Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy.
Discoidin Domain Receptors 1 Inhibition Alleviates Osteoarthritis via Enhancing Autophagy.
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DOI：
10.3390/ijms21196991
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发表时间：
2020-09-23
影响因子：
5.6
通讯作者：
Wang CZ
中科院分区：
文献类型：
--
作者：
Chou HC;Chen CH;Chou LY;Cheng TL;Kang L;Chuang SC;Lin YS;Ho ML;Wang YH;Lin SY;Wang CZ
我们最近报道，软骨细胞特异性敲除盘状结构域受体1（Ddr 1）延迟软骨内骨化（EO）在生长板通过减少软骨细胞肥大终末分化，和凋亡。骨关节炎（OA）关节软骨中软骨细胞的生物学和表型变化与EO过程中观察到的现象相似。此外，自噬可以促进软骨细胞的存活，防止OA中关节软骨的降解。在此基础上，我们探讨了Ddr 1抑制剂对OA预防的作用，并进一步研究了自噬在Ddr 1抑制剂（7 rh）治疗OA中的作用。采用前交叉韧带横断（ACLT）-OA模型研究7 rh在体内的作用。将40只8周龄小鼠随机分为4组，包括假手术组、ACLT组和两个治疗组（ACLT +7 rh 6.9 nM或13.8 nM）。根据研究设计，将生理盐水或7 rh关节内（IA）注射到研究膝关节中，每周3次，持续2周，然后每周1次，持续4周。结果表明，7 rh处理显著提高了大鼠的负重能力和跑步耐力，减少了软骨的降解，并降低了终末分化标志物（X型胶原、Indian hedgehog和基质金属蛋白酶13）。此外，7 rh通过降低雷帕霉素哺乳动物靶蛋白的表达和增强轻链3和beclin-1的表达来调节软骨细胞自噬，从而减少软骨细胞凋亡。这些结果表明，IA注射7 rh可以减少软骨细胞凋亡，促进软骨细胞自噬，从而减轻软骨降解。我们的观察结果表明，IA注射7 rh可能是一种潜在的疾病改善治疗，以预防OA进展。
We recently reported that the chondrocyte-specific knockout of discoidin domain receptors 1 (Ddr1) delayed endochondral ossification (EO) in the growth plate by reducing the chondrocyte hypertrophic terminal differentiation, and apoptosis. The biologic and phenotypic changes in chondrocytes in the articular cartilage with osteoarthritis (OA) are similar to the phenomena observed in the process of EO. Additionally, autophagy can promote chondrocyte survival and prevent articular cartilage from degradation in OA. On this basis, we explored the effect of Ddr1 inhibition on OA prevention and further investigated the roles of autophagy in treating OA with a Ddr1 inhibitor (7 rh). The anterior cruciate ligament transection (ACLT)–OA model was used to investigate the role of 7 rh in vivo. Forty 8-week-old mice were randomly assigned to four groups, including the sham group, ACLT group, and two treated groups (ACLT with 7 rh 6.9 nM or 13.8 nM). According to the study design, normal saline or 7 rh were intra-articular (IA) injected into studied knees 3 times per week for 2 weeks and then once per week for 4 weeks. The results showed that 7 rh treatment significantly improved the functional performances (the weight-bearing ability and the running endurance), decreased cartilage degradation, and also reduced the terminal differentiation markers (collagen type X, Indian hedgehog, and matrix metalloproteinase 13). Moreover, 7 rh decreased chondrocyte apoptosis by regulating chondrocyte autophagy through reducing the expression of the mammalian target of rapamycin and enhancing the light chain 3 and beclin-1 expression. These results demonstrated that the IA injection of 7 rh could reduce the chondrocyte apoptosis and promote chondrocyte autophagy, leading to the attenuation of cartilage degradation. Our observations suggested that the IA injection of 7 rh could represent a potential disease-modifying therapy to prevention OA progression.
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影响因子：
4.8
作者：
Chou, Liang-Yin;Chen, Chung-Hwan;Wang, Chau-Zen
通讯作者：
Wang, Chau-Zen
影响因子：
7
作者：
Kirsch, T;Swoboda, B;Nah, HD
通讯作者：
Nah, HD
影响因子：
4.8
作者：
Leitinger, B
通讯作者：
Leitinger, B
影响因子：
5.3
作者：
Vogel, WF;Aszódi, A;Pawson, T
通讯作者：
Pawson, T
影响因子：
27.4
作者：
Caramés B;Hasegawa A;Taniguchi N;Miyaki S;Blanco FJ;Lotz M
通讯作者：
Lotz M