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Takeshi Miyamoto 대한내분비학회 2006 Endocrinology and metabolism Vol.21 No.5
Osteoclasts are bone-resorbing multinuclear cells derived from hematopoietic stem cells or monocyte/ macrophage lineage cells. Recent identification of RANK/RANKL has provided new insights into the osteoclast differentiation pathway, enabling us to generate osteoclasts without stromal cells, which support osteoclastogenesis. In order to establish a pure osteoclast culture system, we identified the osteoclast precursor cell (c-Kit+c-Fms+RANK- cell), which is a common precursor cell of osteoclasts, macrophages and dendritic cells. Macrophages are induced by M-CSF alone, while a sequential stimulation of M-CSF followed by RANKL effectively induces osteoclast formation. Furthermore, dendritic cells are induced by GM-CSF or GM-CSF plus RANKL. Therefore, we were able to generate pure osteoclasts, macrophages or dendritic cells from the common precursor cell using specific combinations of cytokines. Using this culture system, we found that an adherent condition is critical for osteoclast differentiation. We also found that the osteoclastogenesis induced by M-CSF plus RANKL is completely inhibited by GM-CSF, and that these cells differentiate into a dendritic cell lineage. The osteoclast multinucleation is believed to be induced by cell-cell fusion of mononuclear osteoclasts. Although various molecules have been implicated in the cell-cell fusion of osteoclasts or macrophages, the essential molecule for cell fusion has not been identified. We identified that the dendritic cell-specific transmembrane protein (DC-STAMP) was an essential cell-cell fusion molecule for osteoclasts and foreign body giant cells, and that DC-STAMP deficient mice have no multinuclear osteoclasts. Here I review the osteoclast development from immature precursor cells to multinuclear osteoclasts. (J Kor Endocrinol Soc 21:347~351, 2006)
Yoshiaki Kubota,Masaaki Miyamoto,Gen Takagi,Takeshi Ikeda,Sonoko Kirinoki-Ichikawa,Kotoko Tanaka,Kyoichi Mizuno 대한의학회 2012 Journal of Korean medical science Vol.27 No.11
The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flowmediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 ± 1.59 vs 5.12 ± 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 ± 11.3vs 14.3 ± 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).
Furukawa Mitsuru,Okuyama Kunimasa,Ninomiya Ken,Yato Yoshiyuki,Miyamoto Takeshi,Nakamura Masaya,Matsumoto Morio 대한척추외과학회 2022 Asian Spine Journal Vol.16 No.1
Study Design: Cross-sectional study.Purpose: To examine whether the number of continuous vertebral bone bridges and bone mineral density (BMD) influence the fracture risk in diffuse idiopathic skeletal hyperostosis (DISH) patients.Overview of Literature: Bone bridges connecting through the intervertebral body in DISH create long lever arms that can increase the risk of fractures from minor trauma. DISH patients have a BMD that is higher than or comparable to those of age-matched healthy subjects.Methods: We examined the computed tomography scans from the thoracic vertebra to the sacrum used to diagnose DISH in 140 patients (98 men and 42 women; average age, 78.6 years). We compared patients who did (n=52) and did not have (n=88) fractures at the continuous vertebral bodies fused by bone bridges. The relationship between the vertebral fractures and the maximum number of vertebrae that are bony cross-linked with contiguous adjacent vertebrae (max VB) from the thoracic vertebra to the sacrum or from the lumbar vertebra to the sacrum and proximal femur BMD were analyzed using a logistic regression model.Results: We found that after adjusting for the confounding factors, higher max VB, both from the thoracic vertebrae to the sacrum and the lumbar vertebrae to the sacrum, was associated with a higher risk of vertebral fractures. This difference was statistically significant. The risk was higher when only the lumbar vertebrae to the sacrum was considered (thoracic vertebrae to the sacrum: odds ratio, 1.21; p<0.05; lumbar vertebrae to the sacrum: odds ratio, 2.78; p<0.01). Moreover, low proximal femur BMD in DISH patients raises the fracture risk (odds ratio, 0.47; p<0.01).Conclusions: Many continuous vertebral bone bridges, especially those that extend to the lumbar spine and low proximal femur BMD, are risk factors for fracture in DISH patients.
Lee, Seoung-Hoon,Rho, Jaerang,Jeong, Daewon,Sul, Jai-Yoon,Kim, Taesoo,Kim, Nacksung,Kang, Ju-Seob,Miyamoto, Takeshi,Suda, Toshio,Lee, Sun-Kyeong,Pignolo, Robert J,Koczon-Jaremko, Boguslawa,Lorenzo, Jo Nature Publishing Group 2006 Nature medicine Vol.12 No.12
Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H<SUP>+</SUP>) ATPase (v-ATPase) V<SUB>0</SUB> domain (Atp6v0d2). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.
Cooperative interaction of Angiopoietin-like proteins 1 and 2 in zebrafish vascular development.
Kubota, Yoshiaki,Oike, Yuichi,Satoh, Shinya,Tabata, Yoko,Niikura, Yuichi,Morisada, Tohru,Akao, Masaki,Urano, Takashi,Ito, Yasuhiro,Miyamoto, Takeshi,Nagai, Norihiro,Koh, Gou Young,Watanabe, Sumiko,Sud National Academy of Sciences 2005 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.102 No.38
<P>Angiopoietin-like protein (Angptl) 1 and Angptl2, which are considered orphan ligands, are highly homologous, particularly in the fibrinogen-like domain containing the putative receptor binding site. This similarity suggests potentially cooperative functions between the two proteins. In this report, the function of Angptl1 and Angptl2 is analyzed by using morpholino antisense technology in zebrafish. Knockdown of both Angptl1 and Angptl2 produced severe vascular defects due to increased apoptosis of endothelial cells at the sprouting stage. In vitro studies showed that Angptl1 and Angptl2 have antiapoptotic activities through the phosphatidylinositol 3-kinase/Akt pathway, and coinjection of constitutively active Akt/protein kinase B mRNA rescued impaired vascular development seen in double knockdown embryos. These results provide a physiological demonstration of the cooperative interaction of Angptl1 and Angptl2 in endothelial cells through phosphatidylinositol 3-kinase/Akt mediated antiapoptotic activities.</P>