Endogenous TNFα lowers maximum peak bone mass and inhibits osteoblastic smad activation through NF-κB

Endogenous TNF alpha prevents the attainment of maximum achievable peak bone mass in vivo. In vitro, TNF alpha suppresses BMP-2- and TGF beta-mediated Smad activation through induction of NF-kappa B. Consistently, pharmacological suppression of NF-kappa B augments osteoblast differentiation and mineralization in vitro. Introduction: Osteoporosis is a major health threat. Traditional therapeutic strategies have centered on anti-catabolic drugs that block bone resorption. Recently focus; has shifted to anabolic agents that actively rebuild lost bone mass. Future strategies may involve elevating peak bone mass to delay osteoporosis development. Recent in vitro studies show that TNF alpha represses osteoblast differentiation and mineralization; however, the mechanisms are poorly understood and the impact of basal TNF alpha concentrations on the acquisition of peak bone mass in vivo is unknown. Materials and Methods: We examined peak BMD, bone volume, and bone turnover makers in mice deficient in TNF alpha or its receptors. We further examined the effect of TNF alpha on Smad-induced signaling by TGF beta and BMP-2 in vitro using a Smad responsive reporter. The effect of TNF alpha-induced NF-kappa B signaling on Smad signaling and on in vitro osteoblast mineralization was examined using specific NF-kappa B inhibitors and activators, and effects of TNFa-induced NF-kappa B signaling on BMP-2-induced Runx2 mRNA were examined using RT-PCR. Results: Mice null for TNF alpha or its p55 receptor had significantly increased peak bone mass, resulting exclusively from elevated bone formation. In vitro, TNF alpha potently suppressed Smad signaling induced by TGF beta and BMP-2, downregulated BMP-2-mediated Runx2 expression., and inhibited mineralization of osteoblasts. These effects were mimicked by overexpression of NF-kappa B and prevented by pharmacological NF-kappa B suppression. Conclusions: Our data suggest that TNF alpha and NF-kappa B antagonists may represent novel anabolic agents for the maximization of peak basal bone mass and/or the amelioration of pathological bone loss.