An increasing number of indirect and correlative arguments suggest that Wnt proteins are involved in the control of bone mass. Given the large number of Wnt ligands and their broad spatial distribution, it has been difficult to address this question directly. We have postulated that the canonical Wnt signaling pathway was the signaling pathway used by Wnt proteins to affect osteoblast biology. B-catenin is an obligatory molecular node in this pathway thus affecting its expression or function should affect Wnt signaling through this pathway. By stabilizing B-catenin in osteoblasts, we have shown in mice that there is a dramatic increase in bone mass. Conversely a deletion of b-catenin in osteoblasts leads to a low bone mass phenotype. This led to the identification of three genes whose expression is regulated by the canonical Wnt signaling pathway. Those genes are the two genes encoding Type I collagen, the main constituent of the bone extracellular matrix and osteoprotegerin, a negative regulator of osteoclast differentiation. Thus, it appears that the canonical Wnt signaling pathway regulates both bone formation and bone resorption directly. We propose, based on this preliminary data, the following specific aims: 1. To demonstrate that canonical Wnt signaling in osteoblasts affects bone formation and bone resorption. 2. To identify b-catenin's transactivation partner(s) in osteoblasts and to demonstrate their involvement in the control of bone mass. 3. To elucidate the transcriptional mechanisms used by the canonical Wnt signaling pathway to regulate Type I collagen and Osteoprotegerin expression.
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