TSP1 is the essential domain of SEMA5A involved in pannus formation in rheumatoid arthritis.

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In this study, we explored the effect of semaphorin5A (SEMA5A) on rheumatoid arthritis (RA) pathogenesis and its specific TSP1 domain on pannus formation.The expression of SEMA5A was detected in synovium, fibroblast-like synoviocytes (FLS) and synovial fluid of RA patients and healthy controls (HCs) by q-PCR, IHC, WB and ELISA. SEMA5A-mAb intervention was performed to appraise the severity of joints in CIA model. Transcriptome sequencing and bioinformatics analysis in SEMA5A transfected FLS from HCs were performed to screen differentially expressed genes after SEMA5A overexpression. MTT assay in RA-FLS, chicken embryo allantoic membrane experiment and tube formation experiment were used to clarify the influence of SEMA5A on cell proliferation and angiogenesis. Furthermore, rescue experiment verified the function of TSP1 domain of SEMA5A in the progress of RA with Sema5a-/- CIA mice.The expression of SEMA5A increased in RA compared with HCs. Simultaneously, SEMA5A-mAb significantly attenuated joint injury and inflammatory response in CIA models. Besides, transcriptome sequencing and angiogenesis-related experiments verified the ability of SEMA5A to promote FLS proliferation and angiogenesis. Moreover, TSP1 was proved as an essential domain in SEMA5A-inducing angiogenesis in vitro. Additionally, rescue of TSP1-deleted SEMA5A failed to deteriorate the severity of arthritis in CIA model constructed with Sema5a -/- mice.In summary, up-regulation of SEMA5A was firstly confirmed in pathological lesion of RA patients. Furthermore, the treatment of SEMA5A-mAb attenuated the progress of RA in CIA model. Moreover, TSP1 was indicated as the key domain of SEMA5A to promote pannus formation in RA.

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Authors: Chipeng Xiao, Chen Lv, Siyuan Sun, Heping Zhao, Hanzhi Ling, Man Li, Yang Qin, Jinhao Zhang, Jianguang Wang, Xinyu Yang