Our long-term objective is to understand the factors that underlie and aggravate postmenopausal bone loss, as a basis for developing effective rational strategies for managing postmenopausal osteoporosis. Impaired calcium absorption is often associated with postmenopausal osteoporosis and is believed to aggravate the bone loss in this condition. The exact cause of the impaired calcium absorption is uncertain. In the pst, 1,25(OH)2 vitamin D deficiency was considered the primary cause, but recent studies indicate that the intestine contains estrogen receptors and that estrogen may be directly involved. The hypotheses to be tested are in three parts: (1) The expression of estrogen receptors (ERs) in intestinal cells is under physiological regulation. (2) The intestinal ERs act in concert with the 1,25(OH)2 vitamin D endocrine system to regulate calcium absorption, and (3) The presence of ERs in intestinal cells has important pathophysiological implications. To evaluate these hypotheses we have four Specific Aims: (1) To examine the factors that modulate the expression and activity of intestinal estrogen receptors including athe affects of aging; (2) To assess the functional relationship between estrogen and the receptors for 1,25(OH)2 vitamin D in the intestine; (3) To examine the impact of therapy with estrogen receptor antagonist on gut absorption of calcium and on intestinal estrogen receptors in young and aged rats, and (4) To use a new mouse model with insertional disruption of the estrogen receptor gene to further investigate the role of estrogen and the estrogen receptor in intestinal calcium absorption and bone metabolism. The procedures that will be used to examine the Specific Aims include ovariectomy, immunocytochemistry, in situ hybridization, Scatchard analysis, Northern blot analysis, solution hybridization, radioimmunoassays, immunodiffusion assays, in vivo and in vitro calcium absorption and atomic absorption spectrophotometry. The studies proposed in this project are important in, at least, four respects: First, they will establish a direct physiological role for estrogen in intestinal calcium absorption. Second, they will establish the mechanism by which estrogen deficiency results in the calcium malabsorption that is believed to aggravate bone loss in postmenopausal osteoporosis and other hypoestrogenic conditions. Third, they will elucidate the functional relationship between estrogen, intestinal vitamin D receptor, and calcium absorption. Fourth, they will provide critical information on the consequences of estrogen antagonist therapy to intestinal calcium absorption.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013309-04
Application #
2732583
Study Section
Special Emphasis Panel (ZRG4-GRM (01))
Project Start
1995-08-15
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Wang, L; Kalu, D N; Banu, J et al. (2006) Effects of ageing on the biomechanical properties of rat articular cartilage. Proc Inst Mech Eng H 220:573-8
Banu, Jameela; Kalu, Dike N (2004) Site-specific effects of cerivastatin on bone in male Sprague-Dawley rats. Bone 34:432-42
Wang, L; McMahan, C A; Banu, J et al. (2003) Rodent model for investigating the effects of estrogen on bone and muscle relationship during growth. Calcif Tissue Int 72:151-5
Banu, J; Wang, L; Kalu, D N (2003) Effects of increased muscle mass on bone in male mice overexpressing IGF-I in skeletal muscles. Calcif Tissue Int 73:196-201
Banu, J; Wang, L; Kalu, D N (2002) Age-related changes in bone mineral content and density in intact male F344 rats. Bone 30:125-30
Banu, J; Kalu, D N (2002) Effects of cerivastatin and parathyroid hormone on the lumbar vertebra of aging male Sprague-Dawley rats. Bone 31:173-9
Wang, L; Orhii, P B; Banu, J et al. (2001) Bone anabolic effects of separate and combined therapy with growth hormone and parathyroid hormone on femoral neck in aged ovariectomized osteopenic rats. Mech Ageing Dev 122:89-104
Banu, M J; Orhii, P B; Wang, L et al. (2001) Separate and combined effects of growth hormone and parathyroid hormone on cortical bone osteopenia in ovariectomized aged rats. Aging (Milano) 13:282-92
Wang, L; Banu, J; McMahan, C A et al. (2001) Male rodent model of age-related bone loss in men. Bone 29:141-8
Wang, L; Orhii, P B; Banu, J et al. (2001) Effects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats. Bone 28:202-7

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