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全身性骨丢失是由于 NF-κB 介导的骨吸收增加以及骨形成不足或减少所致。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，治疗选择有限，并且药物的潜在副作用限制了患者的依从性。 NF-κB 信号传导正向调节破骨细胞 (OC) 的形成，但它也会抑制成骨细胞 (OB) 的形成，并且需要将 TNF 受体相关因子 (TRAF) 招募到细胞因子受体以介导下游信号传导。因此，抑制 NF-κB 或 TRAF 功能的策略可以减少骨吸收并可能增加骨形成。尽管取得了这些进展，但临床试验中还没有 NF-κB 抑制剂。我们之前报道过 TRAF3（通常用于抑制 NF-κB 信号传导）限制 TNF 诱导的 OC 形成。在当前的资助期内，我们扩展了这些研究，并生成了在 OC (LysM;traf3 cKO) 和 OB (Prx1;traf3 cKO) 谱系细胞中条件性删除 TRAF3 的小鼠。我们最近发表的初步数据表明，TRAF3 的表达不仅在 OC 中是必需的，而且在 OB 谱系细胞中也是必需的，以在小鼠衰老过程中维持正常的骨量。具体来说，我们发现 RANKL 通过自噬促进 OC 前体 (OCP) 中 TRAF3 泛素化和降解，而自噬抑制剂氯喹 (CQ) 抑制 RANKL 诱导的 OC 形成并防止 WT 中 PTH 和 OVX 诱导的骨吸收。但在 OC-Traf3 cKO 小鼠中则不然。 Prx1;traf3 cKO 小鼠会出现与年龄相关的骨丢失，并伴有 OC 数量增加和骨形成减少。来自 Prx1;traf3 cKO 小鼠的骨髓基质细胞 (BMSC) 表达高水平的 RANKL，并且 OB 分化显着降低。转化生长因子？降低 OB 中的 TRAF3 水平。这些发现揭示了 TRAF3 在 OC 和 OB 中的新颖且重要的作用，并表明抑制其降解应该可以防止各种临床病症中的骨丢失。在这次竞争性更新中，我们计划研究TRAF3调节破骨细胞形成和抑制成骨细胞功能的机制，以及抑制自噬降解的机制 TRAF3 通过靶向 OC 和 OB 来防止骨质流失。我们的研究结果应将 TRAF3 确定为保存骨量的新的重要治疗靶点，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。