Bone Formation and the Immuno-skeletal Interface

骨形成和免疫骨骼界面

• 批准号: 8762228
• 负责人: Mervyn Neale Weitzmann
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8762228
• 关键词: Age; Aging; Anabolic Agents; Anabolism; B-Lymphocytes; Bone Resorption; CD28 gene; CD8B1 gene; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Deformity; Dose; Effectiveness; Expenditure; FDA approved; Female; Fracture; Frequencies; General Population; Genetic Models; Health; Healthcare; Hip Fractures; Hormone use; Hormones; Immune response; Immune system; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Intractable Pain; Investigation; Joints; Knockout Mice; Lead; Lesion; Mediating; Mediator of activation protein; Medical; Morbidity - disease rate; Mus; Operative Surgical Procedures; Osteogenesis; Osteoporosis; Parathyroid gland; Patients; Pharmaceutical Preparations; Physiological; Production; Resolution; Rheumatoid Arthritis; Risk; Schedule; Signal Transduction; Skeletal system; Skeleton; Societies; System; T cell anergy; T-Lymphocyte; T-Lymphocyte Subsets; Teriparatide; Veterans; Wild Type Mouse; aged; base; bone; bone loss; bone mass; bone metabolism; bone turnover; cell type; clinically relevant; cytokine; human PTH protein; improved; in vivo; inhibitor/antagonist; male; mortality; mouse model; prevent; skeletal

DESCRIPTION (provided by applicant): The immunosuppressive drug Cytotoxic T-Lymphocyte Antigen 4 (CTLA4)-Ig (Abatacept) is an agent now being used to block inflammation and to prevent joint erosions and systemic osteoporosis in rheumatoid arthritis. CTLA4-Ig is a T-cell costimulation inhibitor that suppresses CD28-signaling in T-cells leading to T cell anergy (dormancy) and resolution of inflammation. However, because both physiological (basal) and pathological bone turnover are strongly influenced by the immune response this could undermine the effectiveness of CTLA4-Ig in ameliorating skeletal degeneration by disrupting basal bone turnover. We thus investigated the net effect of CTLA4-Ig on normal basal bone turnover in wild type mice in vivo. Surprisingly, CTLA4-Ig was found to promote a robust increase in skeletal mass, due to a significant elevation in bone formation. These data were further ratified using a genetic model of CD28 deficiency, the CD28 knockout mouse. Our studies further suggested that this bone anabolic activity is a likely consequence of CTLA4-Ig----induced production of Wnt10b by T-cells. Based on these data we hypothesize a direct cause----effect relationship between pharmacologically induced T-cell anergy, T-cell Wnt10b production and bone formation. In this renewal application we propose to intensively investigate this hypothesis in Specific Aim 1 where we will apply mice models to demonstrate that CTLA4-Ig promotes bone formation in vivo by inducing Wnt10b from T-cells. This will be achieved by quantifying CTLA4-Ig- induced bone formation in Wnt10b null mice and in chimeric mice bearing Wnt10b null T----cells. We will further delineate the specific T-cell subsets involved using chimeric mice bearing only CD4+ or CD8+ T-cells. In Specific Aim 2 we will determine if CTLA4-Ig potentiates the anabolic activity of PTH in mice and whether CTLA4-Ig can reduce the PTH dose or frequency of administration. Because CTLA4-Ig is a long acting agent requiring only monthly administration while Teriparatide requires daily injection, if CTLA4-Ig can replace Teriparatide or allow for a reduced dose, or more relaxed delivery schedule, this could lead to a more effective and/or less arduous therapy for patients.

描述（由申请人提供）： 免疫抑制药物细胞毒性T淋巴细胞抗原4（CTLA 4）-IG（阿巴西普）是目前用于阻断炎症和预防关节糜烂和全身性炎症的药剂。 类风湿性关节炎的病因CTLA 4-IG是一种T细胞共刺激抑制剂，可抑制T细胞中的CD 28信号传导，导致T细胞无反应性（休眠）和炎症消退。然而，由于生理性（基础）和病理性骨转换都受到免疫应答的强烈影响，这可能破坏CTLA 4-IG通过破坏基础骨转换来改善骨骼退化的有效性。因此，我们研究了CTLA 4-IG对野生型小鼠体内正常基础骨转换的净效应。令人惊讶的是，发现CTLA 4-IG由于骨形成的显著升高而促进骨骼质量的稳健增加。使用CD 28缺陷的遗传模型，即CD 28敲除小鼠，进一步证实了这些数据。我们的研究进一步表明，这种骨合成代谢活性可能是CTLA 4-IG-诱导T细胞产生Wnt 10 b的结果。基于这些数据，我们假设在环磷酰胺诱导的T细胞无反应性、T细胞Wnt 10 b产生和 骨形成在本更新申请中，我们建议在特定目标1中深入研究该假设，其中我们将应用小鼠模型来证明CTLA 4-IG通过从T细胞诱导Wnt 10 b来促进体内骨形成。这将通过定量Wnt 10 b缺失小鼠和携带Wnt 10 b缺失T细胞的嵌合小鼠中CTLA 4-IG诱导的骨形成来实现。我们将使用嵌合体小鼠进一步描述涉及的特定T细胞亚群 仅携带CD 4+或CD 8 + T细胞。在具体目标2中，我们将确定CTLA 4-IG是否增强小鼠中PTH的合成代谢活性，以及CTLA 4-IG是否可以降低PTH剂量或给药频率。因为CTLA 4-IG是一种长效药剂，仅需要每月给药，而特立帕鲁胺需要每天注射，如果CTLA 4-IG可以替代特立帕鲁胺或允许减少剂量，或更宽松的递送时间表，这可能导致对患者更有效和/或更不费力的治疗。