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.

Automated summary

Proinflammatory cytokine Sema4D plays a critical role in the pathogenesis of joint diseases by directly promoting cartilage destruction. Sema4D induces a proinflammatory response in articular chondrocytes by activating proteolytic enzymes that degrade cartilage. This induction is independent of RhoA but relies on NF-kappa B signaling and Ras-MEK-Erk1/2 signaling mediated by Plexin-B2 and c-Met receptors.