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Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids
S. Kousteni,1J.-R. Chen,1T. Bellido,1L. Han,1A. A. Ali,1C. A. O'Brien,1L. Plotkin,1Q. Fu,1A. T. Mancino,125Y. Wen,125A. M. Vertino,15C. C. Powers,1S. A. Stewart,14R. Ebert,3A. M. Parfitt,1R. S. Weinstein,15R. L. Jilka,15S. C. Manolagas15*
We show that sex steroids protect the adult murine
skeleton through a mechanism that is distinct from that used to
preservethe mass and function of reproductive organs. The classical
genotropicactions of sex steroid receptors are dispensable for their
boneprotective effects, but essential for their effects on
reproductivetissues. A synthetic ligand (4-estren-3,17-diol)
that reproducesthe nongenotropic effects of sex steroids, without
affecting classicaltranscription, increases bone mass and strength in
ovariectomizedfemales above the level of the estrogen-replete state
and is atleast as effective as dihydrotestosterone in orchidectomized
males,without affecting reproductive organs. Such ligands merit
investigationas potential therapeutic alternatives to hormone
replacement forosteoporosis of bone mass in both women and men.
1 Division of Endocrinology and Metabolism,
Department of Internal Medicine, and Center for Osteoporosis and
Metabolic Bone Diseases;
2 Department of Surgery;
3 Department of Pathology;
4 Biometry Division; University of Arkansas for
Medical Sciences, Little Rock, AR 72205, USA.
5 Central Arkansas Veterans Health Care System,
Little Rock, AR 72205, USA.
*
To whom correspondence should be addressed. E-mail:
manolagasstavros{at}uams.edu
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|Full Text »
,17
-diol)
that reproduces the nongenotropic effects of sex steroids, without
affecting classical transcription, increases bone mass and strength in
ovariectomized females above the level of the estrogen-replete state
and is at least as effective as dihydrotestosterone in orchidectomized
males, without affecting reproductive organs. Such ligands merit
investigation as potential therapeutic alternatives to hormone
replacement for osteoporosis of bone mass in both women and men.
