生体内造血機構におけるMT1-MMPの機能解析

University of Tokyo (東京大学

Safety and effectiveness of monthly intravenous ibandronate injections in a prospective, postmarketing, and observational study in Japanese patients with osteoporosis

Objectives: This postmarketing, observational study evaluated the safety and effectiveness of monthly intravenous (IV) ibandronate in Japanese patients with osteoporosis. Methods: Eligible patients received monthly IV ibandronate 1 mg for 12 months. Adverse drug reactions (ADRs) were evaluated. Changes in bone mineral density (BMD) and bone turnover markers (BTMs) were assessed using matched t-test analysis. Cumulative fracture rates were analyzed by Kaplan-Meier methodology. Results: In total, 1062 patients were enrolled, of whom 1025 (n = 887 women, n = 138 men) were treated. Mean patient age was 77 years. Seventy-five ADRs were reported in 54 patients (5.26%). Four patients (0.39%) experienced serious ADRs, including one case of osteonecrosis of the jaw. Acute-phase reactions occurred in 21 patients (2.04%), and half of them arose after the first ibandronate injection. No new safety concerns were identified. Significant increases in BMD at 12 months relative to baseline were observed at the lumbar spine (4.84%, n = 187; 95% confidence interval [CI], 3.47%–6.21%), femoral neck (2.73%, n = 166; 95% CI, 1.46%–4.01%), and total hip (1.93%, n = 133; 95% CI, 0.80%–3.07%). Significant reductions were observed in all BTMs at 12 months (n = 174 in tartrate-resistant acid phosphatase-5b, n = 101 in procollagen type 1 N-terminal propeptide at baseline). The cumulative incidence of nontraumatic, new vertebral and nonvertebral fractures was 3.16% (95% CI, 2.12%–4.70%). Analyses in women only showed similar results to the overall population. Conclusions: These findings confirm the favorable safety and consistent effectiveness of ibandronate, and indicate that monthly IV ibandronate would be beneficial in daily practice for the treatment of Japanese patients with osteoporosis. Keywords: Ibandronate, Intravenous, Japan, Osteoporosis, Prospective observational stud

Effectiveness of monthly intravenous ibandronate injections in a real-world setting: Subgroup analysis of a postmarketing observational study

Objectives: The favorable safety and consistent effectiveness of monthly intravenous (IV) ibandronate injections was demonstrated in a prospective, postmarketing, observational study in Japanese patients with osteoporosis. Here, we present subgroup analyses from the study. Methods: Lumbar spine (L2–4) bone mineral density (BMD) gains were assessed in the following subgroups: aged <75 or ≥75 years, absence or presence of vertebral fractures, previous bisphosphonate (BP) treatment, and concomitant versus naïve osteoporosis drug treatment. The cumulative incidence of fractures and relative change in bone turnover markers were also examined. Results: Of 1062 enrolled patients, 1025 received monthly IV ibandronate 1 mg and were assessed for 12 months. BMD gains with ibandronate were comparable, irrespective of older age or prevalent fractures. Overall, 515 patients (50.2%) had previously received osteoporosis treatment; of these, 166 (16.1%) received other BPs. Mean BMD changes were 3.69% (95% confidence interval [CI], 0.89%–6.50%) in patients previously treated with other BPs, and 4.26% (95% CI, 2.88%–5.64%) in patients who had not received prior osteoporosis treatment. Among the 510 patients (49.7%) concomitantly prescribed active vitamin D drugs, mean BMD changes were 5.74% (95% CI, 2.53%–8.95%) with eldecalcitol versus 3.54% (95% CI, 1.98%–5.10%) with ibandronate alone. The lowest fracture incidence was observed with the combination of ibandronate and eldecalcitol, but differences between the subgroups were not statistically significant. Conclusions: Monthly IV ibandronate demonstrated comparable BMD gains in the patient subgroups analyzed. Concomitant use of ibandronate with eldecalcitol showed a trend of higher BMD gains and lower fracture incidence than ibandronate alone. Keywords: Eldecalcitol, Ibandronate, Japan, Osteoporosis, Observational stud

Effects of Paramylon Extracted from Euglena gracilis EOD-1 on Parameters Related to Metabolic Syndrome in Diet-Induced Obese Mice

Paramylon (PM), a type of &beta;-glucan, functions like dietary fiber, which has been suggested to exert a protective effect against obesity. We evaluated the potential beneficial effects of PM powder on obesity in mice. Male C57BL/6J mice were fed a high-fat diet supplemented with either 2.5 or 5% PM powder, extracted from Euglena gracilis, for 74 days. Growth parameters, abdominal fat content, serum biochemical markers, hepatic lipid accumulation and hepatic mRNA expression were measured. Dietary supplementation with PM resulted in decreased food efficiency ratios and abdominal fat accumulation. Dose-dependent decreases were observed in postprandial glucose levels, serum low-density lipoprotein (LDL)-cholesterol, and serum secretary immunoglobulin A (sIgA) concentrations. PM supplementation increased peroxisome proliferator-activated receptor &alpha; (PPAR&alpha;) mRNA expression in the liver which is suggested to induce &beta;-oxidation through activation of acyl-coenzyme A oxidase (ACOX), carnitine palmitoyltransferase (CPT) and fatty acid transport protein 2 (FATP2) mRNA expression. Changes in fatty acid metabolism may improve lipid and glucose metabolism. In conclusion, a preventive effect against obesity was observed in mice given a PM-enriched diet. The mechanism is suggested to involve a reduction in both serum LDL-cholesterol levels and the accumulation of abdominal fat, in addition to an improvement in postprandial glucose concentration

Role of neutrophil-derived matrix metalloproteinase-9 in tissue regeneration

Ischemic tissue regeneration depends on neovascularization, the growth of new blood vessels. Bone marrow (BM)-derived cells, including neutrophils, have been shown to contribute to neovascularization during hind limb ischemia and inflammation. Neutrophils produce a broad array of angiogenic growth factors and proteases, which promote remodeling of arterioles into arteries through proteolytic mechanisms. Matrix metalloproteinases (MMPs) have been shown to play a role in the recruitment of neutrophils to sites of inflammation, which requires the extravascular migration of neutrophils through the extracellular matrix. Neutrophils control critical steps during angiogenesis and neutrophil-derived MMPs can promote neoangiogenesis, and collateral growth and perfusion recovery, in part by liberating vital angiogenic growth factors, including vascular endothelial growth factor-A (VEGF-A). This review focuses on the role of neutrophils as key players in the control of the angiogenic process during ischemic tissue regeneration. Aspects of neutrophil regulation, in particular regulation by its major growth factor granulocyte colonystimulating factor (G-CSF), the role of the unique, readily available, neutrophil-derived MMP-9, and the functional consequences of this MMP-9 activation for angiogenesis, such as MMP-mediated release of biologically relevant cytokines from the matrix and cell surfaces, will be discussed

Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

Ischemia of the heart, brain, and limbs is a leading cause of morbidity and mortality worldwide. Treatment with tissue type plasminogen activator (tPA) can dissolve blood clots and can ameliorate the clinical outcome in ischemic diseases. But the underlying mechanism by which tPA improves ischemic tissue regeneration is not well understood. Bone marrow (BM)–derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(−) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb ischemia. Thus, tPA mobilizes CD11b(+) cells from the BM and increases systemic and local (cellular) VEGF-A, which can locally promote angiogenesis during ischemic recovery. tPA might be useful to induce therapeutic revascularization in the growing field of regenerative medicine

ホコウ ソクド ケイソクチ ノ バラツキ ハバ ト ホコウ ノウリョク トノ カンケイ

高齢障害者41名を対象に快適歩行と最速歩行の10m歩行所要時間をストップウォッチにて4回計測し、歩行能力・形態とバラツキの関係及び、歩行速度計測のバラツキ特性・信頼性について検討した。歩行速度とそのバラツキ幅は有意な相関がみられ、速歩ほど高い相関傾向を示した。バラツキ幅は、速歩では歩行所要時間30秒以下で5秒以内、所要時間50秒以上で17秒以上であり、緩歩では所要時間20秒以下で6秒以内であった。また、歩行能力・形態とバラツキ幅の関係には、有意差は認められなかったが、監視・3動作といった低い歩行能力群でバラツキが大きくなる傾向があり、速歩ほどよりその傾向を示した。信頼性のあるデータを得るには、緩歩では、1・2回の歩行練習後2～3回以上の計測が必要であり、速歩においては計測回数2～3回目がバラツキの少ない値を示した