Role of IL-17 receptor A in aging bone remodeling

IL-17受体A在衰老骨重塑中的作用

• 批准号: 10719356
• 负责人: HICHAM M DRISSI
• 金额: $ 42.89万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719356
• 关键词: Acceleration; Acetylation; Age Months; Aging; Animals; Anti-Inflammatory Agents; Antigen Presentation; Attenuated; Biological Assay; Biological Products; Bone Injury; Bone Marrow; Bone Resorption; Bone Resorption Inhibition; Bone callus; Bone remodeling; Cell Lineage; Cells; Clinical; Data; Enhancers; Evaluation; Exhibits; Family; Female; Femoral Fractures; Fracture; Genotype; Gonadal Steroid Hormones; Harvest; Histologic; Homeostasis; IL17 gene; Image; Inflammation; Inflammation Mediators; Inflammatory; Knock-out; Laboratories; Ligands; Link; LoxP-flanked allele; Mechanics; Medicine; Molecular; Mus; Myelogenous; Myeloid Cells; Orthopedics; Osteoclasts; Osteoporotic; Outcome Measure; Ovariectomy; Patients; Phagocytosis; Pharmaceutical Preparations; Phase; Phenotype; Play; Population; Proteins; Publications; Publishing; RNA; Role; Senility; Serum; Signal Pathway; Signal Transduction; Skeleton; Sorting; Spleen; Tamoxifen; Testing; Therapeutic; Tissues; Transcription Repressor; Transgenic Mice; Trauma; Up-Regulation; Work; acute myeloid leukemia 1 protein; aged; aging population; bone; bone fracture repair; bone fragility; bone healing; bone health; bone loss; bone mass; bone repair; cartilaginous; conditional knockout; cytokine; density; efficacy evaluation; experimental group; experimental study; glycol-chitosan; healing; in vivo; male; nanoparticle; overexpression; peripheral blood; receptor; sex; skeletal; small molecule; transcriptome sequencing; transcriptomics

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.

总结： 炎性细胞因子是骨吸收的有效刺激因子。随着年龄的增长， 这些炎症介质的水平与骨骼稳态紊乱广泛相关， 最近骨折愈合。在过去的十年中，炎症信号对骨骼健康的影响一直是 许多实验室的焦点。促炎细胞因子的一个特定家族（IL-17家族）已经被发现。 越来越多的研究表明，它在控制骨骼动态平衡中发挥着关键作用。我们发现 与年轻对照相比，骨折老年小鼠中IL-17 α的血清水平显著增加。条件 破骨细胞中IL-17 a主要受体（IL-17 ra）的缺失导致骨吸收减少， 体内骨量增加。基于额外的初步发现，我们假设的IL-10的潜在机制， 17 ra控制骨重建涉及新发现的骨细胞骨转录抑制因子 吸收，Runx 1。基于上述，我们推测OCL中IL-17 ra的缺失会增加骨量 在骨骼稳态和促进骨修复通过阶段特异性抑制骨细胞骨 在骨折骨痂重塑过程中Runx 1的吸收。 在目的1中，我们提出研究OCL产生的IL-17 ra的功能及其调节机制， 在老化骨骼的内环境稳定过程中的骨重建。具体来说，我们将确定IL-17 ra的缺失是否会导致 OCL将增加衰老小鼠的骨量（1A）。然后我们将证明OCL中IL-17 ra的缺失 通过上调Runx 1（1B）抑制骨吸收。最后，我们将确定IL-17 ra的缺失是否会影响IL-17的表达。 OCL足以阻止卵巢切除术诱导的骨丢失（1C）。在第二个目标中，我们建议评估 OCL中IL-17 ra的抑制或Runx 1的激活是否可以阶段依赖性地控制衰老中的骨愈合 通过首先评估IL-17 ra消除对衰老小鼠中骨痂重塑和骨修复的影响， （2A）。然后，我们将研究OCL中Runx 1的阶段依赖性过表达是否足以加速OCL的发生。 老年性骨折的愈合（2B）。最后，我们将设计一种治疗策略，以加速骨折愈合 在衰老小鼠中，通过递送小分子以在骨痂重塑期间暂时激活Runx 1（2C）。 从拟议的实验中获得的数据将揭示新的抗炎下游信号传导 可以作为目前可用的抗吸收生物制剂的可行替代品的途径。