Role of IL-17 receptor A in aging bone remodeling

摘要： 炎性细胞因子是破骨细胞性骨吸收的有力刺激因子。在衰老过程中，有增加的 这些炎症介质的水平广泛与骨骼动态平衡紊乱有关，以及更多 最近骨折愈合了。在过去的十年里，炎症信号对骨骼健康的影响 这是许多实验室关注的焦点。一个特殊的促炎细胞因子家族(IL-17家族) 越来越多的人被证明在控制骨骼动态平衡方面发挥着关键作用。我们偶然发现 骨折老年小鼠的血清IL-17a水平与年轻对照组相比显著升高。有条件的 破骨细胞中IL-17a主要受体(IL-17ra)的缺失导致骨吸收减少和 体内骨量增加。根据更多的初步发现，我们推测的IL-1机制- 17ra调控骨重建涉及新发现的破骨细胞骨转录抑制因子 再吸收，运行1。基于以上，我们推测OCL中IL-17ra的缺失会增加骨量。 在骨骼动态平衡和促进骨修复过程中通过阶段特异性抑制破骨细胞骨 骨折骨痂改建过程中RUNX1的吸收作用。 在目标1中，我们建议研究OCL产生的IL-17ra的功能及其调节机制 老化骨骼在动态平衡过程中的骨重建。具体地说，我们将确定IL-17ra在 OCLS会增加衰老小鼠的骨量(1A)。然后我们将演示IL-17ra在OCL中的缺失 通过上调RUNX1(1B)抑制骨吸收。最后，我们将确定IL-17ra在 OCLS足以阻止卵巢切除引起的骨丢失(1C)。在第二个目标中，我们建议评估 抑制IL-17ra或激活OCL中的RUNX1是否可以阶段性地控制衰老过程中的骨愈合 白介素17受体拮抗剂对衰老小鼠骨痂重塑和骨修复的影响 (2A)。然后我们将检查RUNX1在OCL中的阶段依赖性过表达是否足以加速 老年性骨折的愈合(2B)。最后，我们将制定加速骨折愈合的治疗策略。 在衰老小鼠中，通过输送小分子在骨痂重塑期间暂时激活RUNX1(2C)。 从拟议的实验中获得的数据将揭示新的抗炎下游信号 可以作为目前可用的抗吸收生物制品的可行替代品的途径。

Summary: Inflammatory cytokines are potent stimulators of osteoclastic bone resorption. During aging, there are increased levels of these inflammatory mediators that are widely associated with perturbed skeletal homeostasis, and more recently fracture healing. During the past decade, the influence of inflammatory signals on bone health has been the focus of many laboratories. One particular family of pro-inflammatory cytokines (IL-17 family) has been increasingly shown to play key roles in controlling skeletal homeostasis. We came across the discovery that serum levels of IL-17a in fractured old mice were dramatically increased compared to young controls. Conditional deletion of the main receptor for IL-17a (IL-17ra) in osteoclasts resulted in decreased bone resorption and increased bone mass in vivo. Based on additional preliminary findings, our postulated mechanism underlying IL- 17ra control of bone remodeling involves the newly discovered transcriptional repressor of osteoclastic bone resorption, Runx1. Based on the above, we postulate that deletion of IL-17ra in OCLs will increase bone mass during skeletal homeostasis and promote bone repair through stage specific inhibition of osteoclastic bone resorption by Runx1 during fracture callus remodeling. In Aim 1, we propose to examine the function of OCL-produced IL-17ra and mechanisms via which it modulates bone remodeling during homeostasis in the aging skeleton. Specifically, we will determine if loss of IL-17ra in OCLs will increase bone mass in aging mice (1A). We will then demonstrate that deletion of IL-17ra in OCLs inhibits bone resorption through upregulation of Runx1 (1B). Finally, we will determine if deletion of IL-17ra in OCLs is sufficient to halt ovariectomy-induced bone loss (1C). In the second Aim, we propose to evaluate whether inhibition of IL-17ra or activation of Runx1 in OCLs can stage-dependently control bone healing in aging mice by first evaluating the effects of IL-17ra abrogation on callus remodeling and bone repair in aging mice (2A). We will then examine whether stage-dependent overexpression of Runx1 in OCLs is sufficient to accelerate the healing of senile fractures (2B). Finally, we will devise a therapeutic strategy to accelerate fracture healing in aging mice via delivery of a small molecule to temporally activate Runx1 during callus remodeling (2C). The data obtained from the proposed experiments will reveal new anti-inflammatory downstream signaling pathways that can serve as viable substitutes for the currently available anti-resorptive biologics.