Pharmacological Study on Neural Regulation of Bone Metabolism

骨代谢神经调控的药理学研究

• 批准号: 11671861
• 负责人: TOGARI Akifumi
• 金额: $ 2.24万
• 依托单位: Aichi-Gakuin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671861/
• 关键词: Osteoblast; Osteoclast; Osteoclastogenesis; Sympathetic neurons; Axon guidance molecules; RANKL; OPG; β-受容体; 骨吸収; VIP; CGRP; エピネフリン; インターロイキン; ODF; ニューロトロフィン; セマフォリン; ネトリン

In the present study, analysis of mRNA expression using RT-PCR demonstrated that human osteoblastic and osteoclastic cells are equipped with adrenergic receptors and neuropeptide receptors and constitutively express diffusible axon guidance molecules, suggesting that the extension of axons of sympathetic and peripheral sensory neurons to these cells is required for the dynamic neural regulation of local bone metabolism. Adrenergic stimulation was demonstrated to modulate the expression of IL-6, IL-11, cyclooxygenase-II, ODF/OPGL/TRANCE/RANKL(ODF/RANKL) and OCIF/OPG in osteoblasts/stromal cells. These molecules are well known to be involved in osteoclastogenesis. Especially, ODF/RANKL and OCIF/OPG are noticed as direct molecules modulating osteoclastogenesis. To elucidate the adrenergic regulation of osteoclastogenesis, we examined the effects of epinephrine (Epi), isoprenaline (Isp) and phenylephrine (Phe) on the formation of tartarate-resistant acid phosphatase(TRACP)-positive multinucleated cell (MNC) from mouse bone marrow cells. TRACP-positive MNC formation were stimulated by Isp or Epi, but not Phe. The MNC formation induced by Isp was not observed in the presence of OCIF/OPG, suggesting the importance of physiological balance between ODF/RANKL and OCIF/OPG productions for osteoclastogenesis. From these results, it may be suggested that the activity of sympathetic nerves has a significant effect on osteoclastogenesis by modulating ODF and OCIF expression in bone marrow cells.

在本研究中，RT-PCR分析表明，人成骨细胞和破骨细胞具有肾上腺素能受体和神经肽受体，并结构性地表达可扩散的轴突引导分子，提示交感和外周感觉神经元的轴突向这些细胞延伸是局部骨代谢的动态神经调节所必需的。肾上腺素能刺激可调节成骨细胞/基质细胞IL-6、IL-11、环氧合酶-II、ODF/OPGL/TRANKL(ODF/RANKL)和OCIF/OPG的表达。众所周知，这些分子参与了破骨细胞的形成。尤其是ODF/RANKL和OCIF/OPG被认为是调控破骨细胞发生的直接分子。为阐明肾上腺素对破骨细胞生成的调节作用，我们观察了肾上腺素(Epi)、异丙肾上腺素(Isoprenaline)和苯肾上腺素(Phe)对小鼠骨髓细胞形成酒石酸抗性酸性磷酸酶(TRACP)阳性多核细胞(MNC)的影响。Isp或Epi可刺激TRACP阳性的MNC的形成，而Phe则无此作用。在OCIF/OPG存在的情况下，未观察到isp诱导的MNC形成，提示ODF/RANKL和OCIF/OPG之间的生理平衡对破骨细胞的形成具有重要意义。这些结果提示，交感神经的活动可能通过调节骨髓细胞中ODF和OCIF的表达而对破骨细胞的形成有重要影响。

项目成果

Takeuchi, T.: "Adrenergic stimulation of osteoclastegetiesis mediated by ODF expression in MC3T3-E1 osteoblast-like cells"Biochemical Pharmacology. 61. 579-586 (2001)

Takeuchi, T.：“MC3T3-E1 成骨细胞样细胞中 ODF 表达介导的破骨细胞生成的肾上腺素刺激”生化药理学。

Kinpara, K.: "Osteoclast differentiation factor in human osteosarcoma cell line."Journal of Immunoassay. 21(4). 327-340 (2000)

Kinpara, K.：“人骨肉瘤细胞系中的破骨细胞分化因子。”免疫测定杂志。

Kinpara,K.,Mogi M.,Kuzushima,M.and Togari,A.: "Osteoclast differentiation factor in human osteosarcoma cell line."Journal of Immunoassay. 21(4). 327-340 (2000)

Kinpara，K.，Mogi M.，Kuzushima，M. 和 Togari，A.：“人骨肉瘤细胞系中的破骨细胞分化因子。”免疫测定杂志。

Mogi,M.,Kondo,A.,Kinpara,K.and Togari,A.: "Anti-apoptotic action of nerve growth factor in mouse osteoblastic cell line."Life Sciences. 67. 1197-1206 (2000)

Mogi,M.、Kondo,A.、Kinpara,K. 和 Togari,A.：“神经生长因子在小鼠成骨细胞系中的抗凋亡作用。”生命科学。

Togari, A.: "Expression of mRNAs for neuropeptides receptors, adrenergic receptors, neurotrophins and semaphorin Ill in human osteoblasts and osteoclasts"Frontiers of the Mechanisms of Memory and Dementia. (elsevier). 163-164 (2000)

Togari，A.：“人成骨细胞和破骨细胞中神经肽受体、肾上腺素能受体、神经营养素和脑信号蛋白III的mRNA表达”记忆和痴呆机制的前沿。