RBP-Jκ依赖的Notch信号通路对于小鼠关节软骨和关节维持是必需的。
RBP-Jκ-dependent Notch signaling is required for murine articular cartilage and joint maintenance.
作者信息
Mirando Anthony J, Liu Zhaoyang, Moore Tyler, Lang Alexandra, Kohn Anat, Osinski Alana M, O'Keefe Regis J, Mooney Robert A, Zuscik Michael J, Hilton Matthew J
机构信息
University of Rochester and University of Rochester Medical Center, Rochester, New York.
出版信息
Arthritis Rheum. 2013 Oct;65(10):2623-33. doi: 10.1002/art.38076.
OBJECTIVE
Osteoarthritis (OA) is a degenerative disease resulting in severe joint cartilage destruction and disability. While the mechanisms underlying the development and progression of OA are poorly understood, gene mutations have been identified within cartilage-related signaling molecules, implicating impaired cell signaling in OA and joint disease. The Notch pathway has recently been identified as a crucial regulator of growth plate cartilage development, and components are expressed in joint tissue. This study was undertaken to investigate a novel role for Notch signaling in joint cartilage development, maintenance, and the pathogenesis of joint disease in a mouse model.
METHODS
We performed the first mouse gene study in which the core Notch signaling component, RBP-Jκ, was tissue specifically deleted within joints. The Prx1Cre transgene removed Rbpjk loxP-flanked alleles in mesenchymal joint precursor cells, while the Col2Cre(ERT2) transgene specifically deleted Rbpjk in postnatal chondrocytes. Murine articular chondrocyte cultures were also used to examine Notch regulation of gene expression.
RESULTS
Loss of Notch signaling in mesenchymal joint precursor cells did not affect embryonic joint development in mice, but rather, resulted in an early, progressive OA-like pathology. Additionally, partial loss of Notch signaling in murine postnatal cartilage resulted in progressive joint cartilage degeneration and an age-related OA-like pathology. Inhibition of Notch signaling altered the expression of the extracellular matrix (ECM)-related factors type II collagen (COL2A1), proteoglycan 4, COL10A1, matrix metalloproteinase 13, and ADAMTS.
CONCLUSION
Our findings indicate that the RBP-Jκ-dependent Notch pathway is a novel pathway involved in joint maintenance and articular cartilage homeostasis, a critical regulator of articular cartilage ECM-related molecules, and a potentially important therapeutic target for OA-like joint disease.
目的
骨关节炎（OA）是一种导致严重关节软骨破坏和残疾的退行性疾病。虽然OA发生和进展的潜在机制尚不清楚，但已在软骨相关信号分子中鉴定出基因突变，这表明OA和关节疾病中存在细胞信号传导受损。Notch通路最近被确定为生长板软骨发育的关键调节因子，其成分在关节组织中表达。本研究旨在探讨Notch信号在小鼠模型中关节软骨发育、维持及关节疾病发病机制中的新作用。
方法
我们进行了首例小鼠基因研究，其中核心Notch信号成分RBP-Jκ在关节内被组织特异性缺失。Prx1Cre转基因在间充质关节前体细胞中去除Rbpjk侧翼loxP等位基因，而Col2Cre(ERT2)转基因在出生后软骨细胞中特异性缺失Rbpjk。还使用小鼠关节软骨细胞培养物来检查Notch对基因表达的调节。
结果
间充质关节前体细胞中Notch信号的缺失不影响小鼠胚胎关节发育，而是导致早期进行性OA样病理改变。此外，小鼠出生后软骨中Notch信号的部分缺失导致关节软骨进行性退变和与年龄相关的OA样病理改变。Notch信号的抑制改变了细胞外基质（ECM）相关因子II型胶原（COL2A1）、蛋白聚糖4、COL10A1、基质金属蛋白酶13和含血小板反应蛋白基序的解聚蛋白样金属蛋白酶的表达。
结论
我们的研究结果表明，RBP-Jκ依赖性Notch通路是参与关节维持和关节软骨稳态的新通路；是关节软骨ECM相关分子的关键调节因子；也是OA样关节疾病潜在的重要治疗靶点。
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