Semaphorin 4D induces articular cartilage destruction and inflammation in joints by transcriptionally reprogramming chondrocytes

Proinflammatory cytokines play critical roles in the pathogenesis of joint diseases. Using a mass spectrometry- based cloning approach, we identified Semaphorin 4D (Sema4D) as an inflammatory cytokine that directly pro-moted cartilage destruction. Sema4d-deficient mice showed less cartilage destruction than wild-type mice in a model of rheumatoid arthritis. Sema4D induced a proinflammatory response in mouse articular chondrocytes characterized by the induction of proteolytic enzymes that degrade cartilage, such as matrix metalloproteinases (MMPs) and aggrecanases. The activation of Mmp13 and Mmp3 expression in articular chondrocytes by Sema4D did not depend on RhoA, a GTPase that mediates Sema4D-induced cytoskeletal rearrangements. Instead, it re-quired NF-kappa B signaling and Ras-MEK-Erk1/2 signaling downstream of the receptors Plexin-B2 and c-Met and depended on the transcription factors I kappa B zeta and C/EBP delta. Genetic and pharmacological blockade of these Sema4D signaling pathways inhibited MMP induction in chondrocytes and cartilage destruction in femoral head organ culture. Our results reveal a mechanism by which Sema4D signaling promotes cartilage destruction.

促炎细胞因子在关节疾病的发病机制中起着关键作用。利用基于质谱的克隆方法，我们鉴定出信号素4D（Sema4D）是一种直接促进软骨破坏的炎性细胞因子。在类风湿性关节炎模型中，Sema4d缺陷型小鼠比野生型小鼠表现出更少的软骨破坏。Sema4D在小鼠关节软骨细胞中诱导促炎反应，其特征是诱导降解软骨的蛋白水解酶，如基质金属蛋白酶（MMPs）和聚集蛋白聚糖酶。Sema4D对关节软骨细胞中Mmp13和Mmp3表达的激活不依赖于RhoA（一种介导Sema4D诱导的细胞骨架重排的GTP酶），而是需要Plexin - B2和c - Met受体下游的NF - κB信号通路以及Ras - MEK - Erk1/2信号通路，并依赖于转录因子IκBζ和C/EBPδ。对这些Sema4D信号通路进行基因和药物阻断，可抑制软骨细胞中MMP的诱导以及股骨头器官培养中的软骨破坏。我们的研究结果揭示了Sema4D信号促进软骨破坏的一种机制。