD1 pathway. Upon interacting with COL2A1, integrin β1 (ITGB1), the major receptor for COL2A1, competed with BMP receptors for binding to SMAD1 and then inhibited SMAD1 activation and nuclear import. COL2A1 could also activate ITGB1-induced ERK1/2 phosphorylation and, through ERK1/2-SMAD1 interaction, it further repressed SMAD1 activation, thus inhibiting BMP-SMAD1-mediated chondrocyte hypertrophy. Moreover, COL2A1 expression was downregulated, while chondrocyte hypertrophic markers and BMP-SMAD1 signaling activity were upregulated in degenerative human articular cartilage. Our study reveals novel mechanisms for the inhibition of chondrocyte hypertrophy by COL2A1 and suggests that the degradation and decrease in COL2A1 might initiate and promote osteoarthritis progression.