| Co-Investigator(Kenkyū-buntansha) |
ABE Masahiro The University of Tokushima, Institute of Health Biorsciences, Graduate School, Associate Professor (80263812)
AKAIKE Masashi The University of Tokushima, Universry Medical and Dental Hospital, Lecturer (90271080)
KIDO Shinsuke The University of Tokushima, Institute of Health Biorsciences, Graduate School, Research Associate (30437652)
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| Research Abstract |
In order to clarify the regulatory mechanisms for maintaining structural and functional homeostasis of skeletal system, as well as to elucidate the molecular mechanisms for the development of disorders caused by disruption of the skeletal homeostatic system, the present study was conducted in the following three areas :
(1) Elucidation of the mechanism of bone formation and the pathogenesis of disorders due to impaired bone formation: We have identified ΔFosB as an early response gene to mechanical load to the bone (JBMR'04). Rapidly induced ΔFosB forms heterodimers with JunD), and stimulated its target genes. IL-11 is one of the target genes, and ΔFosB /JunD heterodimer binds to a putative AP-1 site on the IL-11 gene promoter We also found that echanical stimuli enhances phosphorylation of Smadl via an activation of PECd without stimulation by BMP-2, and that phosphorylated Smadl forms complex with ΔFosB/JunD on the IL-11 gene promote fir full transcriptional activation of I-11 gene.
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) Elucidation of the pathogenic mechanisms 'for the destructive bone lesions by multiple myeloma: We have previously found that multiple myeloma enhances osteoclastic bone resorption via the production of MIP-1, a C-C chemokine. (Blood '02, '04) In the present study, we found that myeloma cells constitutively secrete sFRP-2, an inhibitor of Wnt signaling, which strongly inhibits osteoblast differentiation. In addition, TGF-β also suppressed terminal differentiation of osteoblasts. Because TGF-β is released from bone matrix by enhanced bone resorption, these results imply that there is a strong suppression ofbone formation in myeloma-bone microenvironment. If a TGF-β antagonist was added, the suppressed bone formation by myeloma cells was ameliorated, and the restoration of terminal osteoblastic differentiation markedly suppressed myeloma cell growth. These results are consistent with the notion that there is a vicious cycle in myeloma-bone microenvironment, in which myeloma cells enhance bone resorption and suppress bone formation to extend bone destruction, and myeloma cell-derived sFRP-2 as well as TGF-β released from the bone matrix by the enhanced bone resorption co-operatively suppress bone formation. Furthermore, the suppression of osteoblast maturation provides a suitable environment for myeloma cell growth which can be called "myeloma niche". Wnt inhibitors and TGF-β antagonists can be targets for the development of new therapeutic modalities.
(3) Elucidation of the pathogenic mechanisms for disorders caused by disturbances in skeletal circulation: We have previously reported that glucocorticoid excess suppresses endothelium-dependent vasodilatory responses via a reduction in NO by an enhanced production of superoxides in the endothelium (Circ Res '03). We further found that glucocorticoid excess markedly suppresses urinary NOx excretion and aortic eNOS expression. In addition, pitavastatin antagonizes the effects of glucocorticoids. These observations support our hypothesis that glucocorticoid excess causes circulatory disturbances in microvessels of the femoral neck, which plays an important role in the development of idiopathic osteonecrosis of the femoral neck. Statins with high systemic blood levels can be a new candidate for the prevention of superoxide-induced circulatory disturbances. Less
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