Administration of zinc inhibits osteoclastogenesis through the suppression of RANK expression in bone

Zinc (Zn) has been known to inhibit osteoclastic bone resorption and stimulate osteoblastic bone formation. However, the mechanisms responsible for these effects have not been well characterized in vivo. Here, the effects of a dietary administration of Zn on osteoclastogenesis and osteoblastogenesis were investigated in Zn-adequate rats. The administration of Zn decreased the activities of bone tartrate-resistant acid phosphatase (TRAP) and cathepsin K, without affecting the serum osteocalcin level. Histological analysis showed a decrease in the number of osteoclasts with a normal number of osteoblasts in the metaphysis of the proximal tibia. The mRNA levels of receptor for activation of NF-κB (RANK), c-fos, c-jun, TRAP and cathepsin K were significantly decreased, although those of RANK ligand, macrophage colony-stimulating factor and c-fms were unaltered. The gene expression of bone morphogenic protein-2, Runx2, Dlx5, osterix, alkaline phosphatase, osteocalcin and collagen was not affected. The level of the RANK protein decreased, while the levels of the Runx2 and β-catenin proteins were unchanged. Further, the osteoclastic differentiation of precursor cells in vitro was suppressed. The suppressed osteoclastogenesis was associated with decreased levels of reactive oxygen species, extracellular signal-regulated kinase (ERK) activation and RANK expression. A lower lipid peroxide level and a higher glutathione level were also observed. These results suggested that Zn-administration did not affect osteoblastogenesis but decreased osteoclastogenesis by inhibiting RANK expression through suppression of the production of reactive oxygen species and ERK activation in Zn-adequate rats.