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 T _H 1/M1-biased inflammatory microenvironment. In this study, we show that extracellular magnesium ions (Mg ²⁺ ) reshape this osteo-immune niche in a dose- and time-dependent manner. Briefly, Mg ²⁺ suppresses TRPM7-mediated Ca ²⁺ spikes and the NFATc1-driven proinflammatory axis, thereby promoting T _H 2/M2 responses. However, sustained excess Mg ²⁺ attenuates T _H 2/M2 responses by inhibiting Orai1/CaV-dependent Ca ²⁺ influx and reactivating T _H 1/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 Mg ²⁺ release profile, delivering Mg ²⁺ in a time-phased manner. In an ovariectomized mouse fracture model, this optimized IMN reduced T _H 1/M1 of early phase proinflammatory cells, enhanced T _H 2/M2 responses during the remodeling phase, and supported coordinated immune regulation during osteoporotic fracture healing. These findings identify time-phased Mg ²⁺ delivery as a strategy to mitigate excessive inflammatory responses through temporal immunomodulation of CD4 ⁺ T cells during osteoporotic bone healing.