Anti TNF-alpha approach to treat Osteogenesis Imperfecta

抗 TNF-α 方法治疗成骨不全症

• 批准号: 9033816
• 负责人: IVO Kalajzic
• 金额: $ 21.05万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033816
• 关键词: Anabolic Agents; Anti-Inflammatory Agents; Area; Biochemical; Bone Density; Bone Marrow; Bone Resorption; Bone remodeling; C-terminal type I collagen telopeptide; Cartilage; Cell Lineage; Cells; Coculture Techniques; Cyclophosphamide; Data; Development; Dual-Energy X-Ray Absorptiometry; Environment; Epiphysial cartilage; Etanercept; Evaluation; Exhibits; FDA approved; Femoral Fractures; Fracture; Frequencies; Functional disorder; Future; Health; Human; Impaired wound healing; Inflammatory; Interleukin-1; Intraperitoneal Injections; Knowledge; Lead; Length; Ligands; Measures; Mechanics; Modeling; Molecular; Mononuclear; Mus; Myelogenous; N-terminal; Nuclear; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis Imperfecta; Osteotomy; Outcome; Pathway interactions; Patients; Peripheral; Phenotype; Property; Quality of life; Receptor Signaling; Regulation; Research; Roentgen Rays; Role; Serum; Signal Pathway; Signal Transduction; Site; Staining method; Stains; Structure; TNF gene; TNFSF11 gene; Testing; Transgenes; Translating; Treatment Efficacy; Tumor Necrosis Factor Receptor; Type I Procollagen; Wild Type Mouse; Work; X-Ray Computed Tomography; base; bisphosphonate; bone; bone cell; bone circulation; bone mass; bone strength; clinical practice; cytokine; hematopoietic tissue; human subject; improved; inhibitor/antagonist; mouse model; novel; novel therapeutics; osteoblast differentiation; osteoclastogenesis; pre-clinical; progenitor; receptor; research clinical testing; response; success; translational study

 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.

 描述（由申请人提供）：目前成骨不全症（OI）的治疗方法集中于抑制破骨细胞驱动的骨吸收。在过去的十年中，双磷酸盐治疗改善了成骨不全患者的生活质量。尽管这种疗法在成骨不全治疗中的成功已有充分记录，但双磷酸盐的一些潜在负面影响包括骨重塑减少、生长板软骨吸收减少、截骨部位愈合延迟和非典型股骨骨折。我们小组和其他人最近的研究表明炎症分子在成骨不全的病理生理学中发挥作用。在不同的病理条件下已经证实，某些促炎细胞因子，如TNF-α和IL-1，可以与RANKL/RANK信号协同增强破骨细胞的分化和活性。因此，成骨不全症中炎症细胞因子对破骨细胞生成影响的机制和调控将是本提案的重点。我们假设 TNF-α 增加是与 OI 相关的破骨细胞生成增强的主要分子机制。在本研究的目标 1 中，我们建议评估 OIM 小鼠骨髓和外周 OCP 的频率、表型、功能特性和 NF-κB 信号通路谱。根据我们的初步数据，我们预计 TNF-α 会启动骨髓 OCP，以增强 OIM 小鼠对 RANKL 刺激的反应，并使其做出更快速的反应。为此，我们将评估 TNF-α 信号传导对 OIM 小鼠破骨细胞生成增加的贡献。在目标 2 中，我们计划评估 TNF-α 拮抗剂（依那西普）治疗对生长中的 OIM 小鼠骨量、骨结构参数和骨折率的影响。该项目将提供抗 TNF-α 作为抗肿瘤药物的临床前评估。 成骨不全症的新治疗选择。从这项研究中获得的知识对于未来以人类为对象的转化研究的发展以及治疗人类成骨不全患者的潜在应用具有无价的价值。 TNF-α拮抗剂（依那西普）治疗已获得FDA批准用于其他炎症性疾病，这意味着如果结果是积极的，它可以迅速转化为临床实践。