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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 promoted 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 required NF-κB signaling and Ras-MEK-Erk1/2 signaling downstream of the receptors Plexin-B2 and c-Met and depended on the transcription factors IκBζ and C/EBPδ. 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. Description Semaphorin 4D acts as a proinflammatory cytokine that promotes cartilage destruction in joints. Sema4D as cartilage destroyer Various classical proinflammatory cytokines contribute to cartilage destruction in joint diseases. Murakami et al. found that Semaphorin 4D (Sema4D) was released by inflamed macrophages and stimulated cartilage begin{bmatrix} degradation in articular chondrocytes and cartilage explants. In a mouse model of inflammatory arthritis, Sema4D was increased in synovial fluid, and loss of Sema4D protected against cartilage degeneration. Sema4D elicited these effects by stimulating the expression of transcripts encoding begin{bmatrix}-degrading enzymes downstream of the receptors Plexin-B2 and c-Met and intracellular signaling pathways distinct from those by which Sema4D regulates cell morphology and motility. These findings identify Sema4D as a proinflammatory cytokine in joints and contribute to a broader understanding of the factors that drive joint degeneration.