Bone fractures resulting from osteoporosis lead to significant health costs, morbidity, loss of mobility, and often mortality in aged individuals. The bone destruction that drives osteoporosis is mediated by osteoclasts (OCs), bone resorbing cells that form under the influence of the key osteoclastogenic cytokine Receptor- Activator of NF-:B (RANKL). RANKL activity is moderated by its physiological decoy receptor osteoprotegerin (OPG). Historically OPG production has always been associated with osteoblast-lineage cells. However, recently we found that in mice B cells are a critical additional source of OPG in vivo, and that B cell OPG production is regulated by costimulatory signals such as CD40 Ligand (CD40L) derived from T cells. Furthermore, B cell OPG production is dramatically upregulated in aged mice in the face of declining osteoblast OPG production. We hypothesize that 'Lymphocytes, through B cell OPG production, and modulated by T cell costimulation, are critical regulators of basal bone homeostasis in young mice and mitigate in part, the enhanced bone resorption associated with aging'. Novel therapeutic agents that modulate immune function are under intense investigation for treatment of numerous autoimmune and inflammatory diseases, and as anti-rejection agents in bone marrow and solid organ transplantation. The long term effects of these agents on the skeleton are unknown however, our preliminary studies suggest that an unforeseen consequence of immunomodulatory therapies may be to promote osteoporosis by perturbing B cell OPG production. To ratify and extend our preliminary findings and to explore the potential clinical implications thereof, we propose to characterize the role of T cells and B cells, and of T cell to B cell costimulation in the regulation of bone turnover in young, adult and aged mice, and to evaluate the impact of pharmacological B cell depletion, and of T cell to B cell costimulation inhibitors, on B cell and/or total OPG production, bone turnover, and indices of bone structure in mice in vivo.
In Specific Aim 1 we will investigate the impact of B cell depletion in mice in vivo using an anti-CD20 antibody that mimics the agent Rituximab, now used in humans to treat refractory Rheumatoid Arthritis and certain B cell lymphomas.
In Specific Aim 2 we will investigate the role of costimulation in B cell OPG production; the specific T cell subsets involved; and how pharmacological suppression of T cell to B cell costimulation in mice alters B cell OPG production and bone turnover, using in vivo gain and loss of function models.
These Specific Aims will: 1) provide critical data to validate our hypothesis that B cells control basal bone homeostasis in vivo through production of OPG, and regulated by costimulatory signals from T cells, in young, adult and aged mice; and 2) provide important information about the potential for skeletal side-effects relating to the clinical use of immunomodulatory pharmaceuticals to ameliorate disease.
Osteoporosis is endemic among Western societies. Fractures are already a serious medical problem among aging Veterans and in the general population and 1 in 2 females and 1 in 5 males over the age of 50 will suffer a bone fracture in their remaining lifetimes. Fractures lead to huge healthcare expenditures, loss of mobility, and morbidity. Hip fractures almost always require surgery and mortality rates are extremely high in aged individuals following surgery. Elucidating the mechanisms that regulate basal bone turnover in young and aged individuals is central to our understanding of the pathophysiology of bone diseases and to the design of new effective countermeasures. Furthermore, cancers, Rheumatoid Arthritis (RA) and other autoimmune diseases are prevalent in the aging VA population. Rituximab, a B cell depleting antibody, used to treat B cell Non-Hodgkin's lymphoma and CTLA4-Ig (Abatacept) a costimulation inhibitor, are rapidly becoming the standard of care for refractory RA, with new applications for these drugs under intensive investigation for amelioration of numerous conditions including Crohn's disease, psoriasis and psoriatic arthritis, systemic lupus erythematosus; multiple sclerosis; Type I Diabetes, and as anti-rejection agents following solid organ and bone marrow transplantation. Our preliminary studies suggest that these immune modifying agents may illicit a serious skeletal complication that may seriously impact Veteran health by inducing osteoporosis and increasing fracture risk. Understanding the potential complications associated with Rituximab and Abatacept therapy may allow for the modification of the therapeutic regime in order to monitor or address skeletal complications in patients undergoing long term therapy with immune-modulating agents.
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