Effects of higenamine on M1/M2 polarization and osteoclast differentiation in rheumatoid arthritis via the THBS-1/TGF-β signaling pathway

Abstract

This study investigated the therapeutic efficacy of Higenamine (HG), an extract from Monkshood, in the context of rheumatoid arthritis (RA). As an autoimmune disorder, RA is characterized by significant bone destruction primarily driven by inflammatory processes. Analysis demonstrated marked infiltration of macrophages within RA immune cells. HG inhibited iNOS, TNF-α, and IL-1β expression in M1 macrophages while enhancing IL-10, Arg-1, and MCP-1 levels in M2 macrophages. Flow cytometry confirmed HG's capacity to promote the M1 to M2 macrophage transition. Transcriptomic analysis established connections between HG, RA, osteoclast differentiation, and the THBS-1/TGF-β signaling pathway, indicating its potential to mitigate bone destruction. In vitro studies showed that HG diminished osteoclast differentiation and downregulated V-ATPase, Ctsk, TRAP, THBS-1, and TGF-β expression. In vivo, HG alleviated arthritis symptoms in collagen-induced arthritis (CIA) mice, reduced M1 macrophage accumulation, modulated THBS-1/TGF-β signaling, and lessened joint damage. Micro-CT imaging and staining corroborated the reduction in osteoclast numbers and improvement in bone homeostasis. In summary, HG presents a promising therapeutic avenue for RA and associated bone destruction through modulation of the THBS-1/TGF-β signaling pathway.