Reseach for cell-cell communication in bone remodeling and differentiation of osteoblast and osteoclast

在骨重建过程中，再吸收部位的局部钙（Ca^<2+>）浓度升高至高达40 mM，并且在再吸收阶段结束时单核细胞出现在再吸收部位。我们从本研究中获得的证据表明，高Ca^<2+>在单核细胞的出现中起着重要作用，其次是成骨细胞，在吸收部位，单核细胞和高Ca^<2+>在成骨细胞骨形成与骨细胞骨吸收的偶联中也起着重要作用。本研究还表明，细胞外Ca^2+浓度的增加直接通过增加胰岛素样生长因子-1（IGF-1）的产生和分泌，间接通过调节单核细胞释放骨转换的局部因子，从而引起成骨细胞增殖的增加。下一个项目是澄清降钙素是否直接作用于成骨细胞以及破骨细胞。我们的研究表明，降钙素直接作用于成骨细胞，然后通过诱导c-fos基因表达和刺激IGF-1基因表达促进成骨细胞增殖和分化。成骨细胞具有甲状旁腺激素（PTH）反应性双信号转导系统[cAMP依赖性蛋白激酶（PKA）和钙/蛋白激酶C（Ca/PKC）]。在本研究中，我们证明PKA直接参与了PTH刺激骨吸收的过程，并且PTH具有通过从成骨细胞释放可溶性因子来刺激破骨细胞分化的能力，这种作用是通过PTH应答的双重信号转导系统来实现的。另一方面，有证据表明破骨细胞前体中存在PTH结合位点。本研究表明，小鼠脾细胞来源的造血母细胞也具有PTH应答的双重信号转导途径。

In the process of bone remodeling, the local calcium (Ca^<2+>) concentration at the resorption sites rises to as high as 40 mM and mononuclear cells appear at the resorptive sites at the end of a resorption phase. We obtained from the present study the evidence that high Ca^<2+> plays an important role in the appearance of mononuclear cells, followed by osteoblasts, at the resorptive sites and that mononuclear cells as well as high Ca^<2+> at the resorptive site also play an important role in the coupling of osteoblastic bone formation to osteoclastic bone resorption. The present sudy also demonstrated that an increase in extracellular Ca^<2+> concentration caused an increase in osteoblast proliferation directly through an increase in the production and secretion of insulin-like growth factor-1 (IGF-1) and indirectly via modulating the release of local facors of bone turnover from monocytes. The next project was to clarify whether calcitonin directly acts on osteoblasts as well as osteoclasts. Our study demonstrated that calcitonin directly acts on osteoblasts, followed by an increase in osteoblast proliferation and differentiation possiby through inducing c-fos gene expression and stimulating IGF-1 gene expression. Osteoblasts possess parathyroid hormone (PTH)-responsive dual signal transduction systems [cAMP-depindent protein kinase (PKA) and calcium/protein kinase C (Ca/PKC)]. In the present study, we demonstrated the direct involvement of PKA in the stimulation of bone resorption by PTH.Moreover, PTH possessed the ability to stimulate osteoclast differentiation through releasing the soluble factor from osteoblasts and this effect was exerted via these PTH-responsive dual signal transduction systems. On the other hand, there is evidence about the existence of PTH binding sites in osteoclast precursors. The present study demonstrated that hemopoietic blast cells derived from mouse spleen cells also possess PTH-responsive dual signal transducti