A serious obstacle to the rational design of innovative approaches for preventing and/or treating osteoporosis is the idiopathic nature of postmenopausal bone loss. Menopause is the most important risk factor for osteoporosis. However, not all postmenopausal women develop osteoporotic fractures indicating that cessation of the menstrual cycle is insufficient to fully account for the disorder. Our working hypothesis is that the denovo production and metabolism of estrogens are among the most important factors influencing the rate of postmenopausal bone loss. Estrone (E1) and its metabolites, 16alpha-Hydroxyl estrone ( (16alpha-OHE1) and 2-hydroxyesterone (2-OHE1), are the most abundant estrogens in postmenopausal women. 16alpha-OHE1 has been recently shown to be a negative risk factor (reduced risk) for postmenopausal bone loss, whereas 2-OHE1 has been positive risk factor (increased risk). 2-OHE1 does not have estrogenic activity in ovariectomized (OVX'd) rats. In contrast, 16alpha-OHE1 appears to be a tissue selective estrogen agonist with a profile of activity similar to the anti-breast drug tamoxifen; 16alpha-OHE1 is a much more effective estrogen agonist on bone and liver than on reproductive tissues. These observations suggest that differences in the skeletal activities on 2-OHE1 and 16-alpha-OHE1 are responsible for the observed association between bone mass and circulating levels of these metabolites in postmenopausal women. We propose to test this hypothesis in ovary intact and OVX'd rats.
The specific aims are to determine the dose response effects of 2-OHE1 and 16alpha-OHE1 on the expression of immediate response genes in bone and other estrogen target tissues; and establish the long-term effects of the estrone metabolites on bone architecture, turnover and strength. The proposed research will characterize the probably cellular mechanisms of action. The results of these studies are likely to be relevant to women because of the similarity between postmenopausal bone loss and OVX-induced bone loss in rats, as well as the previous success the rat model has enjoyed for predicting the response of the human skeleton to estrogen agonists and markers to predict the rate of postmenopausal bone loss; 2) manipulation of estrone metabolism by changes in diet or by pharmacological intervention may be a valuable tool for reducing bone loss; and 3) analogs of 16alpha-OHE1 may be useful for prevention and treatment of postmenopausal osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR045233-01A2
Application #
2899931
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Sharrock, William J
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kennedy, Angela M; Shogren, Kristen L; Zhang, Minzhi et al. (2005) 17beta-estradiol-dependent activation of signal transducer and activator of transcription-1 in human fetal osteoblasts is dependent on Src kinase activity. Endocrinology 146:201-7
Hatano, Hiroshi; Siegel, Herrick J; Yamagiwa, Hiroshi et al. (2004) Identification of estrogen-regulated genes during fracture healing, using DNA microarray. J Bone Miner Metab 22:224-35
Doran, Patrick M; Turner, Russell T; Chen, David et al. (2004) Native osteoprotegerin gene transfer inhibits the development of murine osteolytic bone disease induced by tumor xenografts. Exp Hematol 32:351-9
Lotinun, Sutada; Sibonga, Jean D; Turner, Russell T (2003) Triazolopyrimidine (trapidil), a platelet-derived growth factor antagonist, inhibits parathyroid bone disease in an animal model for chronic hyperparathyroidism. Endocrinology 144:2000-7
Fitzpatrick, L A; Turner, R T; Ritman, E R (2003) Endochondral bone formation in the heart: a possible mechanism of coronary calcification. Endocrinology 144:2214-9
Sibonga, J D; Lotinun, S; Evans, G L et al. (2003) Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat. Endocrinology 144:785-92
Lotinun, Sutada; Westerlind, Kim C; Kennedy, Angela M et al. (2003) Comparative effects of long-term continuous release of 16 alpha-hydroxyestrone and 17 beta-estradiol on bone, uterus, and serum cholesterol in ovariectomized adult rats. Bone 33:124-31
Maran, A; Zhang, M; Kennedy, A M et al. (2002) 2-methoxyestradiol induces interferon gene expression and apoptosis in osteosarcoma cells. Bone 30:393-8
Sibonga, Jean D; Sommer, Ulrike; Turner, Russell T (2002) Evidence that 2-methoxyestradiol suppresses proliferation and accelerates apoptosis in normal rat growth plate chondrocytes. J Cancer Res Clin Oncol 128:477-83
Bouxsein, Mary L; Rosen, Clifford J; Turner, Charles H et al. (2002) Generation of a new congenic mouse strain to test the relationships among serum insulin-like growth factor I, bone mineral density, and skeletal morphology in vivo. J Bone Miner Res 17:570-9

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