THE ROLE OF ESTROGEN IN BONE METABOLISM

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The candidate, Dr. Orhan K. Oz, is a diagnostic radiologist with previous scientific training in biophysics and tumor biology who seeks to become an independent investigator in the field of bone biology. To make this transition additional training will be necessary under the auspices of a career development award. His long-term career goals are to improve understanding of the pathophysiology of osteoporosis and to use this understanding as the basis for new therapeutic and diagnostic modalities for this disease. A development plan has been developed in which the candidate will conduct research on the role of estrogen in bone metabolism under the guidance of Drs. Zerwekh and Sakhaee experienced investigators in the field of bone biology. They will direct the basic science and clinical activities necessary for this project. Dr. Oz will become an active participant in data conferences and the local Bone Research Society - activities and an environment designed to enhance the candidate's transition to the field of bone science. The broad, long-term objective of the research is to elucidate the mechanisms of estrogen's effect on bone growth and metabolism and to use that information to develop new therapeutic and diagnostic modalities for osteoporosis. The enzyme aromatase synthesizes estrogen from its androgen precursors. Estrogen withdrawal in post-menopausal women is associated with an increase of bone turnover and acceleration of bone loss, that leads to an increased susceptibility to bone fractures and clinically relevant osteoporosis in one third of all women. The recent observation of a phenotype in men with aromatase deficiency or estrogen receptor deficiency comprising failure of epiphyseal fusion closure leading to excessive height together with osteopenia, is indicative of an important role of estrogen in bone growth and metabolism of males, as well as females. This leads to the issue of the origin of the estrogen involved in the bone metabolism and points to the possibility that local formation of estrogen within bone tissues may play an important role in bone mineral metabolism in both sexes. The central hypothesis is that estrogen is an important regulator of growth and metabolism which effects its regulatory function by influencing bone cell differentiation and the differentiated function of bone cells. A model of estrogen deficiency has recently been created, namely the aromatase-deficient (ArKO) mouse. Specific aims designed to test this hypothesis are: 1) To study the cellular distribution of aromatase in sections of bone tissue from mice of various ages; 2) To study bone metabolism in the ArKO knock-out mouse; 3) To determine whether aromatase deficiency affects bone cell differentiation and proliferation and; 4) To study expression of cytokines, critical to bone growth and metabolism, in bone marrow cells from aromtase deficient mice.