Temporal immunomodulation of CD4+ T cells by magnesium regulates osteoimmune responses in osteoporotic fracture healing.

Osteoporotic fracture healing is impaired by dysregulated immune responses characterized by a TH1/M1-biased inflammatory microenvironment. In this study, we show that extracellular magnesium ions (Mg2+) reshape this osteo-immune niche in a dose- and time-dependent manner. Briefly, Mg2+ suppresses TRPM7-mediated Ca2+ spikes and the NFATc1-driven proinflammatory axis, thereby promoting TH2/M2 responses. However, sustained excess Mg2+ attenuates TH2/M2 responses by inhibiting Orai1/CaV-dependent Ca2+ influx and reactivating TH1/M1 responses through JAK-STAT1 signaling under low-calcium stimulation condition. To therapeutically use these dynamics, we engineered a bioceramic intramedullary nail (IMN) with a precisely controlled Mg2+ release profile, delivering Mg2+ in a time-phased manner. In an ovariectomized mouse fracture model, this optimized IMN reduced TH1/M1 of early phase proinflammatory cells, enhanced TH2/M2 responses during the remodeling phase, and supported coordinated immune regulation during osteoporotic fracture healing. These findings identify time-phased Mg2+ delivery as a strategy to mitigate excessive inflammatory responses through temporal immunomodulation of CD4+ T cells during osteoporotic bone healing.