Physiological and excessive mechanical compression of articular cartilage activates Smad2/3P signaling
Physiological and excessive mechanical compression of articular cartilage activates Smad2/3P signaling
复制标题
DOI：
10.1016/j.joca.2014.04.024
复制
发表时间：
2014-07-01
影响因子：
7
通讯作者：
Buma, P.
中科院分区：
文献类型：
--
作者：
Madej, W.;van Caam, A.;Buma, P.
目的：关节软骨中的转化生长因子β（TGF-β）可以通过两种途径发出信号，即ALK 5/Smad 2/3 P和ALK 1/Smad 1/5/8 P途径，第一种途径是保护性的，后者有利于软骨细胞终末分化。由于已知生物力学因素在骨关节炎（OA）的发生和发展中起重要作用，我们研究了过度的机械压缩是否可以改变软骨中的TGF-β信号传导，将其从ALK 5/Smad 2/3 P转移到ALK 1/Smad 1/5/8 P通路，有利于软骨细胞的终末分化。平衡后，外植体经受无侧限动态机械压缩（1 Hz），压力为3 MPa（生理）或12 MPa（过度）。结果：在3 MPa和12 MPa压力下，关节软骨中Smad 2/3 P反应基因bSerpine 1、bSmad 7和bAlk 5的表达上调，而Smad 1/5/8 P反应基因bId 1的表达下调。此外，bTgfb 1的表达在两个压缩组中显著上调。当ALK 5/Smad 2/3 P通路被选择性ALK 4/5/7抑制剂阻断时，过度机械压迫对bSmad 7和bAlk 5表达的影响被阻止。与此相反，我们表明，机械压缩不仅与生理，而且与过度的应力可以激活Smad 2/3 P信号，这是已知的保护关节软骨和阻止软骨细胞终末分化。(C)2014年国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Transforming growth factor beta (TGF-beta) in articular cartilage can signal via two routes, the ALK5/Smad2/3P and the ALK1/Smad1/5/8P route, the first being protective and the latter favoring chondrocyte terminal differentiation. Since biomechanical factors are known to play an essential role in osteoarthritis (OA) initiation and progression, we investigated if excessive mechanical compression can alter TGF-beta signaling in cartilage shifting it from ALK5/Smad2/3P to ALK1/Smad1/5/8P pathway, favoring terminal differentiation of chondrocytes.Design: Articular cartilage explants were harvested from bovine metacarpophalangeal joints. After equilibration, explants were subjected to unconfined dynamic mechanical compression (1 Hz) with 3 MPa (physiological) or 12 MPa (excessive) stress. After different time intervals samples were frozen and mRNA levels of selected genes were examined using real-time polymerase chain reaction.Results: In articular cartilage compressed with 3 MPa and also 12 MPa stress the expression of Smad2/3P responsive genes bSerpine1, bSmad7 and bAlk5 was up-regulated, whereas the expression of Smad1/5/8P responsive gene bId1 was down-regulated. Furthermore, the expression of bTgfb1 was significantly up-regulated in both compression groups. When ALK5/Smad2/3P pathway was blocked with a selective ALK4/5/7 inhibitor, the effect of excessive mechanical compression on bSmad7 and bAlk5 expression was prevented.Conclusions: Here we show that excessive mechanical compression alone is not able to shift TGF-beta signaling toward the ALK1/Smad1/5/8P pathway. In contrast, we show that mechanical compression not only with physiological but also with excessive stress can activate Smad2/3P signaling, which is known to be protective for articular cartilage and to block chondrocyte terminal differentiation. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.