High-dose Vitamin D Supplementation Attenuates NLRP3 Inflammasome-mediated Oxidative Stress in a Novel Murine Model of Comorbid Asthma and Osteoporosis Induced by Vitamin D Deficiency

While vitamin D deficiency (VDD) is implicated in both asthma and osteoporosis, the synergistic mechanisms linking these comorbidities remain unexplored. This study introduces a novel murine model of VDD-induced concurrent asthma and osteoporosis, uniquely addressing their bidirectional exacerbation through NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and oxidative stress crosstalk. Female C57 mice were stratified into control, bronchial asthma (BA), osteoporosis (OP), BA+OP, and VDD+BA+OP groups, with therapeutic evaluation of low-dose (LD) and high-dose (HD) vitamin D supplementation. Unlike prior studies, our results demonstrate that VDD amplifies airway resistance and bone microstructural deterioration via NLRP3-driven pyroptosis (elevated cleaved caspase-1, N-terminal gasdermin D and suppressed antioxidant defenses (reduced glutathione peroxidase and catalase, and elevated malondialdehyde). Critically, HD supplementation reversed these effects more robustly than LD, restoring pulmonary compliance, trabecular integrity (bone volume/total volume: 0.0298 vs 0.0356 in VDD+BA+OP), and suppressing inflammasome activity. Mechanistically, we identify a feedforward loop wherein VDD-induced oxidative stress primes NLRP3 activation, which further exacerbates inflammation and bone resorption-a pathway uniquely mitigated by HD vitamin D. These findings provide the first evidence of HD vitamin D's dual therapeutic efficacy in comorbid asthma-osteoporosis, offering a paradigm shift in targeting the NLRP3/oxidative stress axis for managing multifactorial inflammatory diseases.