MiR-21 promotes osteogenic transformation in ankylosing spondylitis fibroblasts and modulates bone metabolism in a murine arthritis model potentially involving the MAPK NF-κB pathway.

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by pathological bone formation. Synovial fibroblasts are key effector cells in this process, and their dysregulated osteogenic transformation is a critical event. The role of microRNA‑21 (miR‑21) and the mitogen-activated protein kinase (MAPK)/nuclear factor kappa-B‌ (NF‑κB) pathway in inflammation and bone metabolism is established; however, whether miR‑21 promotes AS fibroblast osteogenesis specifically via this pathway is unclear. This study aimed to determine whether miR-21 promotes osteogenic transformation and bone metabolism in AS synovial fibroblasts via the MAPK/NF‑κB pathway. Gain‑ and loss‑of‑function of miR‑21 was achieved in AS synovial fibroblasts by transfection with miR‑21 mimic or inhibitor, followed by evaluation of proliferation, osteogenic differentiation (alkaline phosphatase/alizarin red staining), and MAPK/NF‑κB pathway activity. In a proteoglycan‑induced arthritis (PGIA) mouse model, miR‑21 was inhibited by Antagomir to assess spinal pathology, serum inflammatory cytokines, bone metabolism markers, and MAPK/NF‑κB signaling. In vitro, miR-21 overexpression significantly promoted fibroblast proliferation, osteogenic differentiation, and activated the MAPK/NF-κB pathway, while its inhibition had opposite effects. In vivo, AntagomiR-21 treatment ameliorated spinal cartilage damage, reduced serum levels of inflammatory cytokines (IL-6, IL-1β, TNF-α) and bone metabolism markers (RANKL/OPG), and suppressed the MAPK/NF-κB pathway in PGIA mice. Our findings suggest that miR-21 is associated with synovial fibroblast proliferation and osteogenesis, potentially via the MAPK/NF‑κB pathway, and that its inhibition alleviates inflammatory arthritis phenotypes in mice. These observations indicate that miR‑21 may warrant further investigation as a candidate target in AS-related inflammation and cartilage pathology.