Publication: Semaphorin 4D induces articular cartilage destruction and inflammation in joints by transcriptionally reprogramming chondrocytes
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Issued Date
2022
Resource Type
Language
eng
File Type
application/pdf
ISSN
19450877
Rights Holder(s)
Scopus
Bibliographic Citation
International Journal on Electrical Engineering and Informatics. Vol 14, No.2 (2022), p.392-410
Suggested Citation
Murakami T., Takahata Y., Hata K., Ebina K., Hirose K., Ruengsinpinya L., Nakaminami Y., Etani Y., Kobayashi S., Maruyama T., Nakano H., Kaneko T., Toyosawa S., Asahara H., Nishimura R. Semaphorin 4D induces articular cartilage destruction and inflammation in joints by transcriptionally reprogramming chondrocytes. International Journal on Electrical Engineering and Informatics. Vol 14, No.2 (2022), p.392-410. doi:10.1126/scisignal.abl5304 Retrieved from: https://hdl.handle.net/20.500.14740/9973
Abstract
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. Copyright © 2022 The Authors, some rights reserved.