Studies of the fate of the osteoclast

破骨细胞命运的研究

• 批准号: 10592255
• 负责人: Brendan F Boyce
• 金额: $ 52.56万
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592255
• 关键词: AMD3100; Adverse effects; Age; Age-Related Bone Loss; Age-Related Osteoporosis; Aging; Alendronate; Anatomy; Animal Model; B-Lymphocyte Subsets; B-Lymphocytes; BIRC4 gene; Biological Process; Bone Formation Inhibition; Bone Marrow; Bone Resorption; Bone Resorption Stimulation; CD19 gene; CXCR4 gene; Cells; Chronic; Data; Development; Disease; Dose; Elderly; FDA approved; Formulation; Forteo; Genetic Transcription; Heterogeneity; Human; Immune system; Immunoglobulin D; Immunoglobulin M; In Vitro; Individual; Inflammation; Inflammatory; Leukocytes; Ligands; Location; Longevity; Mammals; Mediating; Memory B-Lymphocyte; Molecular; Mus; Osteoclasts; Osteogenesis; Osteoporosis; PTPRC gene; Pathogenesis; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Prevention; Production; Proteins; Publishing; Reporting; Rheumatoid Arthritis; Route; Signal Transduction; Spleen; Stimulus; Stromal Cell-Derived Factor 1; Surface; TNF receptor-associated factor 3; TNFSF11 gene; Testing; Transforming Growth Factor beta; Vertebral Bone; aged; antagonist; bisphosphonate; bone; bone loss; bone mass; chemokine; conditional knockout; early onset; inhibitor; mesenchymal stromal cell; microCT; novel; novel therapeutics; osteoblast differentiation; prevent; protein function; receptor; response; scale up; substantia spongiosa; ubiquitin-protein ligase

Project Summary/Abstract Osteoporosis is a common disease of aging, caused by a combination of increased osteoclastic (OC) bone resorption and decreased osteoblastic (OB) bone formation. Low-level chronic inflammation (LLCI), characterized by increased levels of pro-inflammatory factors induced by activated NF-κB signaling, contributes to the pathogenesis of age-related osteoporosis by stimulating OC and/or inhibiting OB differentiation. However, the molecular mechanisms by which LLCI induces bone loss remain incompletely understood. Our recently published findings indicate that protein levels of TNF receptor associated factor 3 (TRAF3), which negatively regulates NF-κB signaling, are reduced in the bone marrow (BM) of aged mice. This is because increased amounts of TGFβ released from resorbing bone during aging induce ubiquintin- mediated degradation of TRAF3 by mesenchymal stromal cells (MSCs). This reduction in TRAF3 levels in MSCs leads to increased production of the chemokine, SDF1, and subsequent accumulation of a novel subset of B cell cells (CD19+, B220+ and IgM+) expressing RANKL and CXCR4 (an SDF1 receptor) that we have identified in the BM during aging. We have called this subset of RANKL+CXCR4+ B cells as RCBs for short. RCBs directly induce OC formation and produce a soluble factor(s) that inhibits OB differentiation. Importantly, either plerixafor, a FDA-approved CXCR4 inhibitor, or SM164, an inhibitor of IAP proteins, which prevents TGFβ1-induced TRAF3 degradation in MSCs, increased trabecular bone mass, associated with reduced accumulation of RCBs in the BM of aged mice. Our proposed studies will 1) fully characterize RCBs phenotypically, determine if they are present in humans and if CXCR4 in B cells mediates their accumulation in the BM of aging mice; 2) determine if TRAF3 expressed by MSCs regulates the accumulation of RCBs in BM by modulating SDF1 expression; and 3) determine if plerixafor prevents age-related osteoporosis by depleting RCBs from BM and if targeting it to bone increases its efficacy and reduces adverse effects for the prevention of age-related osteoporosis. Completion of the proposed studies will determine the mechanisms whereby this novel set of B cells contributes to bone loss by stimulating bone resorption and inhibiting bone formation during age-related osteoporosis and importantly, will provide proof of principle that plerixafor or a bone- targeted formulation of it may be a novel treatment for age-related osteoporosis.

项目概要/摘要 骨质疏松症是一种常见的衰老疾病，由破骨细胞（OC）骨增加引起 吸收和成骨细胞（OB）骨形成减少。低水平慢性炎症（LLCI）， 其特点是激活的 NF-κB 信号传导诱导促炎因子水平升高， 通过刺激 OC 和/或抑制 OB 促进与年龄相关的骨质疏松症的发病机制 然而，LLCI 诱导骨丢失的分子机制仍然不完全。 我们最近发表的研究结果表明 TNF 受体相关因子 3 的蛋白质水平。 (TRAF3) 负向调节 NF-κB 信号传导，在老年小鼠的骨髓 (BM) 中减少。 这是因为衰老过程中骨吸收释放的 TGFβ 量增加，会诱导泛素- 间充质基质细胞 (MSC) 介导 TRAF3 的降解。 MSC 导致趋化因子 SDF1 的产生增加，并随后积累新的亚群 我们拥有表达 RANKL 和 CXCR4（一种 SDF1 受体）的 B 细胞（CD19+、B220+ 和 IgM+） 我们将这种 RANKL+CXCR4+ B 细胞子集简称为 RCB。 RCB 诱导 OC 形成并直接产生抑制 OB 分化的可溶性因子。 普乐沙福（FDA 批准的 CXCR4 抑制剂）或 SM164（IAP 蛋白抑制剂） TGFβ1 诱导 MSC 中 TRAF3 降解，增加小梁骨量，并与骨量减少相关 我们提出的研究将 1) 全面表征 RCBs 在老年小鼠的 BM 中的积累。 表型，确定它们是否存在于人类中，以及 B 细胞中的 CXCR4 是否介导它们在 衰老小鼠的BM；2)确定MSC表达的TRAF3是否调节BM中RCB的积累 通过调节 SDF1 表达；3) 确定 plerixafor 是否通过消耗来预防与年龄相关的骨质疏松症 来自 BM 的 RCB 如果将其靶向骨骼，则可以提高其功效并减少预防的副作用 完成拟议的研究将确定其机制。 一组新型 B 细胞通过刺激骨吸收和抑制骨形成导致骨质流失 在与年龄相关的骨质疏松症期间，重要的是，将提供普乐沙福或骨- 它的靶向制剂可能是治疗年龄相关性骨质疏松症的一种新方法。