Anti TNF-alpha approach to treat Osteogenesis Imperfecta

 描述(申请人提供)：目前成骨不全(OI)的治疗方法主要集中在抑制破骨细胞驱动的骨吸收上。在过去的十年里，双膦酸盐疗法改善了OI患者的生活质量。虽然这种治疗方法在OI中的成功已经得到了很好的证明，但双膦酸盐的一些潜在的负面影响包括减少骨重建，减少生长板软骨的吸收，延迟截骨部位的愈合和不典型的股骨骨折。我们小组和其他人最近的研究表明，炎症分子在OI的病理生理学中发挥了作用。在不同的病理条件下已经证实，某些促炎细胞因子，如肿瘤坏死因子-和IL-1，可以协同RANKL/RANK信号通路促进破骨细胞的分化和活性。因此，炎性细胞因子在OI破骨细胞生成中的作用机制及其调控将是本研究的重点。我们推测，增加的肿瘤坏死因子-是OI相关的破骨细胞形成增强的主要分子机制。在研究的目的1中，我们建议评估OCPs在OIM小鼠骨髓和外周的频率、表型、功能特性和NF-B信号转导途径。根据我们的初步数据，我们预期肿瘤坏死因子-可使OIM小鼠的髓系OCPs对RANKL刺激有更快的反应。在这一目标中，我们将评估肿瘤坏死因子-信号在OIM小鼠破骨细胞生成增加中的作用。在目的2中，我们计划评估肿瘤坏死因子-拮抗剂(依那西普)对生长期骨质疏松症小鼠骨量、骨结构参数和骨折发生率的影响。该项目将提供抗肿瘤坏死因子-的临床前评估作为一种 OI的新治疗选择。从这项研究中获得的知识将对未来使用人类受试者的转译研究的发展和治疗人类OI患者的潜在应用具有非常宝贵的价值。肿瘤坏死因子-拮抗剂(依那西普)已被美国食品和药物管理局批准用于其他炎症条件，这意味着如果结果呈阳性，它可能会迅速转化为临床实践。

 DESCRIPTION (provided by applicant): Current treatment approaches for osteogenesis imperfecta (OI) are focused on inhibition of osteoclast-driven bone resorption. Over the last decade, bisphosphonate therapy has improved the quality of life for OI patients. Although the success of this therapy in OI has been well documented, some of the potential negative effects of bisphosphonates include decreased bone remodeling, reduced growth plate cartilage resorption, delayed healing of osteotomy sites and atypical femoral fractures. Recent studies by our group and others have indicated a role for inflammatory molecules in the pathophysiology of OI. It has been confirmed in different pathological conditions that certain proinflammatory cytokines, such as TNF- and IL-1, may enhance osteoclast differentiation and activity in synergy with RANKL/RANK signaling. Therefore, the mechanisms and regulation of the effects of the inflammatory cytokines on osteoclastogenesis in OI will be the focus of this proposal. We hypothesize that increased TNF- is a major molecular mechanism underlying enhanced osteoclastogenesis associated with OI. In the Aim 1 of the study we propose to assess frequency, phenotype, functional properties and NF-B signaling pathway profile of OCPs in bone marrow and periphery of OIM mice. Based on our preliminary data we expect that TNF- primes myeloid OCPs for increased and more rapid response to RANKL stimulation in OIM mice. In this aim we will assess contribution of TNF- signaling to the increased osteoclastogenesis in OIM mice. In the aim 2 we plan to evaluate the effects of TNF- antagonist (etanercept) treatment on the bone mass, bone structural parameters and fracture rate in growing OIM mice. This project will provide a pre-clinical evaluation of anti- TNF- as a new therapeutic option for OI. The knowledge gained from this research will be invaluable for the development of future translational studies using human subjects and potential applications to treat human OI patients. TNF- antagonist (etanercept) treatment has been FDA approved for other inflammatory conditions, meaning that if the results are positive, it could be rapidly translated into clinical practice.