Estrogen (Es) plays a fundamental role in regulating the growth and maintenance of the skeleton. Es deficiency results in osteopenia and is an important contributing factor to the increased fracture risk in aging women. Es replacement therapy can reduce the fracture risk in postmenopausal women by preserving bone mass but the potential health risks of treatment include increased incidence of breast and uterine cancer. It may be possible to minimize the complications of Es replacement with tissue-specific partial Es agonists. The """"""""antiestrogen"""""""" tamoxifen (TAM) is an example of an Es analog that is an Es antagonist on the uterus under treatment conditions for which it is an agonist on the skeleton. The mechanism for the mixed Es agonist/antagonist effects of TAM are unknown. Furthermore, in spite of its important clinical manifestations, the mechanisms and even precise actions of Es on bone cells are unknown. We intend to test the hypothesis that the effects of Es to inhibit bone turnover are mediated by osteoblast-derived growth factors. Although Es may influence multiple growth factors, we will concentrate our efforts on insulin-like growth factor-I (IGF-I). IGF-I is produced by and has effects on bone cells and has been shown to mediate many of the effects of Es on normal uterine and liver cells as well as on breast cancer cells. The differences in the response of bone and uterus to TAM may result from the differential regulation of IGF-I expression in the respective tissues. Also, the pronounced opposing actions of Es and growth hormone (GH) on bone growth may be due to opposing regulation of IGF-I expression by the respective hormones. We will test these possibilities in rats by: 1) determining the effects of Es and TAM on IGF-I expression in bone and uterus, 2) localizing the cells that express IGF-I in bone, 3) establishing whether the pronounced inhibitory effects of Es and TAM on bone matrix synthesis are counteracted with IGF-I, and 4) determining whether Es and TAM interact with GH to regulate IGF-I expression. The results of the proposed studies are expected to increase our understanding of the mechanisms by which Es modulates numbers and activities of bone cells, information that could accelerate the rational design of innovative approaches for the prevention and/or treatment of postmenopausal bone loss.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR041418-01
Application #
3161853
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1991-09-30
Project End
1994-08-31
Budget Start
1991-09-30
Budget End
1992-08-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Turner, R T; Evans, G L; Dobnig, H (2000) The high-affinity estrogen receptor antagonist ICI 182,780 has no effect on bone growth in young male rats. Calcif Tissue Int 66:461-4
Turner, R T; Evans, G L (2000) 2-Methoxyestradiol inhibits longitudinal bone growth in normal female rats. Calcif Tissue Int 66:465-9
Schmidt, I U; Wakley, G K; Turner, R T (2000) Effects of estrogen and progesterone on tibia histomorphometry in growing rats. Calcif Tissue Int 67:47-52
Sibonga, J D; Zhang, M; Ritman, E L et al. (2000) Restoration of bone mass in the severely osteopenic senescent rat. J Gerontol A Biol Sci Med Sci 55:B71-8; discussion B79-84
Turner, R T (1999) Mice, estrogen, and postmenopausal osteoporosis. J Bone Miner Res 14:187-91
Turner, R T (1999) Mechanical signaling in the development of postmenopausal osteoporosis. Lupus 8:388-92
Turner, R T; Kidder, L S; Zhang, M et al. (1999) Estrogen has rapid tissue-specific effects on rat bone. J Appl Physiol 86:1950-8
Gill, R K; Turner, R T; Wronski, T J et al. (1998) Orchiectomy markedly reduces the concentration of the three isoforms of transforming growth factor beta in rat bone, and reduction is prevented by testosterone. Endocrinology 139:546-50
Turner, R T; Evans, G L; Sluka, J P et al. (1998) Differential responses of estrogen target tissues in rats including bone to clomiphene, enclomiphene, and zuclomiphene. Endocrinology 139:3712-20
Zhang, M; Turner, R T (1998) The effects of spaceflight on mRNA levels for cytokines in proximal tibia of ovariectomized rats. Aviat Space Environ Med 69:626-9

Showing the most recent 10 out of 38 publications