| Bone is a dynamic tissue that is remodeled continuously through a balanced process of bone resorption by osteoclasts and bone formation by osteoblasts. An imbalance in this process can lead to a spectrum of bone diseases for which development of new therapies is vital. The socio-economic impact of the most common skeletal disorder, osteoporosis, is high, and will increase further due to increased longevity of the population. To date, treatment of osteoporosis is mainly symptomatic by inhibiting bone resorption, thereby only preventing further bone loss. Biochemical and genetic studies in vertebrate models have revealed that bone morphogenetic proteins (BMPs) are critical for bone formation. BMPs stimulate the differentiation of mesenchymal stem cells (found in bone marrow, fat and muscle) into osteoblasts. Importantly, mutations in SOST, which encodes for sclerostin, a DAN family member of BMP antagonists, and LRP5, a Wnt co-receptor, have been linked to rare human diseases characterized by bone overgrowth. Moreover, we and others recently found that sclerostin antagonizes not only BMP-induced responses, but also inhibits Wnt signaling. This proposal seeks to elucidate new mechanisms by which extracellular cues regulate BMP and LRP5 signaling in bone formation. I plan to take a multidisciplinary approach that encompasses our long established expertise in signal transduction and mesenchymal cell biology with recently acquired innovative techniques of in vivo bioluminescence imaging, in vivo gene transfer and functional genomics. These technologies will be used to unravel new links between known signal transduction pathways and novel extracellular control mechanisms in BMP-induced osteoblast differentiation. The identification of novel mechanisms and factors critical for bone formation will not only help in the elucidation of the pathophysiological basis of diseases characterised by low or high bone mass, but may also lead to the rational design of novel therapeutic agents for the optimal treatment of patients with osteoporosis. |
