Research for the elucidation of bone formation signals applied to the development of bone-forming agents

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Parathyroid hormone (PTH) exerts anabolic action on bone and the canonical Wnt as well as TGFβ-smad3 pathways are important in bone formation. We demonstrated that PTH activates Wnt-β-catenin signal through Smad3, resulting in the inhibition of osteoblast apoptosis. Next, we examined how Smad3 affects osteoblast at the different differentiation stage. Smad3 inhibits osteoblastic commitment of multipotential mesenchymal cells, while it promotes early stage of differentiation and maturation of osteoblastic committed cells. On the other hand, statins possess pleiotropic effects and among them, their bone anabolic action's have been noted. We examined whether statins would affect TGF-β-Smad3 pathway and apoptosis in osteoblasts. Pitavastatin suppressed osteoblast apoptosis through Smad3.Glucocorticoid (GC)-induced osteoporosis (GIO) is caused by the suppression of osteogenesis, and effectively treated by bisphosphonate (BP) and PTH. However, the exact mechanisms by which GC suppresses oste … More oblast functions, or BP and PTH alleviate GIO are still unclear. The present study indicates that GC inhibits osteoblastic differentiation by suppressing BMP and Wnt signaling pathways through enhanced expressions of their antagonists, follistatin/Dan and sFRP, respectively, and that the effectiveness of BP and PTH may be partly explained by the cancellation of these processes. Our recent study indicates that adiponectin stimulates the proliferation, differentiation and mineralization of osteoblasts via the AdipoR1 and AMP kinase (AMPK) signaling pathway in autocrine and/or paracrine fashions. Both AMPK and Rho-kinase (ROK) are known to modulate mevalonate pathway. Inhibition of HMG-CoA reductase by AICAR and that of ROK by hydroxyfasudil stimulated the differentiation and mineralization of osteoblasts, indicating that agents modulating the mevalonate pathway might be candidate drugs that promote bone formation. Strontium stimulates osteoblast differentiation and mineralization via the activation of Ca-sensing receptor (CaSR). The present findings provide the rationale for the therapeutic usefulness of PTH,BP, statin as well as CaSR agonist as bone-forming agents for senile osteoporosis Less