Bone Formation and the Immuno-skeletal Interface

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(CTLA4)-Ig(Abatacept)是一种现在被用来阻止炎症和防止关节侵蚀和系统性疾病的药物。 类风湿关节炎中的骨质疏松症。CTLA4-Ig是一种T细胞共刺激抑制物，可抑制T细胞中的CD28信号，导致T细胞无能(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反应的强烈影响，这可能会削弱CTLA4-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CTLA4-Ig对野生型小鼠体内正常基底骨转换的净影响。令人惊讶的是，由于骨形成的显著增加，CTLA4-Ig被发现能够促进骨骼质量的强劲增加。使用CD28缺陷的遗传模型--CD28基因敲除小鼠--进一步证实了这些数据。我们的研究进一步表明，这种骨合成活性可能是CTLA4-Ig-诱导T细胞产生WNT10b的结果。基于这些数据，我们假设药物诱导的T细胞无能、T细胞Wnt10b的产生和T细胞Wnt10b的产生之间存在直接的因果关系 骨形成。在这个新的应用中，我们建议在特定的目标1中深入研究这一假说，我们将应用小鼠模型来证明CTLA4-Ig通过从T细胞诱导Wnt10b促进体内的骨形成。这将通过量化CTLA4-Ig在Wnt10b缺失小鼠和携带Wnt10b缺失T细胞的嵌合小鼠中诱导的骨形成来实现。我们将利用嵌合小鼠进一步描述所涉及的特定T细胞亚群 只有CD4+或CD8+T细胞。在具体目标2中，我们将确定CTLA4-Ig是否增强小鼠甲状旁腺激素的合成代谢活性，以及CTLA4-Ig是否可以减少甲状旁腺素的剂量或给药频率。由于CTLA4-Ig是一种长效剂，只需要每月给药，而Teriparatide需要每天注射，如果CTLA4-Ig能够取代Teriparatide，或允许减少剂量，或更宽松的给药时间表，这可能会为患者带来更有效和/或更轻松的治疗。

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.