Function of Estrogen on Bone and the Characterization of the Skeletal Phenotype of Steroid Receptor Coactivator (SRC)-1 KO Mice

Estrogen is known to have important effects on both reproductive and non-reproductive tissues. In this study it was demonstrated that an E2 dose of as little as 5µg/kg/d completely prevented loss of cancellous bone (at the lumbar spine and tibial metaphysis), and it had no stimulatory effects on th...

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1. Verfasser: Mödder, Ulrike
Beteiligte: Arnold, Rudolf (Professor Dr. med.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2005
Innere Medizin
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Zusammenfassung:Estrogen is known to have important effects on both reproductive and non-reproductive tissues. In this study it was demonstrated that an E2 dose of as little as 5µg/kg/d completely prevented loss of cancellous bone (at the lumbar spine and tibial metaphysis), and it had no stimulatory effects on the uterus in 6 month old C57BL/6 mice. By contrast, when 3 month old C56BL/6 mice were administered the same doses of E2 and studied after 1 month; the 5 g/kg/d dose resulted in uterine hypertrophy, but was not able to prevent loss of cancellous bone. These results, thus, a) provide data on the dose response for E2 effects on mouse bone; and b) indicate that the relative effects of E2 on bone versus the uterus are highly dependent on the particular experimental conditions used. This issue needs to be considered in evaluating agents with potential ?selective? effects on bone versus reproductive tissues. 2. Steroid receptor coactivator (SRC)-1 is an important nuclear receptor coactivator that enhances estrogen action in a number of tissues. The presented study has established that SRC-1 KO female and male mice have a comparable skeletal phenotype to their WT littermates at 3 and 5 months of age. The treatment of ovariectomized SRC-1 KO female mice with a physiological concentration of E2 led to a predominant defect in estrogen action in cancellous bone, with a relative preservation of estrogen effects on cortical bone. However, the deficit in estrogen action in the female SRC-1 KO mice was overcome by using a higher dose of E2, consistent with estrogen resistance in bone. The differential expression of the interacting nuclear receptors, ER- and -, in cancellous versus cortical bone and the specific interactions of these receptor isoforms with SRC-1 may, in part, explain why cancellous bone is more susceptible to loss of SRC-1 than cortical bone. 3. In contrast, the SRC-1 male mice lack the defect in estrogen action on bone. These findings are consistent with a gender-related difference that in male mice ER-α but not ER- is mediating the estrogen action on bone. The treatment of SRC-1 KO male mice with 5α-DHT resulted in a significant better response of the cortical bone from the KO male mice compared to the WT mice. The findings lead to the suggestion that in male WT mice SRC-1 might inhibit the action of 5α-DHT on bone. 4. Peripheral tissues including bone are dependent on circulating active sex steroids, but also synthesize estrogen from circulating C19 precursor locally. The conversion of the precursors to estrogen is mediated by aromatase. In this work it has been shown that human and rodent osteoblastic cells at different stages of differentiation express aromatase. Furthermore, the expression and activity has been demonstrated in bone tissues of mice and rats. Although a regulation of the aromatase by E2 was reported by other investigators in certain tissues, such as breast tissue and mammary glands, I did not find a change of aromatase expression and activity in the various bone cell lines and bone tissue under estrogen deficiency and estrogen exposure.