Multiple variants of soluble CD146 are involved in Systemic Sclerosis: identification of a novel pro-fibrotic factor

Arthritis Rheumatol. 2022 Jan 9. doi: 10.1002/art.42063. Online ahead of print.

Abstract

Objective: Systemic sclerosis (SSc) is an autoimmune disorder characterized by excessive fibrosis, immune dysfunction and vascular damages, in which expression of many growth factors is deregulated. CD146 was recently described as a major actor in SSc. As CD146 also exists as a circulating soluble form (sCD146) acting as a growth factor in numerous angiogenic- and inflammatory-related pathologies, we sought to identify the mechanisms underlying the generation of sCD146 and characterized the regulation and functions of the different identified variants in SSc.

Methods: To this end, we performed in vitro experiments, including RNA-seq and antibody arrays, and in vivo experiments using animal models of SSc induced by bleomycin and of hindlimb ischemia.

Results: Multiple forms of sCD146, generated by both shedding and alternative splicing of the primary transcript, were discovered. The shed form of sCD146 was generated from the cleavage of both long and short membrane isoforms of membrane CD146 through Adam10 and Tace metalloproteinases, respectively. In addition, two novel sCD146 splice variants, I5-13-sCD146 and I10-sCD146 were identified. Of interest, I5-13-sCD146 was significantly increased in sera of SSc patients, in particular in patients with pulmonary fibrosis, whereas I10-sCD146 was decreased. Further experiments revealed that shed sCD146 and I10-sCD146 displayed pro-angiogenic activity through FAK and PKCε signalling pathways, respectively, whereas I5-13-sCD146 displayed pro-fibrotic effects through wint1/β-catenin/wisp1 pathway.

Conclusion: Variants of sCD146, and in particular the novel I5-13-sCD146 splice variant, could thus constitute novel biomarkers and/or molecular targets for the diagnosis and treatment of SSc, but also of other angiogenesis- or fibrosis-related pathologies.