title: Regulation of circulating sclerostin levels by sex steroids in women and in men.
abstract: Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels. E treatment of postmenopausal women (n = 17) for 4 weeks led to a 27% decrease in serum sclerostin levels [versus +1% in controls (n = 18), p < .001]. Similarly, in 59 elderly men, we eliminated endogenous E and T production and studied them under conditions of physiologic T and E replacement, and then following withdrawal of T or E, we found that E, but not T, prevented increases in sclerostin levels following induction of sex steroid deficiency. In both sexes, changes in sclerostin levels correlated with changes in bone-resorption, but not bone-formation, markers (r = 0.62, p < .001, and r = 0.33, p = .009, for correlations with changes in serum C-terminal telopeptide of type 1 collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E but not by T. Moreover, consistent with recent data indicating important effects of Wnts on osteoclastic cells, our findings suggest that in humans, changes in sclerostin production may contribute to effects of E on bone resorption.
authors.affiliation: Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Ulrike Il
authors.initials: UI
authors.lastname: Mödder
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Clowes
authors.forename: Kelley
authors.initials: K
authors.lastname: Hoey
authors.forename: James M
authors.initials: JM
authors.lastname: Peterson
authors.forename: Louise
authors.initials: L
authors.lastname: McCready
authors.forename: Merry Jo
authors.initials: MJ
authors.lastname: Oursler
authors.forename: B Lawrence
authors.initials: BL
authors.lastname: Riggs
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000097:blood*; D016723:Bone Remodeling / Q000187:drug effects; D024042:Collagen Type I / Q000097:blood; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood; D010455:Peptides / Q000097:blood; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; D005819:Genetic Markers; D053244:Osteoprotegerin; D010455:Peptides; C422903:SOST protein, human; C052929:collagen type I trimeric cross-linked peptide; D013739:Testosterone; D004958:Estradiol