mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis
mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis
复制标题
mTORC1 激活下调关节软骨细胞中的 FGFR3 和 PTH/PTHrP 受体，引发骨关节炎
DOI：
10.1016/j.joca.2016.12.024
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发表时间：
2017-06-01
影响因子：
7
通讯作者：
Cai, D.
中科院分区：
文献类型：
--
作者：
Zhang, H.;Wang, H.;Cai, D.
目的：关节软骨细胞活化，包括异常增殖和肥大前分化，是骨关节炎（OA）发生和发展的关键。破坏雷帕霉素复合物1（mTORC 1）的机制靶点促进软骨细胞自噬和存活，并降低实验性OA的严重程度。然而，软骨mTORC1激活在OA启动中的作用尚不清楚。本研究旨在阐明mTORC1在OA发病中的作用，并探讨其可能的机制。方法：采用免疫组化方法检测mTORC1在OA患者和OA小鼠关节软骨中的表达。产生软骨特异性结节性硬化症复合物1（Tsc 1，mTORC 1上游抑制剂）敲除（TSC1CKO）和诱导型Tsc 1 KO（TSC1CKO（ER））小鼠。采用免疫组化、Western blotting和qPCR方法检测mTORC1在OA发生发展过程中对其下游靶点的作用。TSC1CKO小鼠表现出自发性OA，TSC1CKO（ER）小鼠（2个月）表现出加速的年龄相关和DMM诱导的OA表型，伴有异常软骨细胞增殖和肥大分化。这与mTORC 1的过度活化和FGFR 3和PPR的显著下调有关，这两种受体对防止软骨细胞增殖和分化至关重要。雷帕霉素治疗逆转了KO小鼠的这些表型。结论：mTORC1激活后可通过下调FGFR 3和PPR的表达，促进关节软骨细胞的增殖和分化，从而诱导OA的发生。(C)2017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: Articular chondrocyte activation, involving aberrant proliferation and prehypertrophic differentiation, is essential for osteoarthritis (OA) initiation and progression. Disruption of mechanistic target of rapamycin complex 1 (mTORC1) promotes chondrocyte autophagy and survival, and decreases the severity of experimental OA. However, the role of cartilage mTORC1 activation in OA initiation is unknown. In this study, we elucidated the specific role of mTORC1activation in OA initiation, andidentify the underlying mechanisms.Method: Expression of mTORC1 in articular cartilage of OA patients and OA mice was assessed by immunostaining. Cartilage-specific tuberous sclerosis complex 1 (Tsc1, mTORC1 upstream inhibitor) knockout (TSC1CKO) and inducible Tsc1 KO (TSC1CKO(ER)) mice were generated. The functional effects of mTORC1 in OA initiation and development on its downstream targets were examined by immunostaining, western blotting and qPCR.Results: Articular chondrocyte mTORC1 was activated in early-stage OA and in aged mice. TSC1CKO mice exhibited spontaneous OA, and TSC1CKO(ER) mice (from 2 months) exhibited accelerated age-related and DMM-induced OA phenotypes, with aberrant chondrocyte proliferation and hypertrophic differentiation. This was associated with hyperactivation of mTORC1 and dramatic downregulation of FGFR3 and PPR, two receptors critical for preventing chondrocyte proliferation and differentiation. Rapamycin treatment reversed these phenotypes in KO mice. Furthermore, in vitro rescue experiments demonstrated that p73 and ERK1/2 may mediate the negative regulation of FGFR3 and PPR by mTORC1.Conclusion: mTORC1 activation stimulates articular chondrocyte proliferation and differentiation to initiate OA, in part by downregulating FGFR3 and PPR. (C) 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.