VEGF-C silencing unlocks therapeutic synergy between MSCs and dexamethasone for osteoarthritis repair.

Glucocorticoids are widely used to relieve pain and inflammation in osteoarthritis (OA), yet repeated or high-dose exposure is associated with cartilage toxicity and systemic adverse effects. Mesenchymal stromal cell (MSC)-based therapies have emerged as a regenerative strategy. Whether clinically relevant, low-dose corticosteroid exposure can be integrated with MSC-based therapies remains unclear. Here, using a deliberately low-dose dexamethasone (DEX) regimen, we show that DEX preserves MSC viability, stemness, and anti-inflammatory polarization under pro-inflammatory stress in vitro, yet unexpectedly fails to enhance MSC-mediated joint repair in vivo in a papain-induced early-stage OA model. Mechanistically, DEX induces robust VEGF-C expression in MSCs, particularly under inflammatory conditions, and consequently promotes CD8+ T-cell accumulation and activation in the synovium. Notably, silencing of VEGF-C in MSCs restored therapeutic synergy between DEX and MSCs, resulting in improved cartilage integrity, enhanced proteoglycan preservation, and reduced synovial inflammation in a papain-induced OA model. This cooperative effect is further maintained in a surgically induced, mechanically driven late-stage OA model. Our findings establish VEGF-C silencing as a strategy to improve low-dose DEX-MSC therapeutic cooperation in OA.