A human rheumatoid arthritis bone–cartilage interface organoid recapitulates bone, cartilage, and immune interactions

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, cartilage degradation, and bone erosion. Fibroblast-like synoviocytes (FLS) play a central role in perpetuating joint damage, yet current therapies inadequately address FLS-driven pathology. Existing preclinical models, including murine collagen-induced arthritis and conventional in vitro cultures, lack the complexity to fully recapitulate human disease mechanisms. Here, we describe the development of a three-dimensional (3D) RA bone–cartilage interface (BCI) organoid that integrates primary human mesenchymal stem cell-derived osteoblasts, peripheral blood mononuclear cell-derived osteoclasts and lymphocytes, immortalized human chondrocyte spheroids, and the RA synovial fibroblast cell line SW982. Exposure to TNF-α, IL-1β, and TGF-β induced pro-inflammatory cytokines, matrix-degrading enzymes, and increased fibrotic gene expression, accompanied by histological and microCT evidence of bone dysregulation. Therapeutic testing showed that methotrexate, etanercept, and tofacitinib reduced cytokine production and pro-inflammatory gene expression but had limited impact on profibrotic gene expression. This modular, human-derived RA BCI organoid reproduced key features of RA pathogenesis that can enable direct assessment of therapeutic mechanisms at the bone–cartilage–synovial interface. The RA BCI organoid provides a physiologically relevant, scalable platform for preclinical drug discovery and for identifying combination strategies that address both the inflammatory and fibrotic components of RA pathology.