Studies on the fate of the Osteoclast

破骨细胞命运的研究

• 批准号: 8762069
• 负责人: Brendan F Boyce
• 金额: $ 33.77万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762069
• 关键词: Activities of Daily Living; Adverse drug effect; Age; Age-Related Bone Loss; Aging; Autoimmune Diseases; Autophagocytosis; Biological Preservation; Bone Diseases; Bone Marrow; Bone Resorption; Cell Lineage; Cells; Chloroquine; Clinical; Clinical Trials; Coculture Techniques; Cytokine Receptors; Data; Disease; Funding; Human; Inflammation; Inflammatory; Malignant Neoplasms; Measures; Mediating; Menopause; Mus; Myelogenous; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pharmaceutical Preparations; Phenotype; Proteins; Publishing; Regulation; Reporting; Role; Signal Transduction; Stromal Cells; TNF Receptor-Associated Factors; TNF gene; TNF receptor-associated factor 3; TNFSF11 gene; TRAF6 gene; Therapeutic; Transgenic Mice; Ubiquitination; Work; age related; bone; bone cell; bone loss; bone mass; compliance behavior; cytokine; inhibitor/antagonist; joint destruction; mutant; novel; osteoblast differentiation; prevent; public health relevance; skeletal; therapeutic target

DESCRIPTION (provided by applicant): Most forms of localized or generalized bone loss are due to NF-?B-mediated increased bone resorption and inadequate or decreased bone formation. Despite recent major advances, understanding of the mechanisms involved remains incomplete, therapeutic options are limited, and potential adverse effects of drugs limit patient compliance. NF-?B signaling positively regulates osteoclast (OC) formation, but it also inhibits osteoblast (OB) formation, and requires recruitment of TNF receptor-associated factors (TRAFs) to cytokine receptors to mediate downstream signaling. Thus, strategies to inhibit NF-?B or TRAF functions could reduce bone resorption and potentially increase formation. Despite these advances, there are no NF-?B inhibitors in clinical trials. We reported previously that TRAF3 (which generally works to inhibit NF-?B signaling) limits TNF-induced OC formation. In the current funding period, we extended these studies and generated mice with TRAF3 conditionally deleted in OC (LysM;traf3 cKO) and OB (Prx1;traf3 cKO) lineage cells. Our recently published and preliminary data show that expression of TRAF3 is required not only in OC, but also in OB lineage cells to maintain normal bone mass in mice as they age. Specifically, we have found that RANKL promotes TRAF3 ubiquitylation and degradation in OC precursors (OCPs) via autophagy, and the autophagy inhibitor, chloroquine (CQ), inhibits RANKL-induced OC formation and prevents PTH- and OVX-induced bone resorption in WT, but not in OC-Traf3 cKO mice. Prx1;traf3 cKO mice develop age-related bone loss with increased OC numbers and reduced bone formation. Bone marrow stromal cells (BMSCs) from Prx1;traf3 cKO mice express high levels of RANKL and have markedly decreased OB differentiation. TGF? reduces TRAF3 levels in OBs. These findings reveal novel and important roles for TRAF3 in OCs and OBs and suggest that inhibition of its degradation should prevent bone loss in a variety of clinical settins. In this competitive renewal, we plan to study the mechanisms whereby TRAF3 regulates osteoclast formation and inhibits osteoblast functions, and if inhibition of autophagic degradation of TRAF3 prevents bone loss by targeting both OCs and OBs. Our findings should identify TRAF3 as a new and important therapeutic target for preservation of bone mass and determine if CQ can prevent bone resorption and increase bone formation by inhibiting autophagy in bone cells.

描述（由申请人提供）：大多数形式的局部或广义骨质流失是由于NF- b介导的增加的骨吸收增加，骨形成不足或减少。尽管最近取得了重大进展，但对所涉及机制的理解仍然不完整，治疗选择是有限的，并且药物的潜在不利影响限制了患者的依从性。 NF-？b信号传导正向调节破骨细胞（OC）的形成，但也抑制成骨细胞（OB）的形成，并需要募集TNF受体相关因子（TRAFS）到细胞因子受体以介导下游信号传导。因此，抑制NF-或TRAF功能的策略可以减少骨吸收并可能增加形成。尽管有这些进展，但在临床试验中仍未进行NF- b抑制剂。我们先前报告说，TRAF3（通常可以抑制NF-信号传导）限制了TNF诱导的OC形成。在当前的资金期间，我们扩展了这些研究，并用在OC（Lysm； Traf3 CKO）和OB（PRX1； TRAF3 CKO）谱系细胞中有条件删除的TRAF3产生了小鼠。我们最近发表的和初步的数据表明，TRAF3的表达不仅需要在OC中，而且还需要OB谱系细胞，以使小鼠随着年龄的增长而维持正常的骨骼质量。 Specifically, we have found that RANKL promotes TRAF3 ubiquitylation and degradation in OC precursors (OCPs) via autophagy, and the autophagy inhibitor, chloroquine (CQ), inhibits RANKL-induced OC formation and prevents PTH- and OVX-induced bone resorption in WT, but not in OC-Traf3 cKO mice. PRX1; TRAF3 CKO小鼠随着OC数量增加并减少骨骼形成而导致与年龄相关的骨质流失。 PRX1; TRAF3 CKO小鼠的骨髓基质细胞（BMSC）表达了高水平的RANKL，并且显着降低了OB分化。 TGF？降低了traf3水平。这些发现揭示了TRAF3在OC中的新颖和重要作用，并表明抑制其降解应防止各种临床沉降中的骨质流失。在这种竞争性更新中，我们计划研究TRAF3调节破骨细胞形成并抑制成骨细胞功能的机制，如果抑制自噬降解 Traf3的of通过靶向OC和OBS来防止骨质流失。我们的发现应将TRAF3识别为保存骨骼的新的重要治疗靶标，并确定CQ是否可以通过抑制骨细胞自噬来防止骨吸收并增加骨形成。