Osteoporosis is a significant and growing cause of morbidity and mortality in the United States. Cytokines produced in bone tissue can impact on bone resorption and formation, and may also play a role in the pathogenesis of osteoporosis. Defining the pathophysiologic mechanisms which cause osteoporosis, including cytokine-mediated mechanisms, has been hampered by the lack of convenient animal models. This proposal seeks to define the mechanisms which lead mice bearing in lck-IL-4 transgene to invariably develop severe osteoporosis. In the lck-IL-4 transgene, the transcription of the cytokine, interleukin-4 (IL-4), is directed by the proximal promoter of the lymphoid-specific protein tyrosine kinase gene, lck. This results in increased expression of IL-4 by T-lineage cells of the thymus, and, to a lesser extent, by peripheral and bone marrow lymphoid cells. It is hypothesized that the development of osteoporosis in lck-IL-4 mice requires transgene expression, particularly within bone tissue. This will be tested by generating additional lines of lck-IL-4 mice and by determining if: a) anti-IL-4 antibody treatment ameliorates osteoporosis; b) transgene expression by bone marrow T cells positively correlates with disease severity; c) osteoporosis requires, and can be adoptively transferred by, lck-IL-4 peripheral T cells; d) osteoporosis in lck-IL-4 mice is cured by transplantation with wild-type bone marrow. If none of these predictions are correct, it will be assumed that transgene integration has disrupted or altered an endogenous gene, which may be critical for bone homeostasis; this gene will be cloned and characterized. Alternatively, if any of these predictions are correct, additional transgenic mice will be generated in which increased IL-4 production is selectively limited to osteoblasts. This will directly test whether locally-increased IL-4 production in bone tissue is sufficient to induce osteoporosis. In parallel with the above studies, osteoblast and osteoclast function in bone will be assessed in situ by enzymo- and immuno-histochemical assays as well as by histomorphometry. Serum will be assayed to exclude metabolic and/or endocrinologic disorders as the cause of osteoporosis. These studies should provide new insights in to the pathogenesis of osteoporosis, and the role that IL-4 may play in this disease. They may also point out potential pitfalls of systemic immunotherapy with cytokines such as IL-4.
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