title: Zinc stimulates osteoblastogenesis and suppresses osteoclastogenesis by antagonizing NF-κB activation.
abstract: Zinc is essential for numerous biochemical pathways in the body and is known to significantly affect the skeleton. Zinc has a profound effect on bone turnover promoting bone formation and mineralization, but paradoxically inhibiting osteoclastic bone breakdown (resorption). How zinc regulates these disparate effects on bone cells, however, is poorly understood. We recently characterized several pharmacological and nutritional factors that are likewise endowed with the capacity to promote bone formation and suppress bone resorption and demonstrated that a common centralized mechanism for achieving such actions is through suppression of NF-κB activation. NF-κB is a pathway required for osteoclastogenesis, but suppresses osteoblast differentiation. In this study, we investigated the actions of zinc on NF-κB activation in osteoclast and osteoblast precursors in vitro. Our data show that zinc suppressed osteoclast differentiation and promoted osteoblast mineralization and did indeed act as a potent NF-κB activation antagonist in both osteoclast and osteoblast precursors. Importantly, zinc antagonized NF-κB activation driven by TNFα, a potent inflammatory mediator or bone resorption and suppressor of bone formation in vitro and in vivo. Zinc further alleviated the suppressive effect of TNFα on Smad activation induced by TGFβ and BMP2, cytokines that play critical roles in osteoblast commitment, differentiation, and recruitment to sites of bone remodeling. In conclusion, our data reveal for the first time that a major mechanism by which zinc promotes osteoblastogenesis and suppresses osteoclastogenesis may center on the antagonism of NF-κB activation.
authors.affiliation: Division of Endocrinology and Metabolism and Lipids, Department of Medicine, 101 Woodruff Circle, 1329 WMRB, Atlanta, GA 30322, USA. yamamasa1155@yahoo.co.jp
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: M Neale
authors.initials: MN
authors.lastname: Weitzmann
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D017930:Genes, Reporter; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019287:Zinc Sulfate / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D019287:Zinc Sulfate; D008156:Luciferases