Studies of the fate of the osteoclast

项目总结/摘要 骨质疏松症是一种常见的老年性疾病，由骨密度增加（OC）骨 骨吸收和成骨细胞（OB）骨形成减少。低水平慢性炎症（LLCI）， 其特征在于由活化的NF-κB信号传导诱导的促炎因子水平增加， 通过刺激OC和/或抑制OB而促进年龄相关性骨质疏松症的发病机制 分化然而，LLCI诱导骨丢失的分子机制仍然不完全 明白我们最近发表的研究结果表明，TNF受体相关因子3的蛋白水平 负调节NF-κB信号传导的TRAF 3在老年小鼠的骨髓（BM）中减少。 这是因为在衰老过程中，从吸收骨中释放的TGFβ的量增加， 间充质基质细胞（MSC）介导的TRAF 3降解。TRAF 3水平的降低， MSC导致趋化因子SDF 1的产生增加，并随后积累一种新的亚群 表达RANKL和CXCR 4（SDF 1受体）的B细胞（CD 19+、B220+和IgM+）， 在老化过程中在BM中识别。我们将这种RANKL+ CXCR 4 + B细胞亚群简称为RCB。 RCB直接诱导OC形成并产生抑制OB分化的可溶性因子。重要的是， 普乐沙福（一种FDA批准的CXCR 4抑制剂）或SM 164（一种IAP蛋白抑制剂）， TGFβ1诱导MSC中TRAF 3降解，增加骨小梁质量，与减少 RCB在老年小鼠BM中的蓄积。我们提出的研究将1）充分表征RCB 表型上，确定它们是否存在于人体中，以及B细胞中的CXCR 4是否介导它们在 2）确定MSC表达的TRAF 3是否调节RCB在BM中的积累 通过调节SDF 1表达;和3）确定普乐沙福是否通过消耗 来自BM的RCB，如果将其靶向骨，则可增加其有效性并减少预防的不良反应 与年龄有关的骨质疏松症完成拟议的研究将确定这一机制， 一组新的B细胞通过刺激骨吸收和抑制骨形成而导致骨丢失 在年龄相关性骨质疏松症期间，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新方法。

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.