Substance P exacerbation of staphylococcal bone damage

项目摘要 由细菌感染引起的骨髓炎等骨骼疾病与 伴有严重炎症和进行性骨质丢失。金黄色葡萄球菌是最多的 骨髓炎的常见致病因素及发病率和严重程度 葡萄球菌性骨髓炎似乎在增加，尽管在 预防和诊断。破骨细胞形成和活性的失调导致 感染部位的骨破坏和/或异常骨重塑，以及成骨细胞 在这些骨吸收细胞的调节中起着至关重要的作用。此外, 细菌感染的成骨细胞和破骨细胞能够产生一系列 免疫介质可促进炎性细胞的募集和激活 骨组织中的白细胞。神经肽P物质(SP) 公认可加重一系列组织的炎症，包括肠道、皮肤和 中枢神经系统。鉴于SP对骨组织的广泛神经支配- 含神经纤维的SP(NK-1R)特异性受体的功能表达 通过骨骼细胞，以及先前的证据表明这种神经肽可以调节骨骼细胞 反应，我们认为SP/NK-1R的相互作用加剧了炎症 骨髓炎。在这个应用中，我们提出了一个全面的临床前评估 该神经肽对人和小鼠离体炎的增强作用 常驻骨细胞与葡萄球菌体内动物模型的建立 骨髓炎。这项工作建立在我们之前的工作基础上，并将检验以下假设 抑制SP/NK-1R相互作用减弱免疫和溶骨反应 将常驻骨细胞转化为细菌。此外，这些研究是必不可少的一步。 评价临床批准的NK-1R再利用的治疗潜力 拮抗剂作为限制葡萄球菌性骨髓炎相关性的辅助治疗 炎症性骨丢失和/或异常骨重建，并可能指向神经源性 作为治疗炎症性骨病的治疗靶点的投入。

Project Summary Bone disorders such as osteomyelitis that result from bacterial infection are associated with severe inflammation and progressive bone loss. Staphylococcus aureus is the most common causative agent of osteomyelitis and the incidence and severity of staphylococcal osteomyelitis appears to be increasing despite improvements in prophylaxis and diagnosis. Dysregulation of osteoclast formation and activity results in bone destruction and/or abnormal bone remodeling at sites of infection, and osteoblasts play an essential role in the regulation of these bone-resorbing cells. In addition, bacterially infected osteoblasts and osteoclasts are capable of producing an array of immune mediators that could promote the recruitment and activation of inflammatory leukocytes in bone tissue. The neuropeptide substance P (SP) is increasingly recognized to exacerbate inflammation in a range of tissues including the gut, skin, and central nervous system. Given the extensive innervation of bone tissue with SP- containing nerve fibers, the functional expression of the specific receptor for SP (NK-1R) by bone cells, and previous evidence that this neuropeptide can modulate bone cell responses, we suggest that SP/NK-1R interactions exacerbate inflammation in osteomyelitis. In this application, we propose a comprehensive preclinical evaluation of the ability of this neuropeptide to augment inflammation in isolated murine and human resident bone cells and an established in vivo animal model of staphylococcal osteomyelitis. This work builds upon our prior work and will test the hypothesis that inhibition of SP/NK-1R interactions attenuates the immune and osteolytic responses of resident bone cells to bacteria. Furthermore, these studies represent an essential step in evaluating the therapeutic potential of repurposing clinically approved NK-1R antagonists as an adjunctive therapy to limit staphylococcal osteomyelitis-associated inflammatory bone loss and/or abnormal bone remodeling, and may point to neurogenic input as a therapeutic target for the treatment of inflammatory bone disorders in general.