Substance P exacerbation of staphylococcal bone damage

项目摘要 由细菌感染引起的骨疾病，如骨髓炎， 严重的炎症和进行性骨质流失金黄色葡萄球菌是最 骨髓炎的常见病原体以及 葡萄球菌性骨髓炎似乎正在增加，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/或异常骨重建，以及成骨细胞 在这些骨吸收细胞的调节中发挥重要作用。此外，本发明还提供了一种方法， 细菌感染的成骨细胞和破骨细胞能够产生一系列 免疫介质可以促进炎症细胞的募集和激活， 骨组织中的白细胞神经肽P物质（SP）越来越多， 被认为会加剧一系列组织中的炎症，包括肠道、皮肤和 中枢神经系统考虑到骨组织的广泛神经支配， 含有神经纤维的细胞，SP特异性受体（NK-1 R）的功能表达， 以前的证据表明，这种神经肽可以调节骨细胞， 反应，我们认为SP/NK-1 R的相互作用加剧了炎症反应， 骨髓炎在本申请中，我们提出了一个全面的临床前评价， 这种神经肽在分离鼠和人中增加炎症的能力 常驻骨细胞和建立的葡萄球菌感染的体内动物模型 骨髓炎这项工作建立在我们以前的工作，并将测试的假设， 抑制SP/NK-1 R相互作用可减弱 骨细胞转化为细菌此外，这些研究代表了一个重要步骤， 在评估重新利用临床批准的NK-1 R的治疗潜力时， 拮抗剂作为限制葡萄球菌性骨髓炎相关性 炎症性骨丢失和/或异常骨重建，并可能指向神经源性 作为治疗炎症性骨疾病的治疗靶点。

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.