Regulation of osteoblastic differentiation and its implication in involutional osteoporosis

成骨细胞分化的调控及其在退化性骨质疏松症中的意义

• 批准号: 07671111
• 负责人: TAKEUCHI Yasuhiro
• 金额: $ 1.41万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671111/
• 关键词: osteoblast; aging; osteoporosis; matrix proteins; collagen; integrin; adhesion molecules; bone marrow cells; 骨髄間質細胞

Modulation of TGF-beta actions in osteoblasts by bone matrix proteinsWe demonstrated that decorin, a bone matrix protein synthesized by osteoblasts, binds TGF-beta and enhances the binding to its receptors on osteoblastic cells, resulting in the augmentation of bioactivity of TGF-beta. Thus, decorin is not only a component of bone matrix but may be involved in the bone formation that is stimulated by TGF-beta.Involvement of collagen-integrin interactions in osteoblastic differentiationInteractions of osteoblastic cells to type I collagen (COL) via alpha2beta1 integrin were shown to be required for osteoblastic differentiation. The binding of COL to the integrin provoked tyrosine phosphorylation and activation of focal adhesion kinase (FAK) and ERK,a member of MAP kinase family. Several inhibitors that inhibit FAK suppressed collagen-induced osteoblastic differentiation. Furthermore, decrease in FAK expression with the stable expression of antisense mRNA for FAK disrupted both ERK activ … More ation and osteoblastic differentiation. Because transient expression of protein phosphatase CL100 that inactivates ERK prevented the differentiation, the direct involvement of ERK was suggested. These observations indicate that cell-matrix interactions, especially COL-integrin interactions, are essentially involved in the osteoblastic differentiation via activations of signaling cascades directly associated with the integrin, FAK and ERK.Osteoblastic differentiation in bone marrow cells in advancing with ageP6 strain of senescence-accerelated mice (SAM) is a murine model of involutional osteoporosis. We showed that osteoblastogenesis of bone marrow stromal cells was impaired in SAMP6 mice compared with the control SAMR1 mice. Treatment with interleukin (IL)-11 could restore this disturbance. We further showed that IL-11 expression in bone marrow cells of SAMP6 was less than that of SAMR1, suggesting that insufficient IL-11 actions causes the impaired osteoblastogenesis in SAMP6. Thus, a decrease in actions of cytokines like IL-11 is further to be investigated for the pathogenesis of involutional osteoporosis. Less

骨基质蛋白对成骨细胞中TGF-β作用的调节我们证明，核心蛋白聚糖（一种由成骨细胞合成的骨基质蛋白）与TGF-β结合并增强与其在成骨细胞上的受体的结合，从而增强TGF-β的生物活性。因此，核心蛋白聚糖不仅是骨基质的组成部分，而且可能参与 TGF-β 刺激的骨形成。 胶原蛋白-整联蛋白相互作用参与成骨细胞分化成骨细胞通过 α2β1 整联蛋白与 I 型胶原蛋白 (COL) 的相互作用被证明是成骨细胞分化所必需的。 COL 与整合素的结合引发酪氨酸磷酸化以及粘着斑激酶 (FAK) 和 ERK（MAP 激酶家族成员）的激活。几种抑制 FAK 的抑制剂可抑制胶原蛋白诱导的成骨细胞分化。此外，随着 FAK 反义 mRNA 的稳定表达，FAK 表达的减少破坏了 ERK 激活和成骨细胞分化。因为使 ERK 失活的蛋白磷酸酶 CL100 的瞬时表达阻止了分化，因此表明 ERK 直接参与。这些观察结果表明，细胞-基质相互作用，特别是COL-整合素相互作用，本质上通过激活与整合素、FAK和ERK直接相关的信号级联参与成骨细胞分化。衰老加速相关小鼠(SAM)的ageP6品系的骨髓细胞中的成骨细胞分化是退化性骨质疏松症的小鼠模型。我们发现，与对照 SAMR1 小鼠相比，SAMP6 小鼠的骨髓基质细胞成骨细胞受损。白细胞介素 (IL)-11 治疗可以恢复这种紊乱。我们进一步表明，SAMP6 的骨髓细胞中 IL-11 的表达低于 SAMR1，表明 IL-11 作用不足会导致 SAMP6 中的成骨细胞生成受损。因此，IL-11等细胞因子作用的降低有待进一步研究渐进性骨质疏松症的发病机制。较少的

项目成果

Seiji Fukumoto: "Absence of mutations in parathyroid hormone (PTH) /PTH-rolated protein receptor complementary deoxyribonucleic acid in patients with pseudohypoparathyroidism type 1b." Journal of Clinical Endocrinology and Metabolism. 81・7. 2554-2558 (199

Seiji Fukumoto：“1b 型假性甲状旁腺功能减退症患者的甲状旁腺激素 (PTH)/PTH 相关蛋白受体互补脱氧核糖核酸不存在突变。”临床内分泌与代谢杂志 81・7。

Kodama, Y.et al.: "Role of collagen in retinoic acid-induced differentiation and down-regulation of TGF-beta receptors in rat preosteoblastic RCT-1 cells." Endocrine J. (in press).

Kodama, Y. 等人：“胶原蛋白在视黄酸诱导的大鼠前成骨细胞 RCT-1 细胞分化和 TGF-β 受体下调中的作用。”

Yoshiaki Kodama: "Role of collagen in retinoic acid-induced differentiation and down-regulation of TGF-β receptors in rat preosteoblastic RCT-1 cells." Endocrine Journal. (in press). (1997)

Yoshiaki Kodama：“胶原蛋白在大鼠前成骨细胞 RCT-1 细胞分化和 TGF-β 受体下调中的作用”（正在出版）。

Takeuchi, Y.et al.: "Relationship between actions of transforming growth factor-beta and cell surface expression of its receptors in clonal osteoblastic cells." J Cell Physiol.162. 315-321 (1995)

Takeuchi, Y.等人：“克隆成骨细胞中转化生长因子-β 的作用与其受体的细胞表面表达之间的关系。”

Seiji Fukumoto: "Absence of mutations in parathyroid hormone(PTH)/PTH-related protein receptor complementary deoxyribonucleic acid in patients with pseudohypoparathyroidism type 1b." Journal of Clinical Endocrinology and Metabolism. 81・7. 2554-2558 (1996)

Seiji Fukumoto：“1b 型假性甲状旁腺功能减退症患者中甲状旁腺激素 (PTH)/PTH 相关蛋白受体互补脱氧核糖核酸不存在突变。临床内分泌与代谢杂志 81・7”。