Combination of magnesium ions and vitamin C alleviates synovitis and osteophyte formation in osteoarthritis of mice

Introduction: We previously demonstrated that magnesium ions (Mg²⁺) was a novel therapeutic alternative for osteoarthritis (OA) through promoting the hypoxia inducible factor-1α (HIF-1α)-mediated cartilage matrix synthesis. However, oxidative stress can inhibit the expression of HIF-1α, amplify the inflammation that potentially impairs the therapeutic efficacy of Mg²⁺ in OA. Vitamin (VC), a potent antioxidant, may enhance the efficacy of Mg²⁺ in OA treatment. This study aims to investigate the efficacy of combination of Mg²⁺ and VC on alleviating joint destruction and pain in OA. Material and methods: Anterior cruciate ligament transection with partial medial meniscectomy induced mice OA model were randomly received intra-articular injection of either saline, MgCl₂ (0.5 mol/L), VC (3 mg/ml) or MgCl₂ (0.5 mol/L) plus VC (3 mg/ml) at week 2 post-operation, twice weekly, for 2 weeks. Joint pain and pathological changes were assessed by gait analysis, histology, western blotting and micro-CT. Results: Mg²⁺ and VC showed additive effects to significantly alleviate the joint destruction and pain. The efficacy of this combined therapy could sustain for 3 months after the last injection. We demonstrated that VC enhanced the promotive effect of Mg²⁺ on HIF-1α expression in cartilage. Additionally, combination of Mg²⁺ and VC markedly promoted the M2 polarization of macrophages in synovium. Furthermore, combination of Mg²⁺ and VC inhibited osteophyte formation and expressions of pain-related neuropeptides. Conclusions: Intra-articular administration of Mg²⁺ and VC additively alleviates joint destruction and pain in OA. Our current formulation may be a cost-effective alternative treatment for OA.