CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection
CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection
复制标题
DOI：
10.1111/nyas.14021
复制
发表时间：
2019-04-01
影响因子：
5.2
通讯作者：
Sun, Hui B.
中科院分区：
文献类型：
--
作者：
He, Zhiyong;Leong, Daniel J.;Sun, Hui B.
骨关节炎 (OA) 发病机制主要是通过基质金属蛋白酶 (MMP) 13 等蛋白水解酶的作用介导。转录调节因子 CITED2 抑制软骨细胞中 MMP13 的表达，由 T 细胞和巨噬细胞中的白细胞介素 (IL)-4 以及软骨细胞中的适度机械负荷诱导。我们测试了这样的假设：CITED2 介导 IL-4 信号传导和机械负荷诱导途径之间的串扰，从而至少部分通过下调 MMP13 来实现软骨保护。 IL-4 通过 JAK/STAT 信号传导以剂量和时间依赖性方式诱导人软骨细胞中 CITED2 基因表达。机械负荷与 IL-4 相结合，在体外诱导人软骨细胞 CITED2 表达和下调 MMP13 方面产生累加效应。在体内，IL-4 基因敲除 (KO) 小鼠的软骨细胞中 CITED2 表达基础水平降低。虽然在野生型小鼠中适度的跑步机跑步会诱导 CITED2 表达并降低 MMP13 表达，但这些作用在 IL-4 基因 KO 小鼠的软骨细胞中减弱（对于 CITED2）或消除（对于 MMP13）。此外，与仅用 IL-4 处理的固定小鼠相比，关节内注射重组 IL-4 并结合常规的笼子活动可以更大程度地减轻创伤后 OA。这些数据表明，使用中等负荷来增强 IL-4 可能是保护 OA 软骨的潜在治疗策略。
Osteoarthritis (OA) pathogenesis is mediated largely through the actions of proteolytic enzymes such as matrix metalloproteinase (MMP) 13. The transcriptional regulator CITED2, which suppresses the expression of MMP13 in chondrocytes, is induced by interleukin (IL)-4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. We tested the hypothesis that CITED2 mediates cross-talk between IL-4 signaling and mechanical loading-induced pathways that result in chondroprotection, at least in part, by downregulating MMP13. IL-4 induced CITED2 gene expression in human chondrocytes in a dose- and time-dependent manner through JAK/STAT signaling. Mechanical loading combined with IL-4 resulted in additive effects on inducing CITED2 expression and downregulating of MMP13 in human chondrocytes in vitro. In vivo, IL-4 gene knockout (KO) mice exhibited reduced basal levels of CITED2 expression in chondrocytes. While moderate treadmill running induced CITED2 expression and reduced MMP13 expression in wild-type mice, these effects were blunted (for CITED2) or abolished (for MMP13) in chondrocytes of IL-4 gene KO mice. Moreover, intra-articular injections of mouse recombinant IL-4 combined with regular cage activity mitigated post-traumatic OA to a greater degree compared to immobilized mice treated with IL-4 alone. These data suggest that using moderate loading to enhance IL-4 may be a potential therapeutic strategy for chondroprotection in OA.