Studies of the fate of the osteoclast

项目摘要/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)， 以激活的NF-κB信号诱导的促炎因子水平升高为特征， 通过刺激OC和/或抑制OB参与老年性骨质疏松症的发病 差异化。然而，LLCI导致骨丢失的分子机制仍不完全。 明白了。我们最近发表的研究结果表明，肿瘤坏死因子受体相关因子3的蛋白水平 负向调节NF-κB信号的TRAF3在衰老小鼠的骨髓(BM)中减少。 这是因为在衰老过程中，从吸收骨释放的转化生长因子β增加，从而诱导泛奎宁- 间质基质细胞(MSCs)介导TRAF3的降解TRAF3水平的降低 MSCs导致趋化因子SDF1的产生增加，并随后积累新的亚群 表达RANKL和CXCR4(SDF1受体)的B细胞(CD19+、B220+和IgM+) 在老化过程中在BM中标识。我们将RANKL+CXCR4+B细胞亚群简称为RCB。 RCB直接诱导OC形成，并产生一种抑制OB分化的可溶性因子(S)。重要的是 要么是FDA批准的CXCR4抑制剂plerixafor，要么是IAP蛋白的抑制剂SM164，后者可以防止 转化生长因子β1诱导骨髓间充质干细胞TRAF3降解，骨小梁骨量增加，与减少相关 RCBs在老龄小鼠骨髓中的蓄积。我们提议的研究将1)全面描述RCB 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 2)骨髓间充质干细胞表达的TRAF3是否调节骨髓中RCBs的积聚 通过调节SDF1的表达；以及3)确定plerixafor是否通过消耗 BM来源的RCBs和IF靶向骨骼可提高其疗效并减少不良反应，用于预防 与年龄相关的骨质疏松症。拟议研究的完成将确定这方面的机制 一组新的B细胞通过刺激骨吸收和抑制骨形成促进骨丢失 在年龄相关性骨质疏松症期间，重要的是，将提供原则证明，普利沙或一根骨头- 靶向制剂可能是治疗老年性骨质疏松症的一种新方法。

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.