A Longitudinal Murine Model Reveals Biphasic T Cell Remodeling and Progressive Skeletal Deterioration Under Chronic High-Salt Exposure

Excessive dietary sodium intake has been associated with immune dysregulation, yet its impact on bone health and immune cell dynamics within the bone–immune axis remains poorly understood. We developed a longitudinal murine model to investigate the effects of a high-salt diet (HSD) on bone properties and immunity. Male and female C57BL/6J and Foxp3-GFP mice underwent unilateral nephrectomy and were fed either a normal salt diet (0.2% NaCl) or HSD (4% NaCl) for 20, 60, or 150 days. HSD mice exhibited a transient increase in systolic blood pressure and sustained calciuria without changes in serum calcium or PTH. Progressive impairment of femoral strength and tibial trabecular microarchitecture were observed, along with reduced cortical calcium and phosphorus content. Immune analysis revealed early splenic and bone marrow activation of effector T cells, with increased Th17 and Tc17 populations and a disrupted Th17/Treg balance at 20 days. These changes normalized by 60 days and shifted to suppressed T cell activation at 150 days, suggesting a biphasic immune response. Th17/Treg ratio was associated with bone deterioration. Notably, both sexes showed comparable physiological and immune trends. This integrative model provides a platform to dissect mechanisms linking chronic salt overload, immune dysregulation, and bone fragility.