Studies on the fate of the Osteoclast

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-κ b介导的骨吸收增加和骨形成不足或减少。尽管最近取得了重大进展，但对相关机制的了解仍然不完整，治疗选择有限，药物的潜在不良反应限制了患者的依从性。NF-κB信号传导积极调节破骨细胞（OC）的形成，但也抑制成骨细胞（OB）的形成，并需要TNF受体相关因子（TRAFs）向细胞因子受体募集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，但在临床试验中还没有NF-κB抑制剂。我们之前报道过TRAF3(通常可以抑制

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.