The roles of nuclear transcription factors in calcium homeostasis

核转录因子在钙稳态中的作用

• 批准号: 10307046
• 负责人: SUDA Tatsuo
• 金额: $ 24.19万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10307046/
• 关键词: parathyroid hormone; 1α,25-dihydroxyvitamin D3; 1α-hydroxylase; osteoclast; ODF; OCIF; RANK; M-CSF; ビタミンD; カルシトニン; 腎臓; ステロイドホルモン; カルシウム

The physiologically active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], is a nuclear hormone with pleiotropic action on the control of calcium homeostasis and bone formation, induction of cellular differentiation and apoptosis, inhibition of cellular proliferation, and other cellular signaling processes. The actions of the hormone are mediated by the vitamin D receptor (VDR), a transcription factor that is a nuclear receptor for 1α,25(OH)2D3 and a member of the nuclear receptor superfamily.A full-length cDNA for the rat kidney mitochondrial cytochrome P450 mixed function oxidase, 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), was cloned from a vitamin D-deficient rat kidney cDNA library. The sequence analysis showed that CYP27B1 consisted of 2469 bp in length and contained an open reading frame encoding 501 amino acids. The expression of CYP27B1 mRNA was greatly increased in the kidney of hypocalcemic rats fed a low Ca diet. It is believed that the major regulator for … More renal CYP27B1 is parathyroid hormone (PTH) secreted in response to hypocalcemia. Administration of PTH into normocalcemic normal rats, however, did not induce at all renal expression of CYP27B1 mRNA. In contrast, a single injection of calcitonin (CT) dose- and time-dependently increased the expression of CYP27B1 mRNA in the kidney of normal rats. These results suggest that CT plays an important role in the maintenance of serum 1α,25(OH)2D3 under normocalcemic physiological conditions at least in rats.Osteoclast differentiation factor (ODF), a novel member of the TNF ligand family, is expressed as a membrane-associated protein by osteoblasts/stromal cells. The soluble form of ODF (sODF) induces the differentiation of osteoclast precursors into osteoclasts in the presence of M-CSF. A soluble form of RANK as well as osteoprotegerin/osteoclastogenesis inhibitory factor, a decoy receptor of ODF, blocked OGL formation and prevented the survival, multinucleation, and pit-forming activity of prefusion osteoclasts induced by sODF. These results suggest that ODF regulates not only osteoclast differentiation but also osteoclast function in mice through the receptor RANK. Less

维生素D3的生理活性形式，1α，25-二羟基维生素D3[1α，25(OH)2D3]，是一种核激素，在控制钙稳态和骨形成、诱导细胞分化和凋亡、抑制细胞增殖等细胞信号过程中具有多效性作用。该激素的作用由维生素D受体介导。维生素D受体是1羟基维生素D3和25(OH)2D3的核受体，也是核受体超家族成员之一。序列分析表明，该基因全长2469个碱基，含有一个编码501个氨基酸的开放阅读框。低钙饲料喂养的低钙大鼠肾脏细胞色素P27B1mRNA的表达显著增加。据信，…的主要监管机构更多的肾脏细胞色素P27B1是甲状旁腺激素(PTH)分泌，以应对低钙血症。正常大鼠给予甲状旁腺激素后，肾脏细胞色素P27B1mRNA的表达完全不受影响。相比之下，单次注射降钙素(CT)可剂量和时间依赖性地增加正常大鼠肾脏中CYP27B1mRNA的表达。这些结果表明，至少在正常血钙生理条件下，CT在维持血清1-α，25(OH)2D3方面起着重要作用。破骨细胞分化因子是肿瘤坏死因子配体家族的新成员，在成骨细胞/基质细胞中以膜相关蛋白的形式表达。可溶性ODF(SODF)在M-CSF存在下诱导破骨细胞前体向破骨细胞分化。可溶性RANK和ODF的诱骗受体--骨保护素/破骨细胞生成抑制因子可阻断OGL的形成，并阻止sODF诱导的再灌流破骨细胞的存活、多核和凹坑形成活性。这些结果表明，ODF不仅通过受体RANK调节小鼠破骨细胞的分化，而且还调节破骨细胞的功能。较少

项目成果

Udagawa, N. et al.: "Osteoblasts/stromal cells stimulate osteoclast function through the expression of osteoclast differentiation factor but not macrophage colony-stimulating factor."Bone. 25. 517-523 (1999)

Udakawa, N. 等人：“成骨细胞/基质细胞通过表达破骨细胞分化因子而不是巨噬细胞集落刺激因子来刺激破骨细胞功能。”骨。

Brenza, H.L. et al.: "Parathyroid hormone activation of the 25-hydroxyvitamin D3-1 a-hydroxylase gene promoter."Proc. Natl. Acad. Sci. USA. 95. 1387-1391 (1998)

Brenza, H.L. 等人：“25-羟基维生素 D3-1 a-羟化酶基因启动子的甲状旁腺激素激活。”Proc.

Suda,T.,et al.: "Modulation of osteoclast differentation and function by osteoblasts/stromal cells." Endocrine Rev.in press. (1999)

Suda,T.,et al.：“成骨细胞/基质细胞对破骨细胞分化和功能的调节。”

Yasuda,H.,et al.: "A novel molecular mechanism modulating osteoclast differentiation and function."Bone. 25. 109-113 (1999)

Yasuda, H., et al.：“一种调节破骨细胞分化和功能的新分子机制。”骨。

Yamamoto,K.,et al.: "Three-dimensional structure-function relationship of vitamin D:side chain location and various activities."Bioorg.Med.Chem.Lett.. 9. 1041-1046 (1999)

Yamamoto,K.,et al.：“维生素 D 的三维结构-功能关系：侧链位置和各种活性。”Bioorg.Med.Chem.Lett.. 9. 1041-1046 (1999)