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 previ...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,integrinβ1(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.展开更多
目的:观察电针(EA)治疗兔膝骨关节炎(KOA)模型关节软骨中骨形态发生蛋白-2(BMP-2)、Smad1表达的变化,探讨电针治疗KOA的作用机制。方法:制作兔膝关节炎模型,将建模成功的新西兰兔纳入模型对照组;正常组和模型组行常规饲养,不行治疗;电...目的:观察电针(EA)治疗兔膝骨关节炎(KOA)模型关节软骨中骨形态发生蛋白-2(BMP-2)、Smad1表达的变化,探讨电针治疗KOA的作用机制。方法:制作兔膝关节炎模型,将建模成功的新西兰兔纳入模型对照组;正常组和模型组行常规饲养,不行治疗;电针组行电针治疗20d。实验结束后,分别观察各组兔行为学评分、右膝关节宽度、软骨大体形态及组织学评分、软骨BMP-2、Smad1免疫组化及实时荧光定量PCR的变化。结果:电针组与模型组在行为学评分、软骨大体形态及组织学评分(Mankin评分)方面差异均无显著性(P>0.05),电针组兔右膝关节宽度小于模型组(P<0.05)。各组BMP-2免疫组化结果无显著差异,电针组较模型组Smad1蛋白质表达降低。模型组和模型对照组BMP-2 m RNA表达水平较正常组上调,差异无显著性意义(P>0.05),模型组Smad1m RNA表达水平较模型对照组和正常组均显著上调(P<0.05),电针组BMP-2及Smad1 m RNA表达水平较模型对照组和模型组均显著下调(P<0.05)。结论:电针可能通过下调早期兔膝骨关节炎软骨BMP-2/Smad1的表达抑制骨赘形成,延缓膝骨关节炎的病理进程。展开更多
基金supported by the National Natural Science Foundation of China (No.81371907,No.81572134,and No.81802217)the China Postdoctoral Science Foundation (No.2017M622873)+2 种基金the Natural Science Foundation of Guangdong Province,China (No.2018A0303130260,No.2016A030313284,and No.2017A030311008)the Guangzhou Science and Technology Plan (No.201804010057)the Fundamental Research Funds for the Central Universities (No.17ykpy06)
文摘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,integrinβ1(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.
文摘目的:观察电针(EA)治疗兔膝骨关节炎(KOA)模型关节软骨中骨形态发生蛋白-2(BMP-2)、Smad1表达的变化,探讨电针治疗KOA的作用机制。方法:制作兔膝关节炎模型,将建模成功的新西兰兔纳入模型对照组;正常组和模型组行常规饲养,不行治疗;电针组行电针治疗20d。实验结束后,分别观察各组兔行为学评分、右膝关节宽度、软骨大体形态及组织学评分、软骨BMP-2、Smad1免疫组化及实时荧光定量PCR的变化。结果:电针组与模型组在行为学评分、软骨大体形态及组织学评分(Mankin评分)方面差异均无显著性(P>0.05),电针组兔右膝关节宽度小于模型组(P<0.05)。各组BMP-2免疫组化结果无显著差异,电针组较模型组Smad1蛋白质表达降低。模型组和模型对照组BMP-2 m RNA表达水平较正常组上调,差异无显著性意义(P>0.05),模型组Smad1m RNA表达水平较模型对照组和正常组均显著上调(P<0.05),电针组BMP-2及Smad1 m RNA表达水平较模型对照组和模型组均显著下调(P<0.05)。结论:电针可能通过下调早期兔膝骨关节炎软骨BMP-2/Smad1的表达抑制骨赘形成,延缓膝骨关节炎的病理进程。
