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Chisato Miyaura

Publications and source records attributed to Chisato Miyaura.

7 recordsLinked to original sources
PubMed2004

Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification.

Collagenase-3 (MMP13), a member of the matrix metalloproteinase (MMP) family of neutral endopeptidases, is expressed in the skeleton during embryonic development and is highly overexpressed in human carcinomas and in chondrocytes and synovial cells in rheumatoid arthritis and osteoarthritis. To determine the functional roles of Mmp13, we generated Mmp13-null mice that showed profound defects in growth plate cartilage with markedly increased hypertrophic domains as well as delay in endochondral ossification and formation and vascularization of primary ossification centers. Absence of Mmp13 resulted in significant interstitial collagen accumulation due, in part, to the lack of appropriate collagenase-mediated cleavage that normally occurs in growth plates and primary ossification centers. Cartilaginous growth plate abnormalities persisted in adult mice and phenocopied defects observed in human hereditary chondrodysplasias. Our findings demonstrate a unique role of Mmp13 in skeletal development.

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PubMed2004

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PubMed2003

An essential role of cytosolic phospholipase A2alpha in prostaglandin E2-mediated bone resorption associated with inflammation.

Prostaglandin E (PGE)2 produced by osteoblasts acts as a potent stimulator of bone resorption. Inflammatory bone loss is accompanied by osteoclast formation induced by bone-resorbing cytokines, but the mechanism of PGE2 production and bone resorption in vivo is not fully understood. Using cytosolic phospholipase A2alpha (cPLA2alpha)-null mice, we examined the role of cPLA2alpha in PGE2 synthesis and bone resorption. In bone marrow cultures, interleukin (IL)-1 markedly stimulated PGE2 production and osteoclast formation in wild-type mice, but not in cPLA2alpha-null mice. Osteoblastic bone marrow stromal cells induced the expression of cyclooxygenase (COX)-2 and membrane-bound PGE2 synthase (mPGES) in response to IL-1 and lipopolysaccharide (LPS) to produce PGE2. Osteoblastic stromal cells collected from cPLA2alpha-null mice also induced the expression of COX-2 and mPGES by IL-1 and LPS, but could not produce PGE2 due to the lack of arachidonic acid release. LPS administration to wild-type mice reduced femoral bone mineral density by increased bone resorption. In cPLA2alpha-null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2alpha plays a key role in PGE production by osteoblasts and in osteoclastic bone resorption, and suggest a new approach to inflammatory bone disease by inhibiting cPLA2alpha.

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PubMed2003

Role of prostaglandin E produced by osteoblasts in osteolysis due to bone metastasis.

Prostaglandin E2 (PGE2) is produced in bone mainly by osteoblasts and stimulates bone resorption. Osteolytic bone metastasis of cancers is accompanied by bone resorption. In this study, we examined the roles of PGE2 in osteolysis due to bone metastasis of breast cancer. Injection of human breast cancer cells, MDA-MB-231 (MDA-231), into nude mice causes severe osteolysis in the femur and tibia. The expression of cyclo-oxygenase-2 (COX-2) and the receptor activator of NF-kappaB ligand (RANKL), a key molecule in osteoclast differentiation, mRNAs was markedly elevated in bone with metastasis. When MDA-231 cells were cocultured with mouse calvaria, COX-2-induced PGE2 production and bone resorption progressed. The contact with MDA-231 cells could induce the expression of COX-2 and RANKL in osteoblasts by mechanisms involving MAP kinase and NF-kappaB. The blockage of PGE2 signal by indomethacin and EP4 antagonist abrogated the osteoclast formation induced by the breast cancer cells. Here, we show a PGE-dependent mechanism of osteolysis due to bone metastasis.

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PubMed2002

Dietary bisphenol A prevents ovarian degeneration and bone loss in female mice lacking the aromatase gene (Cyp19 ).

We previously generated mice lacking aromatase activity by targeted disruption of Cyp19 (ArKO mice), and reported phenotypes of the female mice, showing hemorrhage formation and follicular depletion in the ovary, diminution in uterine size, and bone loss. In the present study, we examined the influence of dietary bisphenol A (BPA), a monomer used for the production of polycarbonate and known to have estrogenic activity, on these phenotypes of the ArKO mice. When ArKO mice were fed chow diets supplemented with 0.1% or 1% (w/w) BPA for 5 months, they were protected from ovarian degeneration, uterine diminution and bone loss in a dose-dependent manner. Northern blot analyses of ovarian RNA of ArKO mice showed differences in the expression levels of insulin-like growth factor (IGF)-I, IGF-I receptor, growth differentiation factor 9 and bone morphogenetic protein 15 as compared with those in the ovaries of wild-type mice. The differences in the expression levels were restored by dietary BPA. In the ArKO uteri, expression of progesterone receptor and vascular endothelial growth factor mRNAs was diminished, and was restored by BPA to the levels in wild-type mice. In contrast, BPA had little effect on the ovarian, uterine and skeletal structures of wild-type mice. In conclusion, estrogenic effects of BPA on the reproductive tract as well as skeletal tissue were evident in adult female ArKO mice. These results suggest that the ArKO mouse is an animal model suitable for studying effects of estrogenic chemicals as well as estrogen in vivo.

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