Problem: Bone formation is a dynamic process and is regulated by local bone growth factors. The mechanisms of bone formation during bone remodeling remain undefined. Bone morphogenetic proteins (BMPs) are multi-functional growth factors, which regulate a variety of biological functions. The physiological role of BMP receptor signaling in bone formation and bone remodeling in adult mice is not fully understood. Purpose: We will determine the role and mechanism of BMP receptor signaling in bone formation. The underlying hypothesis is that BMP receptor signaling plays an essential role in bone formation during bone development, postnatal bone growth and adult bone remodeling. Methods: To investigate the role of the type I BMP receptors in bone formation in vivo, we have generated transgenic mice, which overexpress a dominant-negative type IB BMP receptor (dnBMPR-IB) transgene. Expression of dnBMPRIB was targeted to ostcoblasts by using a type I collagen promoter, which is specific for the osteoblast lineage. Characterization of the skeletal phenotype of these transgenic mice has shown that BMP receptor signaling, bone growth and bone formation are impaired in 1-month-old transgenic mice. Bone mineral density, bone volume and bone formation rates in these transgenic mice are significantly reduced compared with 1-month-old wild-type littermates. Our results show that BMP receptor signaling is a necessary component for postnatal bone formation in vivo. In the proposed studies, we plan to further determine the role of BMP receptor in bone formation and bone remodeling using the same adult transgenic mice. Our working hypothesis is that BMP receptor signaling plays a critical role m bone formation and bone remodeling in adult mice.
The specific aims are that we will use the Collal-dnBMPR-IB transgenic mouse model to determine 1) the role of the type 1 BMP receptor in bone formation and bone remodeling in adult mice and 2) whether the bone regulatory growth thctors IGF-I and FGF-2 or the bone anabolic agent PTH induce bone formation through activating BMP signaling. Expected Outcomes: The proposed studies will lead to a better understanding of the physiological importance of BMP signaling in bone formation during bone remodeling and likely uncover the pathological consequences for osteoporosis and other related diseases. Benefit: These studies will provide molecular insights into the mechanism involved in bone formation and bone remodeling in adult mice and define molecular targets for drug development for the treatment of osteoporosis and other bone-loss associated diseases.
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