Negative regulation of BMP/Smad signaling by Tob in osteoblasts

Bone morphogenetic protein (BMP) controls osteoblast proliferation and diff erentiation through Smad proteins. Here we show that Tob, a member of the e merging family of antiproliferative proteins, is a negative regulator of BM P/Smad signaling in osteoblasts. Mice carrying a targeted deletion of the t ob gene have a greater bone mass resulting from increased numbers of osteob lasts. Orthotopic bone formation in response to BMP2 is elevated in tob-def icient mice. Overproduction of Tob represses BMP2-induced, Smad-mediated tr anscriptional activation. Finally, Tob associates with receptor-regulated S mads (Smad1, 5, and 8) and colocalizes with these Smads in the nuclear bodi es upon BMP2 stimulation. The results indicate that Tob negatively regulate s osteoblast proliferation and differentiation by suppressing the activity of the receptor-regulated Smad proteins.