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), while modulating inflammatory and cartilage extracellular matrix (ECM)-degrading mediators in human articular chondrocytes from OA patients (OA-hAC). BM-hMSC from healthy donors were cultured in pellet under chondrogenic conditions with or without VIP up to 21 days. The production of type II collagen (COL2A1), and the expression of chondrogenic ( SOX9, COL2A1 , and ACAN ) and hypertrophy ( RUNX2 , COL10A1 , and MMP13 ) genes were assessed at different time points. VIP increased the expression of the chondrogenic genes on day 12 of differentiation, compared to day 21 in untreated BM-hMSC cells, advancing chondrogenesis. Furthermore, OA-hAC were dedifferentiated in monolayer followed by redifferentiation in alginate microbeads and treated with fibronectin fragments (Fn-fs) in presence and absence of VIP. We analysed VIP effects on cell proliferation, glycosaminoglycans (GAG) production, and modulation of components of the complement system (C1R and C3) and matrix metalloproteinases (MMP1, MMP3, MMP9, and MMP13). VIP enhanced cell proliferation, increased GAG deposition, and reduced production of complement factor C1R, and metalloproteinases MMP1 and MMP13 in OA-hAC. This study highlights the potential of VIP in modulating chondrogenesis, inflammation, and cartilage degradation supporting the development of future VIP-based therapies to slow OA progression.