The loss of Smad3 results in a lower rate of bone formation and osteopeniathrough dysregulation of osteoblast differentiation and apoptosis

Smad3 is a well-characterized intracellular effector of the transforming gr owth factor beta (TGF-beta) signaling pathway and was implicated recently i n the potentiation of vitamin D receptor (VDR)-mediated signaling. Given th at both TGF-beta and vitamin D are important regulators of bone remodeling, it is expected that Smad3 plays an integral role in normal maintenance of bone. However, the exact mechanisms by which Smad3 functions in bone remode ling are unknown. Here, we show that mice with targeted deletion of Smad3 a re osteopenic with less cortical and cancellous; bone compared with wild-ty pe littermates. Decreases in bone mineral density (BMD) in Smad3 null mice reflect the inability of osteoblasts to balance osteoclast activity, althou gh osteoclast numbers are normal and vitamin D mediated serum calcium homeo stasis is maintained. The osteopenia of Smad3 null mice is attributed to a decreased rate of bone formation associated with increased osteocyte number and apoptosis. These findings are supported by studies with isolated prima ry osteoblasts that show TGF-beta can no longer inhibit the differentiation of osteoblasts in the absence of Smad3; yet, TGF-beta -stimulated prolifer ation remains intact. Together these data support a model that a loss of Sm ad3 increases the osteocyte fate of the osteoblast and decreases the durati on of osteoblast function by shortening lifespan, ultimately resulting in o steopenia.