Studies on the fate of the Osteoclast

破骨细胞命运的研究

• 批准号: 9307726
• 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/9307726
• 关键词: Activities of Daily Living; Adverse drug effect; Age; Age-Related Bone Loss; Aging; Autoimmune Diseases; Autophagocytosis; 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; Recruitment Activity; Regulation; Reporting; Role; Signal Transduction; Stromal Cells; TNF Receptor-Associated Factors; TNF gene; TNF receptor-associated factor 3; TNFSF11 gene; TRAF6 gene; Therapeutic; Transforming Growth Factor beta; Transgenic Mice; Ubiquitination; Work; bone; bone cell; bone loss; bone mass; bone preservation; 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-κB-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-κB 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-κB or TRAF functions could reduce bone resorption and potentially increase formation. Despite these advances, there are no NF-κB inhibitors in clinical trials. We reported previously that TRAF3 (which generally works to inhibit NF-κB 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. TGFß 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 介导的骨吸收增加和骨形成不足或减少所致，尽管最近取得了重大进展，但对所涉及机制的了解仍然不完整，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，但它也抑制成骨细胞（OB）的形成，并且需要招募TNF受体相关因子（TRAF）来发挥作用。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。起到抑制作用 在当前的资助期间，我们扩展了这些研究并产生了在 OC (LysM;traf3 cKO) 和 OB (Prx1;traf3 cKO) 谱系细胞中条件性删除 TRAF3 的小鼠。已发表的数据和初步数据表明，不仅在 OC 中需要表达 TRAF3，在 OB 谱系细胞中也需要表达 TRAF3，以在小鼠衰老过程中维持正常的骨量。 RANKL 通过自噬促进 OC 前体 (OCP) 中 TRAF3 泛素化和降解，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 中则不然cKO 小鼠。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 TGFβ 显着降低 OB 中的 TRAF3 水平。这些发现揭示了 TRAF3 在 OC 和 OB 中的新的重要作用，并表明对其的抑制。在这种竞争性更新中，我们计划研究 TRAF3 调节破骨细胞形成和抑制的机制。成骨细胞功能，以及抑制自噬降解 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的自噬来防止骨吸收并增加骨形成。