在自发性骨关节炎小鼠模型中，通过条件性去除盘状结构域受体2延缓膝关节软骨退变。

Delay in articular cartilage degeneration of the knee joint by the conditional removal of discoidin domain receptor 2 in a spontaneous mouse model of osteoarthritis.

作者信息

Li Xiaolong, Chen Yi, Xu Rui, Wang Yan, Jian Fan, Long Hu, Lai Wenli

机构信息

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.

出版信息

Ann Transl Med. 2020 Sep;8(18):1178. doi: 10.21037/atm-20-5786.

DOI:10.21037/atm-20-5786

PMID:33241027

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7576030/

Abstract

BACKGROUND

Discoidin domain receptor 2 () is a rate-limiting factor in articular cartilage degeneration, a condition which normally leads to joint destruction. In human osteoarthritic tissues and mouse models of osteoarthritis (OA), the expression of increases and interacts with collagen type II, inducing the expression of matrix metalloproteinase 13 (MMP-13) and the receptor itself in chondrocytes. Moreover, conditional deletion of Ddr2 can significantly delay the progression of articular cartilage degeneration in post-traumatic OA mouse models. However, the biological effect of the conditional removal of in aging-related OA is still unknown. Therefore, this investigation was to determine whether the conditional removal of Ddr2 in articular cartilage could delay the cartilage degeneration in an aging-related mouse model ( ) of OA.

METHODS

Mice were bred with mice to generate mice. mice were crossed with mice to produce mice. A similar breeding procedure was used to generate mice, in which mice were replaced by mice. mice were bred with mice to produce mice that were then treated with tamoxifen or oil at the age of 10 weeks. Knee joints from oil- and tamoxifen-treated mice, and mice at the ages of 3, 9 and 15 months were collected for histology and immunohistochemistry analyses. The protein expressions of Ddr2 and Mmp-13 and the degraded collagen type II were examined.

RESULTS

The cartilage degeneration was significantly delayed in tamoxifen-treated mice. The scores, representing the severity of the cartilage damage, between oil- and tamoxifen-treated mice were: (mean ± SD) 1.33±0.47 1.29±0.45 (P>0.05) at the age of 3 months, 3.50±0.50 2.14±0.35 (P<0.001) at the age of 9 months, and 5.33±0.47 2.71±0.55 (P<0.001) at the age of 15 months. The protein expressions of Ddr2, Mmp-13 and the degraded collagen type II were significantly decreased in tamoxifen-treated mice.

CONCLUSIONS

The removal of Ddr2 could significantly attenuate the cartilage degeneration in mice.

摘要

背景

盘状结构域受体2（Ddr2）是关节软骨退变的一个限速因子，关节软骨退变通常会导致关节破坏。在人类骨关节炎组织和骨关节炎（OA）小鼠模型中，Ddr2的表达增加，并与II型胶原相互作用，诱导软骨细胞中基质金属蛋白酶13（MMP - 13）和受体自身的表达。此外，在创伤后OA小鼠模型中，条件性删除Ddr2可显著延缓关节软骨退变的进展。然而，在与衰老相关的OA中条件性去除Ddr2的生物学效应仍不清楚。因此，本研究旨在确定在与衰老相关的OA小鼠模型（SAMP8）中，关节软骨中条件性去除Ddr2是否能延缓软骨退变。

方法

将SAMP8小鼠与C57BL/6小鼠杂交产生SAMP8/C57BL/6小鼠。SAMP8/C57BL/6小鼠与Ddr2flox/flox小鼠杂交产生SAMP8;Ddr2flox/+小鼠。使用类似的育种程序产生SAMP8;Ddr2Δ/+小鼠，其中SAMP8小鼠被SAMP8;Ddr2flox/+小鼠取代。SAMP8;Ddr2Δ/+小鼠与C57BL/6小鼠杂交产生SAMP8;Ddr2Δ/Δ小鼠，然后在10周龄时用他莫昔芬或油处理。收集油处理和他莫昔芬处理的SAMP8;Ddr2Δ/Δ小鼠以及3、9和15月龄的SAMP8小鼠的膝关节用于组织学和免疫组织化学分析。检测Ddr2、Mmp - 13的蛋白表达以及II型胶原的降解情况。

结果

他莫昔芬处理的SAMP8;Ddr2Δ/Δ小鼠的软骨退变明显延迟。油处理和他莫昔芬处理的小鼠之间代表软骨损伤严重程度的评分如下：3月龄时，（平均值±标准差）1.33±0.47对1.29±0.45（P>0.05）；9月龄时，3.50±0.50对2.14±0.35（P<0.001）；15月龄时，5.33±0.47对2.71±0.55（P<0.001）。他莫昔芬处理的小鼠中Ddr2、Mmp - 13的蛋白表达以及II型胶原的降解明显降低。