Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1-SMAD1 interaction
Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1-SMAD1 interaction
复制标题
II 型胶原蛋白通过促进整合素 β1 与 SMAD1 相互作用抑制关节软骨细胞肥大和骨关节炎进展
DOI：
10.1038/s41413-019-0046-y
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发表时间：
2019-03-06
期刊：
影响因子：
12.7
通讯作者：
Su, Peiqiang
中科院分区：
文献类型：
--
作者：
Lian, Chengjie;Wang, Xudong;Su, Peiqiang
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（COL 2A 1）以前被认为只是软骨基质的结构成分，但最近，它已被发现是一种细胞外信号分子，可以显着抑制软骨细胞肥大。然而，COL 2A 1调节肥大分化的机制仍不清楚。在我们的研究中，Col 2a 1 p.Gly1170Ser突变小鼠模型的构建，并证明纯合子Col 2a 1的损失。发现Col 2a 1的缺失通过骨形态发生蛋白（BMP）-SMAD 1途径加速软骨细胞肥大。整合素β1（integrin β1，ITGB 1）是COL 2A 1的主要受体，它与BMP受体竞争结合SMAD 1，从而抑制SMAD 1的活化和核输入。COL 2A 1还可以激活ITGB 1诱导的ERK 1/2磷酸化，并通过ERK 1/2-SMAD 1相互作用，进一步抑制SMAD 1激活，从而抑制BMP-SMAD 1介导的软骨细胞肥大。此外，COL 2A 1表达下调，而软骨细胞肥大标志物和BMP-SMAD 1信号转导活性在退行性人类关节软骨中上调。我们的研究揭示了COL 2A 1抑制软骨细胞肥大的新机制，并表明COL 2A 1的降解和减少可能引发和促进骨关节炎的进展。
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.