Vasoactive intestinal peptide advances chondrogenesis and modulates pathogenic mediators in human osteoarthritis.

Current therapies for osteoarthritis (OA) focus on symptom management, rather than halting disease progression. Vasoactive intestinal peptide (VIP) has shown promising effects in musculoskeletal diseases, preserving joint integrity and modulating inflammation. This study investigates the potential of VIP to promote chondrogenic differentiation of human bone marrow mesenchymal stem cells (BM-hMSC) and to modulate inflammatory and cartilage extracellular matrix (ECM)-degrading mediators in human osteoarthritis articular chondrocytes (OA-hAC). BM-hMSC from healthy donors were cultured in 3D pellet sytems under chondrogenic conditions, with or without VIP, for up to 21 days. Chondrogenesis was evaluated through the expression of key markers (SOX9, COL2A1, and ACAN), hypertrophic markers (RUNX2, COL10A1, and MMP13), and glycosaminoglycans (GAG). VIP accelerated chondrogenic differentiation by inducing earlier mRNA and protein expression of chondrogenic markers and enhancing GAG production. In parallel, OA-hAC were cultured in 3D alginate microbeads and stimulated with fibronectin fragments (Fn-fs) in the presence and absence of VIP. We analysed the effects of VIP on cell proliferation, GAG production, and the modulation of complement components (C1R and C3) and matrix metalloproteinases (MMP1, MMP3, MMP9, and MMP13). VIP increased cell proliferation and GAG deposition while significantly reducing the production of complement component C1R and matrix metalloproteinases MMP1 and MMP13. Overall, these findings demonstrate that VIP advances chondrogenesis and exerts anti-inflammatory and anti-catabolic effects in 3D culture models. This study highlights the potential of VIP as a therapeutic agent and supports the combination of MSC-based approaches with VIP as a promising strategy to enhance cartilage regeneration and slow OA progression.