Deficient Mechanical Activation of Anabolic Transcripts and Post-Traumatic Cartilage Degeneration in Matrilin-1 Knockout Mice.
Deficient Mechanical Activation of Anabolic Transcripts and Post-Traumatic Cartilage Degeneration in Matrilin-1 Knockout Mice.
复制标题
DOI：
10.1371/journal.pone.0156676
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chen Q
中科院分区：
文献类型：
--
作者：
Chen Y;Cossman J;Jayasuriya CT;Li X;Guan Y;Fonseca V;Yang K;Charbonneau C;Yu H;Kanbe K;Ma P;Darling E;Chen Q
Matrilin-1（Matn 1）是一种软骨特异性的细胞外基质（ECM）蛋白，被认为可以调节ECM之间的相互作用并传递软骨中的机械信号。由于Matn 1基因敲除（Matn 1-/-）小鼠表现出正常的骨骼，其在体内的功能尚不清楚。在这项研究中，我们发现，合成代谢Acan和Col 2a转录水平显着高于野生型（MATN 1 +/+）小鼠软骨比MATN 1-/-小鼠体内。然而，在体外静止条件下培养的Matn 1 +/+和MATN 1-/-软骨细胞之间没有观察到这种差异。循环负荷显着刺激Matn 1 +/+中的Acan和Col 2a转录水平，但不刺激Matn 1-/-软骨细胞中的Acan和Col 2a转录水平。这表明，虽然Matn 1 +/+软骨细胞响应于机械负荷增加其合成代谢基因表达，但由于机械转导的缺陷，MATN 1-/-软骨细胞未能这样做。我们还发现，在Matn 1-/-小鼠中，软骨基质的弹性模量改变，表明由于Matn 1的缺乏，机械转导发生了变化。为了了解这种缺陷对关节疾病的影响，通过内侧半月板的不稳定来改变体内的机械负荷。虽然Matn 1 +/+小鼠表现出与关节机械损伤一致的浅表裂缝和裂缝，但Matn 1-/-小鼠表现出更严重的软骨病变，其特征在于蛋白聚糖损失和细胞和ECM的解体。这表明Matn 1缺乏通过不能上调合成代谢基因表达而影响创伤后骨关节炎的发病机制。这是Matn 1在体内功能的首次证明，这表明它在改变的机械环境下对软骨退化具有保护作用。
Matrilin-1 (Matn1), a cartilage-specific peri-cellular and extracellular matrix (ECM) protein, has been hypothesized to regulate ECM interactions and transmit mechanical signals in cartilage. Since Matn1 knock-out (Matn1-/-) mice exhibit a normal skeleton, its function in vivo is unclear. In this study, we found that the anabolic Acan and Col2a transcript levels were significantly higher in wildtype (Matn1+/+) mouse cartilage than that of MATN1-/- mice in vivo. However, such difference was not observed between Matn1+/+ and MATN1-/- chondrocytes cultured under stationary conditions in vitro. Cyclic loading significantly stimulated Acan and Col2a transcript levels in Matn1+/+ but not in MATN1-/- chondrocytes. This suggests that, while Matn1+/+ chondrocytes increase their anabolic gene expression in response to mechanical loading, the MATN1-/- chondrocytes fail to do so because of the deficiency in mechanotransduction. We also found that altered elastic modulus of cartilage matrix in Matn1-/- mice, suggesting the mechanotransduction has changed due to the deficiency of Matn1. To understand the impact of such deficiency on joint disease, mechanical loading was altered in vivo by destabilization of medial meniscus. While Matn1+/+ mice exhibited superficial fissures and clefts consistent with mechanical damage to the articular joint, Matn1-/- mice presented more severe cartilage lesions characterized by proteoglycan loss and disorganization of cells and ECM. This suggests that Matn1 deficiency affects pathogenesis of post-traumatic osteoarthritis by failing to up-regulate anabolic gene expression. This is the first demonstration of Matn1 function in vivo, which suggests its protective role in cartilage degeneration under altered mechanical environment.