Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice.
Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice.
复制标题
DOI：
10.1002/art.34645
复制
发表时间：
2012-12
影响因子：
--
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Weng, Tujun;Yi, Lingxian;Huang, Junlan;Luo, Fengtao;Wen, Xuan;Du, Xiaolan;Chen, Qian;Deng, Chuxia;Chen, Di;Chen, Lin
成纤维细胞生长因子（FGF）家族成员参与关节软骨稳态的调节。本研究旨在探讨成纤维细胞生长因子受体1（FGFR-1）在骨关节炎（OA）发生发展中的作用及其机制。以软骨特异性和他莫昔芬诱导的方式从成年小鼠的关节软骨细胞中删除FGFR-1。在Fgfr 1缺陷型和野生型（WT）小鼠中建立并测试了两种OA模型（衰老相关自发性OA和不稳定诱导的OA）以及抗原诱导的关节炎（AIA）模型。使用这3种关节炎模型，在任一基因型小鼠的膝关节中评估软骨结构的改变和蛋白聚糖的损失。分离原代软骨细胞并定量评估关键调节分子的表达。此外，检查了FGFR-1抑制剂对人关节软骨细胞的作用。在出生后和成年阶段，Fgfr 1缺陷小鼠的大体形态学特征与WT小鼠的大体形态学特征相当。与12月龄WT小鼠相比，12月龄Fgfr 1缺陷小鼠的关节软骨显示出更大的聚集蛋白聚糖染色。Fgfr 1缺陷赋予抵抗AIA诱导的蛋白多糖损失，并减弱手术诱导的膝关节不稳定后软骨破坏的发展。FGFR-1抑制的软骨保护作用在很大程度上与小鼠和人关节软骨细胞中基质金属蛋白酶13（MMP-13）表达的降低和FGFR-3的上调相关。成年小鼠关节软骨细胞中FGFR-1的破坏抑制软骨退化的进展。MMP-13表达的下调和FGFR-3水平的上调可能有助于在Fgfr 1缺陷小鼠中观察到的表型变化。
Fibroblast growth factor (FGF) family members are involved in the regulation of articular cartilage homeostasis. The aim of this study was to investigate the function of FGF receptor 1 (FGFR-1) in the development of osteoarthritis (OA) and its underlying mechanisms. FGFR-1 was deleted from the articular chondrocytes of adult mice in a cartilage-specific and tamoxifen-inducible manner. Two OA models (aging-associated spontaneous OA, and destabilization-induced OA), as well as an antigen-induced arthritis (AIA) model, were established and tested in Fgfr1-deficient and wild-type (WT) mice. Alterations in cartilage structure and the loss of proteoglycan were assessed in the knee joints of mice of either genotype, using these 3 arthritis models. Primary chondrocytes were isolated and the expression of key regulatory molecules was assessed quantitatively. In addition, the effect of an FGFR-1 inhibitor on human articular chondrocytes was examined. The gross morphologic features of Fgfr1-deficient mice were comparable with those of WT mice at both the postnatal and adult stages. The articular cartilage of 12-month-old Fgfr1-deficient mice displayed greater aggrecan staining compared to 12-month-old WT mice. Fgfr1 deficiency conferred resistance to the proteoglycan loss induced by AIA and attenuated the development of cartilage destruction after surgically induced destabilization of the knee joint. The chondroprotective effect of FGFR-1 inhibition was largely associated with decreased expression of matrix metalloproteinase 13 (MMP-13) and up-regulation of FGFR-3 in mouse and human articular chondrocytes. Disruption of FGFR-1 in adult mouse articular chondrocytes inhibits the progression of cartilage degeneration. Down-regulation of MMP-13 expression and up-regulation of FGFR-3 levels may contribute to the phenotypic changes observed in Fgfr1-deficient mice.
登录
查看更多内容
影响因子：
15.9
作者：
Little, Christopher B.;Meeker, Clare T.;Fosang, Amanda J.
通讯作者：
Fosang, Amanda J.
影响因子：
1.5
作者：
Chen, Mo;Lichtler, Alexander C.;Chen, Di
通讯作者：
Chen, Di
影响因子：
3.5
作者：
Ellman, Michael B.;An, Howard S.;Im, Hee-Jeong
通讯作者：
Im, Hee-Jeong
影响因子：
4.8
作者：
Minond, Dmitriy;Lauer-Fields, Janelle L.;Fields, Gregg B.
通讯作者：
Fields, Gregg B.
影响因子：
4.8
作者：
Muddasani, Prasuna;Norman, Jim C.;Im, Hee-Jeong
通讯作者：
Im, Hee-Jeong