Signal transduction and cell-to-cell communication in the bone resorption induced by inflammation

炎症诱导的骨吸收中的信号转导和细胞间通讯

• 批准号: 14370599
• 负责人: TAKAHASHI Naoyuki
• 金额: $ 8.83万
• 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: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370599/
• 关键词: Lipopolysaccharide (LPS); IL-1; osteoclast; MyD88; Muramyl dipeptide (MDP); Nod2; TRIF; PGE_2 receptor; マクロファージ; 骨芽細胞; インターロイキン1; 樹状細胞; RANKL; p38MAPK

Aim of the study :The discovery of RANKL elucidates the mechanism of osteoclast differentiation and function regulated by osteoblasts. Using OPG-deficient (OPG-/-) mice, MyD88-deficient (MyD88-/-) mice, and TRIF-deficient (TRIF-/-) mice, we examined signal transduction and cell-to-cell communication in the bone resorption induced by inflammation PGE_2 has been shown to enhance RANKL-induced differentiation of the precursor cells into osteoclasts. We examined how PGE2 directly enhance differentiation of osteoclast progenitors. The role of PGE_2 receptors in osteoclasts was examined, using an EP4 expression vector.Results :(1)LPS stimulated the survival of purified osteoclasts through TLR4 signals. (2)p38MAP kinase was essentially involved in the differentiation of bone marrow macrophages (osteoclast precursors) into osteoclasts. The p38MAP kinase pathway was all dead in mature osteoclasts. (3)Using OPG-/-mice, we showed that IL-1 as well as LPS stimulated osteoclastogenesis through two … More parallel events : direct enhancement of RANKL expression and suppression of OPG expression. (4)Using MyD88-deficient (-/-) mice and TRF-/-mice, we showed that MyD88 signals but not TRIF signals were essentially involved in RANKL expression in osteoblasts treated with IL-1 and LPS. MyD88 signals were also essential for the survival of osteoclasts supported by LPS and IL-1. (5)Destruxin, bisphosphonates, and strontium compound S12911-2 inhibit osteoclastic bone resorption. Destruxin was shown to inhibit pit-forming activity of osteoclasts without affecting their differentiation and survival. V-ATPase induced acidification beneath the ruffled borders of osteoclasts triggers the incorporation of bisphosphonates into osteoclasts. S12911-2 was shown to inhibit ruffled border formation in osteoclasts. (6)Muramyl dipeptide (MDP) is the essential structure responsible for the immunoadjuvant activity of peptidoglycan of gram-positive and -negative bacterial walls. MDP synergistically enhanced osteoclast formation induced by LPS, IL-1α and TNF-α through RANKL expression in osteoblasts. Nod2mediated signals appear to be involved in the MDP-induced RANKL expression in osteoblasts. (7) PGE_2 has been shown to enhance RANKL-induced differentiation of the precursor cells into osteoclasts. PGE2 synergistically enhanced osteoclastic differentiation of RAW264.7cells through EP2 and EP4. In contrast, mature osteoclasts did not express functional EP2 or EP4. When EP4 cDNA was transfected into mature osteoclasts, the bone-resorbing activity was markedly inhibited by PGE_2. Less

造成骨细胞分化和功能的机理，由成骨细胞（OPG - / - ）小鼠，MyD88缺乏（MyD88 - / - ）小鼠和TRIF缺乏（TRIF - / - ）小鼠，我们检查了信号由炎症诱导的骨骼的转导和通讯pge_2 Ankl诱导的前体细胞分化为骨细胞。 （1）通过tlr4信号进行了骨化的骨化，p38映射激酶途径在成熟的破骨细胞中都死了在用IL-1和IL-1 LPS处理的成骨细胞中，MyD88信号对lps和IL-1的teoclasts也至关重要。双膦酸盐的骨质结构在对比度中，将EP2的ep2分解在EP2和EP4中

项目成果

Takahashi N, Udagawa N, Tanaka S, Suda T: "Generating murine osteoclasts from bone marrow."Methods Mol Med. 80. 129-144 (2003)

Takahashi N、Udakawa N、Tanaka S、Suda T：“从骨髓中生成小鼠破骨细胞。”方法 Mol Med。

Takami M., et al.: "Involvement of vacuolar H^+-ATPase in incorporation of risedronate into osteoclasts."Bone. 32. 341-349 (2003)

Takami M.等人：“利塞膦酸盐掺入破骨细胞中液泡H 2 -ATP酶的参与。”骨。

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. (in press). (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。

Itoh K.et al.: "LPS promotes the survival of osteoclasts via toll-like receptor 4, but cytokine production of osteoclasts in response to LPS is different from that of macrophages."Journal of Immunology. 170・7. 3688-3695 (2003)

Itoh K.等人：“LPS通过Toll样受体4促进破骨细胞的存活，但破骨细胞响应LPS的细胞因子产生与巨噬细胞不同。”免疫学杂志170・7。 2003）

Itoh K, et al.: "LPS promotes the survival of osteoclasts via toll-like receptor 4, but cytokine production of osteoclasts in response to LPS is different from that of macrophages."Journal of Immunology. 170. 3688-3695 (2003)

Itoh K等人：“LPS通过Toll样受体4促进破骨细胞的存活，但破骨细胞响应LPS产生的细胞因子与巨噬细胞不同。”免疫学杂志。