Temporal immunomodulation of CD4T cells by magnesium regulates osteoimmune responses in osteoporotic fracture healing

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

Osteoporotic fracture healing is impaired by dysregulated immune responses characterized by a T1/M1-biased inflammatory microenvironment. In this study, we show that extracellular magnesium ions (Mg) reshape this osteo-immune niche in a dose- and time-dependent manner. Briefly, Mgsuppresses TRPM7-mediated Caspikes and the NFATc1-driven proinflammatory axis, thereby promoting T2/M2 responses. However, sustained excess Mgattenuates T2/M2 responses by inhibiting Orai1/CaV-dependent Cainflux and reactivating T1/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 Mgrelease profile, delivering Mgin a time-phased manner. In an ovariectomized mouse fracture model, this optimized IMN reduced T1/M1 of early phase proinflammatory cells, enhanced T2/M2 responses during the remodeling phase, and supported coordinated immune regulation during osteoporotic fracture healing. These findings identify time-phased Mgdelivery as a strategy to mitigate excessive inflammatory responses through temporal immunomodulation of CD4T cells during osteoporotic bone healing. Time-phased magnesium delivery modulates CD4T cell immunity to mitigate inflammation during osteoporotic fracture healing. teaser