IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function.
IFT80 Is Required for Fracture Healing Through Controlling the Regulation of TGF-β Signaling in Chondrocyte Differentiation and Function.
复制标题
通过控制软骨细胞分化和功能中TGF-β信号传导的调节，需要骨折愈合需要IFT80。
DOI：
10.1002/jbmr.3902
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发表时间：
2020-03
期刊：
影响因子：
--
通讯作者：
Yang S
中科院分区：
文献类型：
--
作者：
Liu M;Alharbi M;Graves D;Yang S
初生纤毛是一种重要的细胞器，固定在细胞表面膜上，负责感知和传递信号。鞭毛内转运(IFT)蛋白是纤毛形成和功能所必需的。虽然在了解这些蛋白在骨发育中的作用方面已经取得了重大进展，但IFT蛋白调控骨修复的机制尚未确定。我们利用他莫昔芬诱导的COL2α1-CRER小鼠，通过有条件地删除软骨细胞中的IFT80，造成小鼠股骨骨折，研究了软骨细胞中IFT80蛋白在骨折愈合中的作用。COL2α1creIFT80f/f小鼠的骨折骨痂比IFT80f/f对照组小。最大宽度和最大愈伤组织面积分别比对照组小31%和48%。COL2α1creIFT80f/f小鼠形成低密度/多孔编织骨组织，骨体积、骨小梁数量、骨小梁厚度比对照组小鼠明显降低，骨小梁间距增大。IFT80缺失可显著下调血管生成标记物--血管内皮生长因子、血小板衍生生长因子和血管生成素的表达，抑制骨折端骨痂的血管生成。在机制上，软骨细胞中IFT80的缺失导致骨折骨痂中的纤毛形成和软骨细胞增殖率与对照小鼠相比降低。同时，IFT80缺失通过抑制骨折骨痂中转化生长因子-βI、转化生长因子-β受体的表达和Smad2/3的磷酸化而下调转化生长因子-β信号转导通路。在体外培养的原代软骨细胞中，IFT80缺失显著降低了软骨细胞的增殖、纤毛组装以及成软骨基因的表达和分化。总之，我们的研究结果表明，IFT80和初级纤毛可能通过控制软骨细胞的增殖、分化和转化生长因子-β信号通路在骨折愈合中发挥重要作用。
Primary cilia are essential cellular organelles that are anchored at the cell surface membrane to sense and transduce signaling. Intraflagellar transport (IFT) proteins are indispensable for cilia formation and function. Although major advances in understanding the roles of these proteins in bone development have been made, the mechanisms by which IFT proteins regulate bone repair have not been identified. We investigated the role of the IFT80 protein in chondrocytes during fracture healing by creating femoral fractures in mice with conditional deletion of IFT80 in chondrocytes utilizing tamoxifen inducible Col2α1-CreER mice. Col2α1creIFT80f/f mice had smaller fracture calluses than IFT80f/f (control) mice. The max-width and max-callus area were 31% and 48% smaller than those of the control mice. Col2α1creIFT80f/f mice formed low-density/porous woven bony tissue with significantly lower ratio of bone volume, Trabecular (Tb) number, Tb thickness and greater Tb spacing compared to control mice. IFT80 deletion significantly down-regulated the expression of angiogenesis markers-VEGF, PDGF and angiopoietin and inhibited fracture callus vascularization. Mechanistically, loss of IFT80 in chondrocytes resulted in a decrease in cilia formation and chondrocyte proliferation rate in fracture callus compared to the control mice. Meanwhile, IFT80 deletion down-regulated the TGF-β signaling pathway by inhibiting the expression of TGF-βI, TGF-βR, and phosphorylation of Smad2/3 in the fracture callus. In primary chondrocyte cultures in vitro, IFT80 deletion dramatically reduced chondrocyte proliferation, cilia assembly and chondrogenic gene expression and differentiation. Collectively, our findings demonstrate that IFT80 and primary cilia play an essential role in the fracture healing, likely through controlling chondrocyte proliferation, differentiation and TGF-β signaling pathway.
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