Intrinsic Restriction of TNF-Mediated Inflammatory Osteoclastogenesis and Bone Resorption.
Intrinsic Restriction of TNF-Mediated Inflammatory Osteoclastogenesis and Bone Resorption.
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DOI：
10.3389/fendo.2020.583561
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发表时间：
2020
影响因子：
5.2
通讯作者：
Zhao B
中科院分区：
文献类型：
--
作者：
Zhao B
肿瘤坏死因子是一种多效性细胞因子，在免疫和炎症性骨破坏中发挥重要作用。核因子kappa-B受体激活剂(RANKL)能有效地诱导动态平衡的破骨细胞生成。相反，肿瘤坏死因子通常作用于破骨细胞以外的细胞类型，或与RANKL协同作用，间接促进破骨细胞生成和骨吸收。肿瘤坏死因子和RANKL是肿瘤坏死因子超家族的成员。但是，与RANKL相比，肿瘤坏死因子的直接破骨作用要弱得多。最近的研究揭示了肿瘤坏死因子作用于破骨细胞前体抑制破骨细胞生成的关键内在机制，包括RBP-J信号、RBP-J和ITAM(基于免疫受体酪氨酸的激活基序)串扰、RBP-J介导的调控网络、NF-κB P100、IRF8和Def6。其中一些机制，如RBP-J及其介导的调控网络，独特且主要地限制了由肿瘤坏死因子而不是RANKL介导的破骨细胞的形成。因此，靶向RBP-J活性可抑制炎症性骨破坏，但不会显著影响正常骨重建或炎症。因此，这些内在抑制机制的发现解决了为什么肿瘤坏死因子具有较弱的破骨形成能力，解释了RANKL和肿瘤坏死因子信号转导之间的显著差异，并提供了潜在的新的或补充的治疗策略，以选择性地治疗炎症性骨吸收，而不会对疾病背景下的正常骨重建或免疫反应产生不良影响。
TNF (Tumor necrosis factor) is a pleiotropic cytokine that plays an important role in immunity and inflammatory bone destruction. Homeostatic osteoclastogenesis is effectively induced by RANKL (Receptor activator of nuclear factor kappa-B ligand). In contrast, TNF often acts on cell types other than osteoclasts, or synergically with RANKL to indirectly promote osteoclastogenesis and bone resorption. TNF and RANKL are members of the TNF superfamily. However, the direct osteoclastogenic capacity of TNF is much weaker than that of RANKL. Recent studies have uncovered key intrinsic mechanisms by which TNF acts on osteoclast precursors to restrain osteoclastogenesis, including the mechanisms mediated by RBP-J signaling, RBP-J and ITAM (Immunoreceptor tyrosine-based activation motif) crosstalk, RBP-J mediated regulatory network, NF-κB p100, IRF8, and Def6. Some of these mechanisms, such as RBP-J and its mediated regulatory network, uniquely and predominantly limit osteoclastogenesis mediated by TNF but not by RANKL. As a consequence, targeting RBP-J activities suppresses inflammatory bone destruction but does not significantly impact normal bone remodeling or inflammation. Hence, discovery of these intrinsic inhibitory mechanisms addresses why TNF has a weak osteoclastogenic potential, explains a significant difference between RANKL and TNF signaling, and provides potentially new or complementary therapeutic strategies to selectively treat inflammatory bone resorption, without undesirable effects on normal bone remodeling or immune response in disease settings.
影响因子：
3.7
作者：
Chan AS;Jensen KK;Skokos D;Doty S;Lederman HK;Kaplan RN;Rafii S;Rivella S;Lyden D
通讯作者：
Lyden D