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条件性敲低关节软骨中的透明质酸酶 2 可刺激小鼠模型中的骨关节炎进展。

Conditional knockdown of hyaluronidase 2 in articular cartilage stimulates osteoarthritic progression in a mice model.

机构信息

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Multidisciplinary Pain Center, Aichi Medical University, Nagakute, Japan.

出版信息

Sci Rep. 2017 Aug 1;7(1):7028. doi: 10.1038/s41598-017-07376-5.

DOI:10.1038/s41598-017-07376-5
PMID:28765635
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5539311/
Abstract

The catabolism of hyaluronan in articular cartilage remains unclear. The aims of this study were to investigate the effects of hyaluronidase 2 (Hyal2) knockdown in articular cartilage on the development of osteoarthritis (OA) using genetic manipulated mice. Destabilization of the medial meniscus (DMM) model of Col2a promoter specific conditional Hyal2 knockout (Hyal ) mice was established and examined. Age related and DMM induced alterations of articular cartilage of knee joint were evaluated with modified Mankin score and immunohistochemical staining of MMP-13, ADAMTS-5, KIAA11199, and biotinylated- hyaluronan binding protein staining in addition to histomorphometrical analyses. Effects of Hyal2 suppression were also analyzed using explant culture of an IL-1α induced articular cartilage degradation model. The amount and size of hyaluronan in articular cartilage were higher in Hyal2 mice. Hyal2 mice exhibited aggravated cartilage degradation in age-related and DMM induced mice. MMP-13 and ADAMTS-5 positive chondrocytes were significantly higher in Hyal2 mice. Articular cartilage was more degraded in explant cultures obtained from Hyal2 mice. Knockdown of Hyal2 in articular cartilage induced OA development and progression possibly mediated by an imbalance of HA metabolism. This suggests that Hyal2 knockdown exhibits mucopolysaccharidosis-like OA change in articular cartilage similar to Hyal1 knockdown.

摘要

关节软骨中透明质酸的分解代谢仍不清楚。本研究的目的是通过遗传操作的小鼠研究软骨细胞中透明质酸酶 2 (Hyal2) 敲低对骨关节炎 (OA) 发展的影响。建立并检测了 Col2a 启动子特异性条件性 Hyal2 敲除 (Hyal2-/-) 小鼠内侧半月板不稳定 (DMM) 模型。采用改良的 Mankin 评分和 MMP-13、ADAMTS-5、KIAA11199 的免疫组织化学染色以及生物素化透明质酸结合蛋白染色，评估膝关节关节软骨的年龄相关性和 DMM 诱导变化，并进行组织形态计量学分析。还使用 IL-1α诱导的关节软骨降解模型的体外培养分析 Hyal2 抑制的效果。Hyal2-/-小鼠关节软骨中透明质酸的含量和大小更高。Hyal2-/-小鼠在年龄相关性和 DMM 诱导的小鼠中表现出更严重的软骨降解。MMP-13 和 ADAMTS-5 阳性软骨细胞在 Hyal2-/-小鼠中明显更高。从 Hyal2-/-小鼠获得的外植体培养物中，关节软骨降解更为严重。软骨细胞中 Hyal2 的敲低可能通过透明质酸代谢失衡诱导 OA 发展和进展。这表明 Hyal2 敲低在关节软骨中表现出类似于 Hyal1 敲低的粘多糖贮积症样 OA 变化。

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