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

Abstract

Osteoporotic fracture healing is impaired by dysregulated immune responses characterized by a T_H1/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 T_H2/M2 responses. However, sustained excess Mg²⁺ attenuates T_H2/M2 responses by inhibiting Orai1/CaV-dependent Ca²⁺ influx and reactivating T_H1/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 T_H1/M1 of early phase proinflammatory cells, enhanced T_H2/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.