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.
Osteoporosis is endemic among Western societies. Fractures are already a serious medical problem among aging Veterans and in the general population as 1 in 2 females and 1 in 5 males over the age of 50 will suffer an osteoporosis related bone fracture in their remaining lifetimes. Fractures lead to huge healthcare expenditures, loss of mobility, and morbidity. Hip fractures almost always require major surgery and mortality rates are extremely high in aged individuals following surgery. Historically, anti-resorptive agents have been used to stall further bone degeneration but these agents are inefficient at restoring lost bone mass after the fact. Our proposed studies will evaluate the potential of CTLA4-Ig to act as a bone anabolic agent that may have considerable value in treating osteoporosis, alone or to improve the anabolic activity of Teriparatide or allow for a reduced dose, or more relaxed PTH delivery schedule.
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