Molecular functions of Shank2 and Shank3 in bone integrity and osteoporosis

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Osteoporosis is a degenerative disease of the aging society, which is a significant burden for the health system. To increase bone quality novel drug targets favoring bone forming osteoblasts and their derived osteocytes are required. We identified novel regulators of osteoblast differentiation and function that could also lead to novel targets in osteoporosis treatment with a siRNA screen in primary osteoblasts. We found Shank family proteins (in particular Shank3) and many of their interacting factors required for osteoblast differentiation. Shank proteins localize to postsynaptic densities of excitatory synapses and are major scaffolding molecules. Shank mutations are known to be causative for neuropsychiatric disorders of the autism spectrum but in several cases also lead to short stature and facial dysmorphias indicating a Shank related misregulation of bone homeostasis in humans. Accordingly, we found that knockout mice for Shank2/3 have a dramatic osteopenia. We further detected that in undifferentiated osteoblasts Shank3 is nuclear localized and is found subsequently in cytoplasm and subcortical regions of the cell during osteoblast differentiation. We hypothesize that scaffolding proteins known from synapses have an essential role for bone formation and that during ageing their function decreases. We further hypothesize that distinct subcellular localizations of these proteins are regulating the differentiation process. We address this by the analysis of compound knockout mice, their primary cells and human osteoblasts derived from iPS cells of Phelan McDermid syndrome patients carrying mutations within Shank3 gene. Finally, we will test the hypothesis that treatment regimens used to treat Phelan McDermid patients might lead to improved bone formation. The expected results will give insights into molecular mechanisms of the bone abnormalities of Phelan McDermid syndrome patients as well as for bone disorders, such as osteoporosis in general.