The expression and activation of EphA4 in the various cell types in a knee joint was upregulated upon an intraarticular injury. To determine if EphA4 signaling plays a role in osteoarthritis, we determined whether deficient EphA4 expression (in EphA4 knockout mice) or upregulation of the EphA4 signaling (with the EfnA4-fc treatment) would alter cellular functions of synoviocytes and articular chondrocytes. In synoviocytes, deficient EphA4 expression enhanced, whereas activation of the EphA4 signaling reduced, expression and secretion of key inflammatory cytokines and matrix metalloproteases. Conversely, in articular chondrocytes, activation of the EphA4 signaling upregulated, while deficient EphA4 expression reduced, expression levels of chondrogenic genes (e.g., aggrecan, lubricin, type-2 collagen, and Sox9). EfnA4-fc treatment in wildtype, but not EphA4-deficient, articular chondrocytes promoted the formation and activity of acidic proteoglycan-producing colonies. Activation of the EphA4 signaling in articular chondrocytes upregulated Rac1/2 and downregulated RhoA via enhancing Vav1 and reducing Ephexin1 activation, respectively. However, activation of the EphA4 signaling in synoviocytes suppressed the Vav/Rac signaling while upregulated the Ephexin/Rho signaling. In summary, the EphA4 signaling in synoviocytes is largely of anti-catabolic nature through suppression of the expression of inflammatory cytokines and matrix proteases, but in articular chondrocytes the signaling is pro-anabolic in that it promotes the biosynthesis of articular cartilage. The contrasting action of the EphA4 signaling in synoviocytes as opposing to articular chondrocytes may in part be mediated through the opposite differential effects of the EphA4 signaling on the Vav/Rac signaling and Ephexin/Rho signaling in the two skeletal cell types.

膝关节中各种细胞类型中 EphA4 的表达和激活在关节内损伤时上调。为了确定 EphA4 信号是否在骨关节炎中起作用，我们确定了 EphA4 表达缺陷（在 EphA4 敲除小鼠中）或 EphA4 信号的上调（用 EfnA4-fc 处理）是否会改变滑膜细胞和关节软骨细胞的细胞功能。在滑膜细胞中，缺乏的 EphA4 表达增强，而 EphA4 信号的激活降低了关键炎症细胞因子和基质金属蛋白酶的表达和分泌。相反，在关节软骨细胞中，EphA4 信号传导的激活上调，而缺乏的 EphA4 表达降低，软骨形成基因（例如蛋白聚糖、润滑素、2 型胶原蛋白和 Sox9）的表达水平。野生型中的 EfnA4-fc 处理，但不是 EphA4 缺陷的，关节软骨细胞促进了酸性蛋白聚糖产生集落的形成和活性。关节软骨细胞中 EphA4 信号的激活分别通过增强 Vav1 和减少 Ephexin1 激活来上调 Rac1/2 和下调 RhoA。然而，滑膜细胞中 EphA4 信号的激活抑制了 Vav/Rac 信号，同时上调了 Ephexin/Rho 信号。总之，滑膜细胞中的 EphA4 信号主要通过抑制炎性细胞因子和基质蛋白酶的表达而具有抗分解代谢的性质，但在关节软骨细胞中，信号是促合成代谢的，因为它促进了关节软骨的生物合成。