Yao Qing, Gong Weiyuan, Wu Xiaohao, Gan Donghao, Tao Chu, Lin Sixiong, Qu Minghao, Ouyang Zhongtian, Chen Mingjue, Hu Xinjia, Xiao Guozhi
Department of Biochemistry, School of Medicine, Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China.
Department of Osteoarthropathy, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518035, China.
J Orthop Translat. 2023 May 31;41:12-19. doi: 10.1016/j.jot.2023.05.005. eCollection 2023 Jul.
Genetically modified mice are the most useful tools for investigating the gene functions in articular cartilage biology and the pathogenesis of osteoarthritis. The mice are one of the most reported mouse lines used for this purpose. The (proteoglycan 4) gene encodes the lubricin protein and is expressed selectively in chondrocytes located at the superficial layer of the articular cartilage. While the knock-in inducible-Cre transgenic mice were generated a while ago, so far, few studies have used this mouse line to perform gene functional studies in cartilage biology.
We have recently reported that deleting the gene, which encodes the key focal adhesion protein Kindlin-2, in articular chondrocytes by using the transgenic mice, results in spontaneous osteoarthritis (OA) lesions, which highly mimics the human OA pathologies. In this study, we have compared the Kindlin-2 deficiency-caused OA phenotypes induced by with those caused by using imaging and histological analyses.
We find that Kindlin-2 protein is deleted in about 75% of the superficial articular chondrocytes in the tamoxifen (TAM)-treated mice compared to controls. At 6 months after TAM injections, the OARSI scores of and mice were 5 and 3, respectively. The knee joints histological osteophyte and synovitis scores were also significantly decreased in mice compared to those in mice. Furthermore, magnitudes of upregulation of the extracellular matrix-degrading enzymes Mmp13 and hypertrophic chondrocyte markers Col10a1 and Runx2 were decreased in versus mice. We finally examined the susceptibility of mouse model to surgically induce OA lesions. The pathological features of OA in the TAM-DMM model exhibited significant enhancement in cartilage erosion, proteoglycan loss, osteophyte, and synovitis and an increase in OARSI score in articular cartilage compared with those in corn-oil DMM mice.
Kindlin-2 loss causes milder OA-like lesions in than in mice. In contrast, Kindlin-2 loss similarly accelerates the destabilization of the medial meniscus-induced OA lesions in both mice.: Our study demonstrates that is a useful tool for gene functional study in OA research. This study provides useful information for investigators to choose appropriate Cre mouse lines for their research in cartilage biology.
基因工程小鼠是研究关节软骨生物学中基因功能和骨关节炎发病机制最有用的工具。[具体小鼠品系名称1]小鼠是用于此目的报道最多的小鼠品系之一。[具体基因名称]（蛋白聚糖4）基因编码润滑蛋白，并在位于关节软骨表层的软骨细胞中选择性表达。虽然[具体小鼠品系名称2]敲入诱导型Cre转基因小鼠已于不久前培育成功，但迄今为止，很少有研究使用该小鼠品系在软骨生物学中进行基因功能研究。
我们最近报道，通过使用[具体小鼠品系名称2]转基因小鼠在关节软骨细胞中删除编码关键粘着斑蛋白Kindlin-2的基因，会导致自发性骨关节炎（OA）病变，这与人类OA病理高度相似。在本研究中，我们使用影像学和组织学分析，比较了[具体小鼠品系名称2]诱导的Kindlin-2缺陷引起的OA表型与[具体小鼠品系名称1]引起的OA表型。
我们发现，与对照组相比，在他莫昔芬（TAM）处理的[具体小鼠品系名称2]小鼠中，约75%的表层关节软骨细胞中的Kindlin-2蛋白被删除。在注射TAM后6个月，[具体小鼠品系名称2]和[具体小鼠品系名称1]小鼠的OARSI评分分别为5和3。与[具体小鼠品系名称1]小鼠相比，[具体小鼠品系名称2]小鼠膝关节组织学骨赘和滑膜炎评分也显著降低。此外，与[具体小鼠品系名称1]小鼠相比，[具体小鼠品系名称2]小鼠细胞外基质降解酶Mmp13以及肥大软骨细胞标志物Col10a1和Runx2的上调幅度降低。我们最终检查了[具体小鼠品系名称2]小鼠模型对手术诱导的OA病变的易感性。与玉米油DMM小鼠相比，TAM-DMM模型中OA的病理特征在软骨侵蚀、蛋白聚糖丢失、骨赘和滑膜炎方面表现出显著增强，关节软骨的OARSI评分增加。
Kindlin-2缺失在[具体小鼠品系名称2]小鼠中引起的OA样病变比在[具体小鼠品系名称1]小鼠中更轻。相反，Kindlin-2缺失在两种小鼠中同样加速了内侧半月板不稳定诱导的OA病变。我们的研究表明，[具体小鼠品系名称2]是OA研究中基因功能研究的有用工具。本研究为研究人员在软骨生物学研究中选择合适的Cre小鼠品系提供了有用信息。
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