title: Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women.
abstract: Inhibition of sclerostin, a glycoprotein secreted by osteocytes, offers a new therapeutic paradigm for treatment of osteoporosis (OP) through its critical role as Wnt/catenin signaling regulator. This study describes the epigenetic regulation of SOST expression in bone biopsies of postmenopausal women. We correlated serum sclerostin to bone mineral density (BMD), fractures, and bone remodeling parameters, and related these findings to epigenetic and genetic disease mechanisms. Serum sclerostin and bone remodeling biomarkers were measured in two postmenopausal groups: healthy (BMD T-score > -1) and established OP (BMD T-score < -2.5, with at least one low-energy fracture). Bone specimens were used to analyze SOST mRNAs, single nucleotide polymorphisms (SNPs), and DNA methylation changes. The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively). Serum sclerostin and bone SOST mRNA expression correlated positively with age-adjusted and BMI-adjusted total hip BMD (r = 0.47 and r = 0.43, respectively; both p < 0.0005), and inversely to serum bone turnover markers. Five SNPs, one of which replicates in an independent population-based genomewide association study (GWAS), showed association with serum sclerostin or SOST mRNA levels under an additive model (p = 0.0016 to 0.0079). Genetic and epigenetic changes in SOST influence its bone mRNA expression and serum sclerostin levels in postmenopausal women. The observations suggest that increased SOST promoter methylation seen in OP is a compensatory counteracting mechanism, which lowers serum sclerostin concentrations and reduces inhibition of Wnt signaling in an attempt to promote bone formation.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Lovisenberg Diakonale Hospital, Oslo, Norway; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Sjur
authors.initials: S
authors.lastname: Reppe
authors.forename: Agate
authors.initials: A
authors.lastname: Noer
authors.forename: Runa M
authors.initials: RM
authors.lastname: Grimholt
authors.forename: Bjarni V
authors.initials: BV
authors.lastname: Halldórsson
authors.forename: Carolina
authors.initials: C
authors.lastname: Medina-Gomez
authors.forename: Vigdis T
authors.initials: VT
authors.lastname: Gautvik
authors.forename: Ole Kristoffer
authors.initials: OK
authors.lastname: Olstad
authors.forename: Jens Petter
authors.initials: JP
authors.lastname: Berg
authors.forename: Harish
authors.initials: H
authors.lastname: Datta
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Philippe
authors.initials: P
authors.lastname: Collas
authors.forename: Kaare M
authors.initials: KM
authors.lastname: Gautvik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015519:Bone Density / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000097:blood* / Q000235:genetics*; D001842:Bone and Bones / Q000473:pathology; D003710:Demography; D005260:Female; D050723:Fractures, Bone / Q000097:blood* / Q000235:genetics* / Q000652:urine; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008745:Methylation; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000652:urine; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017698:Postmenopause / Q000097:blood* / Q000235:genetics / Q000652:urine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D012333:RNA, Messenger; C422903:SOST protein, human
keywords: DISEASES AND DISORDERS OF/RELATED TO BONE; EPIGENETICS; GENETIC RESEARCH; HUMAN ASSOCIATION STUDIES; OSTEOPOROSIS