Study on mechanism of the coupling between bone resorption and bone formation

骨吸收与骨形成耦合机制研究

• 批准号: 13557155
• 负责人: TAKAHASHI Naoyuki
• 金额: $ 8.96万
• 依托单位: Matsumoto Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557155/
• 关键词: Osteoprotegerin (OPG); Osteoclast; Receptor activator of NF-κB (RANKL); Bisphosphonate; Coupling; Osteoblast; soluble RANKL; ectonic bone formation; マクロファージ; 骨髄間質細胞; オステオプロテゲリン; ビスフォスフォネート; アルカリフォスファターゼ; 骨代謝共役因子; リポ多糖; サイトカイン; BMP; Smad

Aim of the study :The discovery of RANKL elucidates the mechanism of osteoclast differentiation and function regulated by osteoblasts. Osteoprotegerin (OPG), a soluble decoy receptor of RANKL, inhibits both differentiation and function of osteoclasts. OPG-deficient (OPG-/-) mice exhibited severe osteoporosis caused by enhanced osteoclastic bone resorption. Deficiency of OPG in human has been shown to result in juvenile Paget's disease. The previous morphological study showed that osteoblastic bone formation was activated in OPG-/-mice. These results suggest that osteoclastic bone resorption coincidentally induces osteoblastic bone formation by an unknown factor (called coupling factor). In the present study, we examined a possibility that mature osteoclasts produce cytokines which influence bone metabolism using mature osteoclasts treated with LPS. Using OPG -/-mice, we also explored whether such a coupling factor is present in bone in OPG -/-mice.Results :(1)p38MAP kinase was essentia … More lly involved in the differentiation of bone marrow macrophages (osteoclast precursors) into osteoclasts. The p38MAP kinase-signaling pathway was all dead in mature osteoclasts. (2)Mature osteoclasts were shown to produce an osteoblast-activating factor but not bone-resorbing cytokines such as IL-1 and IL-6 in response to LPS. (3)Blood levels of osteocalcin and ALP of OPG-/-mice were markedly increased in OPG-/-mice. Bone histomorphometric studies showed that both bone resorption and bone formation were activated in OPG-/-mice. (4)Serum levels of soluble RANKL were also elevated in OPG-/-mice. (5)When 1,25(OH)_2D_3 was administered into OPG -/-and wild-type mice, serum RANKL concentrations were markedly increased in OPG-/-mice but not in wild-type mice. (6)OPO -/-osteoblasts released a large amount of RANKL in the culture medium, which was completely inhibited by adding OPG (7)When bisphosphonate (risedronate) was injected into OPG -/-mice, bone formation -related parameters as well as bone resorption-related parameters were sharply decreased in the treated mice. (8)Treatment of OPG -/-mice with risedronate decreased serum osteocalcin and ALP levels but not the serum RANKL level. (9)Ectopic bone formation induced by BMP is not accelerated in OPG -/-mice.Conclusion :These results suggest (1)that mature osteoclast produce a coupling factor but not bone resorbing factors, and (2)that bone resorption is tightly coupled with bone formation at the sites where borne resorption takes place. Less

造成骨质细胞差异和功能的机制，pg是一种可溶性的诱饵受体，抑制了由骨质骨的骨骼疾病增强的骨质骨化。在opg - / - 小鼠中激活了骨的骨骼。在OPG中 - /（1）P38 MAP激酶是骨骼巨噬细胞（破骨细胞前体）中的骨骼IL-6对OPG的LPS - / - 鼠标的标志性增加了。 OPG - / - 和野生型小鼠，在野生型小鼠中，OPG的血清RANKL贡献显着增加。随着骨度假胜地相关的参数在处理的小鼠中急剧降低，而不是血清rankl水平。坐在伯恩·伯恩（Borne Borne）的地方少了。

项目成果

Yasuhiro Kobayashi, Toshihide Mizoguchi, Ikuko Take, Saburo Kurihara, Nobuyuki Udagawa, Naoyuki Takahashi.: "Cyclic AMP/protein kinase A signals enhance osteoclastic differentiation through TAK1 in osteoclast precursors."(Submitted for publication.).

Yasuhiro Kobayashi、Toshihide Mizoguchi、Ikuko Take、Saburo Kurihara、Nobuyuki Udakawa、Naoyuki Takahashi.：“环化 AMP/蛋白激酶 A 信号通过破骨细胞前体中的 TAK1 增强破骨细胞分化。”（已提交出版）。

Sato J, Fukuda S, Takahashi N, Sato R, Yasuda J, Naito Y: "Effect of EDTA on Ca metabolism and bone metabolism in a cow."J. Vet Med (Tokyo). 56. 710-714 (2003)

Sato J、Fukuda S、Takahashi N、Sato R、Yasuda J、Naito Y：“EDTA 对奶牛钙代谢和骨代谢的影响。”J。

Katagiri T, Imada M, Yanai T, Suda T, Takahashi N, Kamijo R: "Identification of a BMP-responsive Element in the Id1 gene."Genes Cells. 7. 949-960 (2002)

Katagiri T、Imada M、Yanai T、Suda T、Takahashi N、Kamijo R：“Id1 基因中 BMP 响应元件的鉴定。”基因细胞。

Li X., et al.: "p38 MAPK is crucially involved in osteoclast differentiation but not in cytokine production, phagocytosis or dendritic cell differentiation of bone marrow macrophages."Endocrinology. 144. 4999-5005 (2003)

Li X. 等人：“p38 MAPK 在破骨细胞分化中至关重要，但不参与骨髓巨噬细胞的细胞因子产生、吞噬作用或树突状细胞分化。”内分泌学。

Kotake S, Udagawa N, Hakoda M, Mogi M, Yano K, Tsuda B, Takahashi K, Furuya T, Ishiyama S, Kim KJ, Saito S, Nishikawa T, Takahashi N, Togari A, Tomatsu T, Suda T, Kamatani N: "Activated human T cells directly induce osteoclastogenesis from human monocytes

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