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The TNF-family cytokine RANKL regulates bone resorption and formation.

机译：TNF家族的细胞因子RANKL调节骨吸收和形成。

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摘要

RANKL is a pleiotropic TNF-family cytokine that governs the differentiation and function of bone cells, lymphoid tissue, and mammary epithelium. In bone, RANKL regulates the ontogeny of the osteoclast, the principal resorptive cell of the skeleton. RANKL, via its receptor RANK, is requisite for the inflammatory cytokine TNF to induce bone destruction. TNF potentiates the ability of RANKL to induce osteoclastogenesis, exhibiting synergism at the level of NFκB and SAPK/JNK, essential signaling pathways for osteoclastogenesis. In vivo administration of TNF prompts robust osteoclast formation in marrow-transplanted hosts in which β-galactosidase positive, TNF-responsive osteoclast progenitors develop within a TNF-nonresponsive stroma. While TNF alone does not induce osteoclastogenesis, it does so in vitro and in vivo by directly targeting osteoclast precursors within a stroma that expresses permissive levels of RANKL. The ability of RANKL, but not TNF, to induce osteoclastogenesis lies within specific structural components that enable it to activate RANK. The crystal structure of RANKL at 2.6 Å reveals that it self-associates as a homotrimer with unique surface loops that distinguish it from other TNF-family cytokines. Mutagenesis of its unique loops significantly alters the ability of RANKL to activate RANK, thereby identifying elements that are indispensable for receptor engagement. A polypeptide corresponding to the most unique surface loop of RANKL acts as an antagonist in vitro, successfully competing against the biological activity of RANKL. Such structural determinants of receptor-ligand specificity enables the design of compounds to block osteoclastic bone resorption. Systemic administration of RANKL to mice, initially performed to assess synergy with TNFα, induces an exuberant proliferation of osteoblasts, cells that synthesize bone matrix. Paradoxically, RANKL, the key osteoclastogenic cytokine, profoundly stimulates anabolic bone formation in vitro, ex vivo, and in vivo. The anabolic effect occurs by a mechanism involving RANK signaling in the osteoblast to the transcription factor Cbfa-1 and the ERKs, thereby inducing the osteoblast differentiation and function. RANK-deficient mice exhibit a significantly impairment in bone formation, thus RANKL:RANK signaling plays a physiological role in bone anabolism. When administered exogenously, RANKL exerts an anabolic effect on bone that may be of use in treating diseases of bone loss.
机译：RANKL是一种多效性TNF家族细胞因子，可控制骨细胞，淋巴组织和乳腺上皮的分化和功能。在骨骼中，RANKL调节破骨细胞的发育，破骨细胞是骨骼的主要吸收细胞。 RANKL通过其受体RANK是炎症细胞因子TNF诱导骨破坏的必要条件。 TNF增强RANKL诱导破骨细胞形成的能力，在NFκB和SAPK / JNK（破骨细胞形成的重要信号途径）的水平上表现出协同作用。 TNF的体内给药促进了骨髓移植宿主中强力的破骨细胞形成，在这些宿主中，β-半乳糖苷酶阳性，TNF响应的破骨细胞祖细胞在TNF无响应的基质中形成。尽管单独的TNF不会诱导破骨细胞生成，但它直接通过靶向表达RANKL允许水平的基质中的破骨细胞前体，在体外（italic）体内和体外（italic）体内。 RANKL（而非TNF）诱导破骨细胞形成的能力位于使其能够激活RANK的特定结构组件中。 RANKL的晶体结构在2.6Å处显示出它是同型三聚体，具有独特的表面环，可与其他TNF家族细胞因子区分开来自缔合。其独特环的诱变作用极大地改变了RANKL激活RANK的能力，从而确定了受体结合必不可少的元素。对应于RANKL最独特的表面环的多肽在体外起着拮抗剂的作用，成功地与RANKL的生物学活性竞争。这种受体-配体特异性的结构决定因素使得能够设计化合物以阻断破骨细胞骨吸收。 RANKL对小鼠的全身给药最初是为了评估与TNFα的协同作用而进行的，诱导了成骨细胞（合成骨基质的细胞）的旺盛增殖。矛盾的是，关键的破骨细胞生成因子RANKL在体外，体外，体内和体内刺激了合成代谢骨的形成。通过涉及成骨细胞中的RANK信号传导至转录因子Cbfa-1和ERK的机制发生合成代谢作用，从而诱导成骨细胞分化和功能。缺乏RANK的小鼠在骨骼形成上表现出明显的损伤，因此RANKL：RANK信号传导在骨骼合成代谢中起着生理作用。当外源性施用时，RANKL对骨骼产生合成代谢作用，可用于治疗骨质流失疾病。

著录项

  • 作者

    Lam, Jonathan Jak Sum.;

  • 作者单位

    Washington University.;

  • 授予单位 Washington University.;
  • 学科 Biology Molecular.; Biology Cell.; Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 101 p.
  • 总页数 101
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

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