title: Effects of estrogen on bone mRNA levels of sclerostin and other genes relevant to bone metabolism in postmenopausal women.
abstract: BACKGROUND
  Studies in postmenopausal women have shown that estrogen reduces circulating sclerostin levels, but effects of estrogen on skeletal sclerostin mRNA levels are unknown.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the effects of short-term estrogen treatment on bone mRNA levels of sclerostin and other genes relevant to bone metabolism.
  
  
  METHODS
  Needle bone biopsies were obtained from 20 postmenopausal women treated with transdermal estrogen for 3 weeks and 20 untreated controls. Quantitative PCR analyses were used to examine the expression of sclerostin and other genes related to bone metabolism, including 71 additional genes linked to bone density/fracture from genome-wide association studies.
  
  
  RESULTS
  Estrogen treatment was associated with lower bone sclerostin mRNA levels (by 48%, P<.05) and with lower (by 54%, P<.01) mRNA levels of the sclerostin-related protein, sclerostin domain-containing protein 1 (SOSTDC1), which is also a Wnt/bone morphogenetic protein inhibitor. Consistent with studies in mice showing that ovariectomy increased nuclear factor-κB (NF-κB) activation, we found that estrogen treatment was associated with a significant reduction in inflammatory genes as a group (P=.028), with bone mRNA levels of NFKB2 and RELB (both encoding proteins in the NF-κB transcription factor complex) being significantly reduced individual genes. Eight of the 71 genome-wide association study-related genes examined were modulated by estrogen (P<.05, false discovery rate<0.10).
  
  
  CONCLUSIONS
  In humans, estrogen-induced decreases in two key inhibitors of Wnt/bone morphogenetic protein signaling, sclerostin and SOSTDC1, along with reductions in NF-κB signaling, may be responsible for at least part of the protective effects of estrogen on bone.
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Roforth
authors.forename: Susan
authors.initials: S
authors.lastname: Demaray
authors.forename: Ulrike
authors.initials: U
authors.lastname: McGregor
authors.forename: Salman
authors.initials: S
authors.lastname: Kirmani
authors.forename: Louise K
authors.initials: LK
authors.lastname: McCready
authors.forename: James M
authors.initials: JM
authors.lastname: Peterson
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Drake
authors.forename: David G
authors.initials: DG
authors.lastname: Monroe
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000279:Administration, Cutaneous; D000368:Aged; D000369:Aged, 80 and over; D001707:Biopsy, Needle; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B / Q000502:physiology; D017698:Postmenopause / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D004967:Estrogens; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011506:Proteins; D012333:RNA, Messenger; C422903:SOST protein, human; C480733:SOSTDC1 protein, human