Zinc antagonizes cadmium-induced osteoporosis in mice by inhibiting Cd2+ deposition, enhancing antioxidant capacity and correcting bone metabolic disorders

Chronic cadmium (Cd) exposure is a recognized risk factor for osteoporosis. Zinc (Zn) plays crucial roles in bone metabolism, yet intervention roles of Zn²⁺ against Cd-induced osteoporosis are incompletely understood. The aim of this study was to investigate the antagonistic effect of Zn²⁺ on Cd-induced osteoporosis and expose the underlying mechanism. Osteoporosis in mice was induced by exposing to low (5 mg/L) or high (50 mg/L) concentrations of Cd²⁺ for 12 months, and a Zn intervention model was established by adding 30 mg/L Zn²⁺ to the Cd-exposed mice. Results showed that Zn²⁺ addition effectively alleviated pathological damage, mineral loss and destruction of trabecular structure of bones in osteoporotic mice caused by Cd. Cd exposure resulted in dose-dependent increases in serum calcium ion(Ca²⁺) and phosphorus ion (P³⁺) levels, while Zn²⁺ addition significantly counteracted against the Cd-induced calcium and phosphorus metabolic disorders in serum. Zn²⁺ addition exhibited significant antagonism against Cd-induced abnormal serum bone metabolism indicators by suppressing elevated bone resorption markers (TRACP-5b and BALP), and restoring osteogenic markers of BGP, ALP, RUNX2 and OPG expressions in osteoporotic mice caused by Cd. Zn²⁺ supplement rescued Cd-impaired osteogenic differentiation and mineralization. In addition, Zn²⁺ significantly reduced Cd²⁺ deposition in bone tissue, while elevating bone Zn²⁺ levels in Cd-exposed mice. Importantly, Zn²⁺ supplement significantly enhanced metallothionein (MT) and metal regulatory transcription factor-1 (MTF-1) expressions in bone of Cd-exposed mice. Furthermore, Zn²⁺ addition inhibited osteoclast hyperactivation by reducing the number of TRAP-positive cells and suppressing the expression of osteoclast-related genes (Cathepsin K, MMP-9, OSCAR, TRAP, and RANKL) in Cd-exposed mice. Collectively, Zn²⁺ addition exhibited notable antagonistic effects against Cd-induced osteoporosis in mice, and the mechanism of action was partly achieved by inhibiting the deposition of Cd²⁺ in bone tissue, enhancing antioxidant capacity in bone, and correcting bone metabolic imbalance caused by Cd.