Bone Formation and the Immuno-skeletal Interface

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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.