Metrnl/Meteorin-like/IL-41 Alleviates Rheumatoid Arthritis Via PPARγ-Mediated Suppression of Inflammation, Angiogenesis, and Bone Destruction

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by synovial hyperplasia, vascular occlusion, and bone erosion. Metrnl, a novel secreted protein linked to inflammatory immune regulation, has been implicated in RA pathogenesis, but its precise mechanisms remain undefined. This study aimed to elucidate Metrnl's role in RA progression and therapeutic potential. Proteomic analysis was employed to assess Metrnl's direct effects on RA fibroblast-like synoviocytes (RA-FLS). In vitro, LPS-induced RA-FLS were treated with Metrnl to evaluate proliferation, apoptosis, cell cycle progression, and expression of inflammatory cytokines (IL-6, IL-17, TNF-α) and angiogenic factors (PDGF, VEGF) via PPARγ signaling. Collagen-induced arthritis (CIA) mice models were established to validate therapeutic efficacy, with Micro-CT and histology quantifying joint damage and inflammation. Proteomics results indicated Metrnl's multidirectional role in coordinating vascular homeostasis and immune-inflammatory network activation. Molecular biological results showed that Metrnl suppressed proliferation, promoted apoptosis, and downregulated IL-6, IL-17, TNF-α, PDGF, and VEGF through PPARγ in LPS-induced RA-FLS cells. In CIA mice, Metrnl mitigated weight loss, reduced swollen joints, and improved behavioral scores. Micro-CT confirmed attenuated cartilage/bone destruction and joint deformities, while histology revealed diminished inflammatory infiltration. Metrnl exerts anti-inflammatory and anti-angiogenic effects in RA by modulating PPARγ signaling, highlighting its dual role in suppressing synovitis and vascular remodeling. These findings propose Metrnl as a novel therapeutic target to impede RA progression, offering insights into its pathological mechanisms. Furthermore, Metrnl mitigates bone erosion and joint deformities, underscoring its broader translational potential for treating bone-related disorders.