Positive-Feedback Regulation of Subchondral H-Type Vessel Formation by Chondrocyte Promotes Osteoarthritis Development in Mice
Positive-Feedback Regulation of Subchondral H-Type Vessel Formation by Chondrocyte Promotes Osteoarthritis Development in Mice
复制标题
软骨细胞对软骨下H型血管形成的正反馈调节促进小鼠骨关节炎的发展
DOI：
10.1002/jbmr.3388
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发表时间：
2018-05-01
影响因子：
6.2
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
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作者：
Lu, Jiansen;Zhang, Haiyan;Bai, Xiaochun
活化关节软骨细胞和软骨下骨之间的血管侵袭介导的相互作用对骨关节炎（OA）的发展至关重要。在这里，我们确定了雷帕霉素复合物1 （mTORC1）信号在骨软骨界面串扰中的作用及其调控机制。然后，软骨细胞特异性mTORC1激活（Tsc1 CKO和Tsc1 CKOER）或抑制（Raptor CKOER）的小鼠及其同窝对照分别遭受内侧半月板不稳定（DMM）诱导的OA。用贝伐单抗治疗DMM或Tsc1 CKO小鼠，贝伐单抗是一种血管内皮生长因子(VEGF)-A抗体，可阻断血管生成。关节软骨退变采用国际骨关节炎研究协会评分进行评估。免疫染色和Western blotting检测小鼠h型血管及蛋白水平。用白细胞介素-1 β处理突变小鼠的原代软骨细胞和ADTC5细胞，研究软骨细胞mTORC1在VEGF-A分泌和体外血管形成中的作用。显然，dmm诱导的OA和老年小鼠软骨下骨中h型血管增加。软骨mTORC1激活刺激关节软骨细胞中VEGF-A的产生和软骨下骨中h型血管的形成。软骨细胞mTORC1通过vegf - a刺激软骨下h型血管的形成部分促进OA。特别是，血管源性营养物质激活软骨细胞mTORC1，刺激软骨细胞活化和VEGF的产生，导致软骨下骨进一步血管生成。因此，关节软骨细胞营养感应mTORC1信号对软骨下骨h型血管形成的正反馈调节对OA的发病和进展至关重要。(C) 2018年美国骨与矿物研究学会
Vascular-invasion-mediated interactions between activated articular chondrocytes and subchondral bone are essential for osteoarthritis (OA) development. Here, we determined the role of nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling in the crosstalk across the bone cartilage interface and its regulatory mechanisms. Then mice with chondrocyte-specific mTORC1 activation (Tsc1 CKO and Tsc1 CKOER) or inhibition (Raptor CKOER) and their littermate controls were subjected to OA induced by destabilization of the medial meniscus (DMM) or not. DMM or Tsc1 CKO mice were treated with bevacizumab, a vascular endothelial growth factor (VEGF)-A antibody that blocks angiogenesis. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International score. Immunostaining and Western blotting were conducted to detect H-type vessels and protein levels in mice. Primary chondrocytes from mutant mice and ADTC5 cells were treated with interleukin-1 beta to investigate the role of chondrocyte mTORC1 in VEGF-A secretion and in vitro vascular formation. Clearly, H-type vessels were increased in subchondral bone in DMM-induced OA and aged mice. Cartilage mTORC1 activation stimulated VEGF-A production in articular chondrocyte and H-type vessel formation in subchondral bone. Chondrocyte mTORC1 promoted OA partially through formation of VEGF-A-stimulated subchondral H-type vessels. In particular, vascular-derived nutrients activated chondrocyte mTORC1, and stimulated chondrocyte activation and production of VEGF, resulting in further angiogenesis in subchondral bone. Thus a positive-feedback regulation of H-type vessel formation in subchondral bone by articular chondrocyte nutrient-sensing mTORC1 signaling is essential for the pathogenesis and progression of OA. (C) 2018 American Society for Bone and Mineral Research