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Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women.
J Bone Miner Res. 2015 Feb; 30(2):249-56.JB

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+Show Affiliations

Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; Lovisenberg Diakonale Hospital, Oslo, Norway; Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25155887

Citation

Reppe, Sjur, et al. "Methylation of Bone SOST, Its mRNA, and Serum Sclerostin Levels Correlate Strongly With Fracture Risk in Postmenopausal Women." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 30, no. 2, 2015, pp. 249-56.
Reppe S, Noer A, Grimholt RM, et al. Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. J Bone Miner Res. 2015;30(2):249-56.
Reppe, S., Noer, A., Grimholt, R. M., Halldórsson, B. V., Medina-Gomez, C., Gautvik, V. T., Olstad, O. K., Berg, J. P., Datta, H., Estrada, K., Hofman, A., Uitterlinden, A. G., Rivadeneira, F., Lyle, R., Collas, P., & Gautvik, K. M. (2015). Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 30(2), 249-56. https://doi.org/10.1002/jbmr.2342
Reppe S, et al. Methylation of Bone SOST, Its mRNA, and Serum Sclerostin Levels Correlate Strongly With Fracture Risk in Postmenopausal Women. J Bone Miner Res. 2015;30(2):249-56. PubMed PMID: 25155887.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. AU - Reppe,Sjur, AU - Noer,Agate, AU - Grimholt,Runa M, AU - Halldórsson,Bjarni V, AU - Medina-Gomez,Carolina, AU - Gautvik,Vigdis T, AU - Olstad,Ole Kristoffer, AU - Berg,Jens Petter, AU - Datta,Harish, AU - Estrada,Karol, AU - Hofman,Albert, AU - Uitterlinden,André G, AU - Rivadeneira,Fernando, AU - Lyle,Robert, AU - Collas,Philippe, AU - Gautvik,Kaare M, PY - 2014/03/24/received PY - 2014/07/27/revised PY - 2014/08/12/accepted PY - 2014/8/27/entrez PY - 2014/8/27/pubmed PY - 2016/2/24/medline KW - DISEASES AND DISORDERS OF/RELATED TO BONE KW - EPIGENETICS KW - GENETIC RESEARCH KW - HUMAN ASSOCIATION STUDIES KW - OSTEOPOROSIS SP - 249 EP - 56 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J. Bone Miner. Res. VL - 30 IS - 2 N2 - 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. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/25155887/Methylation_of_bone_SOST_its_mRNA_and_serum_sclerostin_levels_correlate_strongly_with_fracture_risk_in_postmenopausal_women_ L2 - https://doi.org/10.1002/jbmr.2342 DB - PRIME DP - Unbound Medicine ER -