Role of Fibulin 3 in Aging-Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage.
Role of Fibulin 3 in Aging-Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage.
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DOI：
10.1002/art.39963
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Lotz MK
中科院分区：
文献类型：
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作者：
Hasegawa A;Yonezawa T;Taniguchi N;Otabe K;Akasaki Y;Matsukawa T;Saito M;Neo M;Marmorstein LY;Lotz MK
编码纤维蛋白-3的EFEMP1基因在关节软骨的浅表区特异性表达。本研究探讨了纤维蛋白-3在关节老化和骨关节炎（OA）中的表达模式以及纤维蛋白-3在OA发病机制中的作用。对正常和OA人、小鼠膝关节软骨进行免疫组化分析。在野生型和fibulin-3−/−小鼠中诱导实验性OA，并通过组织学评分评估OA的严重程度。为了检验纤维蛋白-3的功能，用siRNA转染软骨细胞单层培养物，进行定量PCR和Western blot分析。用EFEMP1慢病毒转染骨髓间充质干细胞（MSC），分析其软骨形成标志物。Fibulin-3在人和小鼠膝关节正常软骨SZ特异表达，并随着年龄的增长而下降。与野生型小鼠相比，纤维蛋白-3−/−小鼠的衰老相关性OA和实验性OA均明显加重。在未分化的间充质干细胞中，Fibulin-3表达高，在软骨形成过程中表达降低。siRNA抑制纤维蛋白-3可显著增加关节软骨细胞中的SOX9、II型胶原和聚集蛋白，而过表达纤维蛋白-3可抑制间充质干细胞的软骨形成。Fibulin-3在关节软骨SZ特异表达，在衰老和OA中表达减少。Fibulin-3调节成人祖细胞的分化，其衰老相关的下降是OA发病的早期事件。预防或恢复SZ软骨细胞中纤维蛋白-3的衰老相关损失有可能延迟或预防OA的发作。
The EFEMP1 gene encoding fibulin-3 is specifically expressed in the superficial zone of articular cartilage. This study examined fibulin-3 expression patterns in joint aging and osteoarthritis (OA) and the role of fibulin-3 in OA pathogenesis. Immunohistochemical analysis was performed on normal and OA human and mouse knee cartilage. Experimental OA was induced in wild type and fibulin-3−/− mice and OA severity was evaluated by histological scoring. To examine fibulin-3 function, chondrocyte monolayer cultures were transfected with siRNA for quantitative PCR and Western blot analyses. Bone marrow mesenchymal stem cells (MSC) were transduced with EFEMP1 lentivirus and analyzed for chondrogenesis markers. Fibulin-3 was specifically expressed in the SZ of normal cartilage in human and mouse knee joints and declined with aging. Both aging-related OA and experimental OA were significantly more severe in fibulin-3−/− mice compared with wild type mice. Fibulin-3 expression was high in undifferentiated MSC and decreased during chondrogenesis. Suppression of fibulin-3 by siRNA significantly increased SOX9, collagen II and aggrecan in articular chondrocytes, while overexpression of fibulin-3 inhibited chondrogenesis in MSC. Fibulin-3 is specifically expressed in the SZ of articular cartilage and its expression is reduced in aging and OA. Fibulin-3 regulates differentiation of adult progenitor cells and its aging-related decline is an early event in OA pathogenesis. Preventing or restoring aging-associated loss of fibulin-3 in SZ chondrocytes has potential to delay or prevent onset of OA.