软骨中Vhl的缺失加速了与年龄相关的和手术诱导的小鼠骨关节炎的进展。

Loss of Vhl in cartilage accelerated the progression of age-associated and surgically induced murine osteoarthritis.

作者信息

Weng T, Xie Y, Yi L, Huang J, Luo F, Du X, Chen L, Liu C, Chen D, Chen L

机构信息

Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, China.

Department of Orthopedics, Daping Hospital, Third Military Medical University, Chongqing 400042, China.

出版信息

Osteoarthritis Cartilage. 2014 Aug;22(8):1197-205. doi: 10.1016/j.joca.2014.06.031. Epub 2014 Jul 4.

DOI:10.1016/j.joca.2014.06.031

PMID:24999110

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4150692/

Abstract

OBJECTIVE

To investigate the role of Vhl in maintaining the integrity of articular cartilage and in the development of experimental osteoarthritis (OA).

METHOD

Histology of articular cartilage and subchondral bone in both Vhl cKO and WT mice were analyzed by histopathology and micro-CT. Articular cartilage destruction and proteoglycan loss were scored in aged (12-month-old) mice as well as in mice with surgically induced OA. Apoptosis of cartilage in age-related and surgically induced OA was detected with TUNEL assay. Expressions of von Hippel-Lindau (VHL), Fas, LC-3, HIF-1α, HIF-2α, p-mTOR and MMP-13 in the knee joints were analyzed by immunostaining.

RESULTS

No gross differences in cartilage were observed between Vhl cKO and WT mice at age 4 months. However, Vhl cKO mice displayed accelerated age-associated spontaneous OA and surgically induced OA. Cartilage destruction and proteoglycan loss were observed in the absence of Vhl. In addition, inactivation of Vhl resulted in up-regulation of HIF-2α and increased chondrocyte apoptosis and decreased expression of autophagy during OA development. Immunohistochemical staining also showed that Vhl deficiency led to increased expression of Fas, p-mTOR and MMP-13, and those genes were associated with cell apoptosis, autophagy and cartilage matrix breakdown, respectively.

CONCLUSION

Loss of Vhl in adult articular cartilage is associated with earlier dysregulation of cartilage homeostasis, characterized by an increased chondrocyte apoptosis, compromised chondrocyte autophagy, and an accelerated age-related and surgery-induced OA development. These results highlight the novel role of Vhl in maintaining joint homeostasis and OA development.

摘要

目的

研究Vhl在维持关节软骨完整性及实验性骨关节炎（OA）发展过程中的作用。

方法

通过组织病理学和显微CT分析Vhl条件性敲除（cKO）小鼠和野生型（WT）小鼠关节软骨及软骨下骨的组织学情况。对老年（12月龄）小鼠以及手术诱导性OA小鼠的关节软骨破坏和蛋白聚糖损失进行评分。采用TUNEL法检测年龄相关性和手术诱导性OA中软骨细胞的凋亡情况。通过免疫染色分析膝关节中冯·希佩尔-林道（VHL）、Fas、LC-3、低氧诱导因子-1α（HIF-1α）、低氧诱导因子-2α（HIF-2α）、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）和基质金属蛋白酶-13（MMP-13）的表达。

结果

4月龄时，Vhl cKO小鼠和WT小鼠的软骨未见明显差异。然而，Vhl cKO小鼠表现出年龄相关性自发性OA和手术诱导性OA加速发展。在缺乏Vhl的情况下观察到软骨破坏和蛋白聚糖损失。此外，Vhl失活导致OA发展过程中HIF-2α上调、软骨细胞凋亡增加以及自噬表达降低。免疫组织化学染色还显示，Vhl缺乏导致Fas、p-mTOR和MMP-13表达增加，这些基因分别与细胞凋亡、自噬和软骨基质分解相关。