{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:48:13Z","timestamp":1790246893062,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T00:00:00Z","timestamp":1411948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Osteonectin\/SPARC is one of the most abundant noncollagenous extracellular matrix proteins in bone, regulating collagen fiber assembly and promoting osteoblast differentiation. Osteonectin-null and haploinsufficient mice have low-turnover osteopenia, indicating that osteonectin contributes to normal bone formation. In male idiopathic osteoporosis patients, osteonectin 3\u2032 untranslated region (UTR) single-nucleotide polymorphism (SNP) haplotypes that differed only at SNP1599 (rs1054204) were previously associated with bone mass. Haplotype A (containing SNP1599G) was more frequent in severely affected patients, whereas haplotype B (containing SNP1599C) was more frequent in less affected patients and healthy controls. We hypothesized that SNP1599 contributes to variability in bone mass by modulating osteonectin levels. Osteonectin 3\u2032 UTR reporter constructs demonstrated that haplotype A has a repressive effect on gene expression compared with B. We found that SNP1599G contributed to an miR-433 binding site, and miR-433 inhibitor relieved repression of the haplotype A, but not B, 3\u2032 UTR reporter construct. We tested our hypothesis in vivo, using a knock-in approach to replace the mouse osteonectin 3\u2032 UTR with human haplotype A or B 3\u2032 UTR. Compared with haplotype A mice, bone osteonectin levels were higher in haplotype B mice. B mice displayed higher bone formation rate and gained more trabecular bone with age. When parathyroid hormone was administered intermittently, haplotype B mice gained more cortical bone area than A mice. Cultured marrow stromal cells from B mice deposited more mineralized matrix and had higher osteocalcin mRNA compared with A mice, demonstrating a cell-autonomous effect on differentiation. Altogether, SNP1599 differentially regulates osteonectin expression and contributes to variability in bone mass, by a mechanism that may involve differential targeting by miR-433. This work validates the findings of the previous candidate gene study, and it assigns a physiological function to a common osteonectin allele, providing support for its role in the complex trait of skeletal phenotype. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2378","type":"journal-article","created":{"date-parts":[[2014,9,29]],"date-time":"2014-09-29T09:16:38Z","timestamp":1411982198000},"page":"723-732","source":"Crossref","is-referenced-by-count":39,"title":["A Single Nucleotide Polymorphism in Osteonectin 3\u2032 Untranslated Region Regulates Bone Volume and Is Targeted by miR-433"],"prefix":"10.1093","volume":"30","author":[{"given":"Neha S","family":"Dole","sequence":"first","affiliation":[{"name":"Center for Molecular MedicineUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Kapinas","sequence":"additional","affiliation":[{"name":"Center for Molecular MedicineUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine B","family":"Kessler","sequence":"additional","affiliation":[{"name":"Center for Molecular MedicineUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siu-Pok","family":"Yee","sequence":"additional","affiliation":[{"name":"Gene Targeting and Transgenic FacilityUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic SurgeryUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata C","family":"Pereira","sequence":"additional","affiliation":[{"name":"Mattel Children's HospitalUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M","family":"Delany","sequence":"additional","affiliation":[{"name":"Center for Molecular MedicineUniversity of Connecticut Health CenterFarmingtonCTUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,9,29]]},"reference":[{"issue":"2","key":"2024020319173151700_jbmr2378-bib-0001","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1677\/joe.0.1660235","article-title":"Role of genetic factors in the pathogenesis of osteoporosis","volume":"66","author":"Stewart","year":"2000","journal-title":"J Endocrinol."},{"issue":"3","key":"2024020319173151700_jbmr2378-bib-0002","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1210\/edrv.23.3.0464","article-title":"Genetics of osteoporosis","volume":"23","author":"Peacock","year":"2002","journal-title":"Endocr Rev."},{"key":"2024020319173151700_jbmr2378-bib-0003","doi-asserted-by":"crossref","first-page":"6723","DOI":"10.1007\/s11033-012-1496-0","article-title":"Evaluation of ERalpha and VDR gene polymorphisms in relation to bone mineral density in Turkish postmenopausal women","volume":"39","author":"Kurt","year":"2012","journal-title":"Mol Biol Rep."},{"key":"2024020319173151700_jbmr2378-bib-0004","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1097\/00008571-200112000-00004","article-title":"Association of polymorphisms of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis","volume":"11","author":"Yamada","year":"2001","journal-title":"Pharmacogenetics."},{"issue":"2","key":"2024020319173151700_jbmr2378-bib-0005","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.intimp.2013.04.008","article-title":"Association between osteoprotegerin genetic variants and bone mineral density in Chinese women","volume":"16","author":"Shen","year":"2013","journal-title":"Int Immunopharmacol."},{"key":"2024020319173151700_jbmr2378-bib-0006","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1007\/s11033-010-9963-y","article-title":"Sp1 polymorphism in collagen I alpha1 gene is associated with osteoporosis in lumbar spine of Mexican women","volume":"38","author":"Falcon-Ramirez","year":"2011","journal-title":"Mol Biol Rep."},{"issue":"9","key":"2024020319173151700_jbmr2378-bib-0007","first-page":"3116","article-title":"Genome screen for QTLs contributing to normal variation in bone mineral density and osteoporosis","volume":"85","author":"Koller","year":"2000","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2024020319173151700_jbmr2378-bib-0008","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1210\/en.2006-0443","article-title":"Increased notch 1 expression and attenuated stimulatory G protein coupling to adenylyl cyclase in osteonectin-null osteoblasts","volume":"148","author":"Kessler","year":"2007","journal-title":"Endocrinology."},{"issue":"6","key":"2024020319173151700_jbmr2378-bib-0009","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1359\/jbmr.2003.18.6.1005","article-title":"Infrared analysis of the mineral and matrix in bones of osteonectin-null mice and their wild-type controls","volume":"18","author":"Boskey","year":"2003","journal-title":"J Bone Miner Res."},{"issue":"7","key":"2024020319173151700_jbmr2378-bib-0010","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1172\/JCI7039","article-title":"Osteopenia and decreased bone formation in osteonectin-deficient mice","volume":"105","author":"Delany","year":"2000","journal-title":"J Clin Invest."},{"issue":"6","key":"2024020319173151700_jbmr2378-bib-0011","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1210\/en.2002-221044","article-title":"Osteonectin-null mutation compromises osteoblast formation, maturation, and survival","volume":"144","author":"Delany","year":"2003","journal-title":"Endocrinology."},{"issue":"2","key":"2024020319173151700_jbmr2378-bib-0012","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.bone.2008.03.024","article-title":"Accentuated osteoclastic response to parathyroid hormone undermines bone mass acquisition in osteonectin-null mice","volume":"43","author":"Machado","year":"2008","journal-title":"Bone."},{"issue":"7","key":"2024020319173151700_jbmr2378-bib-0013","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1007\/s00198-007-0523-9","article-title":"Osteonectin\/SPARC polymorphisms in Caucasian men with idiopathic osteoporosis","volume":"19","author":"Delany","year":"2008","journal-title":"Osteoporos Int."},{"key":"2024020319173151700_jbmr2378-bib-0014","first-page":"2799","article-title":"Insulin-like growth factor-I in men with idiopathic osteoporosis","volume":"82","author":"Kurland","year":"1997","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020319173151700_jbmr2378-bib-0015","first-page":"2576","article-title":"Normal growth hormone secretory reserve in men with idiopathic osteoporosis and reduced circulating levels of insulin-like growth factor-I","volume":"83","author":"Kurland","year":"1998","journal-title":"J Clin Endocrinol Metab."},{"issue":"4","key":"2024020319173151700_jbmr2378-bib-0016","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0092-8674(01)00583-9","article-title":"When the message goes awry: disease-producing mutations that influence mRNA content and performance","volume":"107","author":"Mendell","year":"2001","journal-title":"Cell."},{"issue":"1","key":"2024020319173151700_jbmr2378-bib-0017","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/jbmr.186","article-title":"Polymorphisms in predicted miRNA binding sites and osteoporosis","volume":"26","author":"Lei","year":"2011","journal-title":"J Bone Miner Res."},{"issue":"10","key":"2024020319173151700_jbmr2378-bib-0018","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1093\/hmg\/ddq083","article-title":"A mutation in the 3\u2032-UTR of the HDAC6 gene abolishing the post-transcriptional regulation mediated by hsa-miR-433 is linked to a new form of dominant X-linked chondrodysplasia","volume":"19","author":"Simon","year":"2010","journal-title":"Hum Mol Genet."},{"issue":"2","key":"2024020319173151700_jbmr2378-bib-0019","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/jbmr.5650100203","article-title":"Development and characterization of a conditionally immortalized human fetal osteoblastic cell line","volume":"10","author":"Harris","year":"1995","journal-title":"J Bone Miner Res."},{"issue":"33","key":"2024020319173151700_jbmr2378-bib-0020","doi-asserted-by":"crossref","first-page":"25221","DOI":"10.1074\/jbc.M110.116137","article-title":"miR-29 modulates Wnt signaling in human osteoblasts through a positive feedback loop","volume":"285","author":"Kapinas","year":"2010","journal-title":"J Biol Chem."},{"issue":"10","key":"2024020319173151700_jbmr2378-bib-0021","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1261\/rna.5248604","article-title":"Fast and effective prediction of microRNA\/target duplexes","volume":"10","author":"Rehmsmeier","year":"2004","journal-title":"RNA."},{"issue":"10","key":"2024020319173151700_jbmr2378-bib-0022","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.lfs.2013.01.015","article-title":"MiR-433 mediates ERR\u03b3-suppressed osteoblast differentiation via direct targeting to Runx2 mRNA in C3H10T1\/2 cells","volume":"92","author":"Kim","year":"2013","journal-title":"Life Sci."},{"issue":"1","key":"2024020319173151700_jbmr2378-bib-0023","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/jcb.22243","article-title":"miR-29 suppression of osteonectin in osteoblasts: regulation during differentiation and by canonical Wnt signaling","volume":"108","author":"Kapinas","year":"2009","journal-title":"J Cell Biochem."},{"key":"2024020319173151700_jbmr2378-bib-0024","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.bone.2004.05.013","article-title":"In vivo and in vitro evidence that the high osteoblastic activity in C3H\/HeJ mice compared to C57BL\/6J mice is intrinsic to bone cells","volume":"35","author":"Sheng","year":"2004","journal-title":"Bone."},{"key":"2024020319173151700_jbmr2378-bib-0025","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1359\/jbmr.2003.18.2.175","article-title":"Congenic strains of mice for verification and genetic decomposition of quantitative trait loci for femoral bone mineral density","volume":"18","author":"Shultz","year":"2003","journal-title":"J Bone Miner Res."},{"issue":"9","key":"2024020319173151700_jbmr2378-bib-0026","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1172\/JCI12939","article-title":"SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury","volume":"107","author":"Bradshaw","year":"2001","journal-title":"J Clin Invest."},{"issue":"5","key":"2024020319173151700_jbmr2378-bib-0027","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.matbio.2012.03.002","article-title":"Bone matrix osteonectin limits prostate cancer cell growth and survival","volume":"31","author":"Kapinas","year":"2012","journal-title":"Matrix Biol."},{"key":"2024020319173151700_jbmr2378-bib-0028","doi-asserted-by":"crossref","first-page":"22062","DOI":"10.1074\/jbc.M700167200","article-title":"SPARC regulates processing of procollagen I and collagen fibrillogenesis in dermal fibroblasts","volume":"282","author":"Rentz","year":"2007","journal-title":"J Biol Chem."},{"key":"2024020319173151700_jbmr2378-bib-0029","first-page":"2016","article-title":"Evaluation of SPARC as a candidate gene of juvenile-onset primary open-angle glaucoma by mutation and copy number analyses","volume":"16","author":"Chen","year":"2010","journal-title":"Mol Vis."},{"issue":"22","key":"2024020319173151700_jbmr2378-bib-0030","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1359\/jbmr.061006","article-title":"Dose-response effects of intermittent PTH on cancellous bone in hindlimb unloaded rats","volume":"2007","author":"Turner","year":"2007","journal-title":"J Bone Miner Res."},{"issue":"3 Pt 1","key":"2024020319173151700_jbmr2378-bib-0031","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1152\/ajpcell.1998.274.3.C734","article-title":"Basic fibroblast growth factor destabilizes osteonectin mRNA in osteoblasts","volume":"274","author":"Delany","year":"1998","journal-title":"Am J Physiol."},{"key":"2024020319173151700_jbmr2378-bib-0032","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1038\/sj.onc.1206713","article-title":"v-Jun downregulates the SPARC target gene by binding to the proximal promoter indirectly through Sp1\/3","volume":"22","author":"Chamboredon","year":"2003","journal-title":"Oncogene."},{"key":"2024020319173151700_jbmr2378-bib-0033","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1002\/jbmr.5650061015","article-title":"Expression of the osteonectin gene potentially controlled by multiple cis- and trans-acting factors in cultured bone cells","volume":"6","author":"Dominguez","year":"1991","journal-title":"J Bone Miner Res."},{"key":"2024020319173151700_jbmr2378-bib-0034","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0378-1119(93)90423-Z","article-title":"Partial characterization of a novel 'GGA' factor which binds to the osteonectin promoter in bovine bone cells","volume":"130","author":"Ibaraki","year":"1993","journal-title":"Gene."},{"key":"2024020319173151700_jbmr2378-bib-0035","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1210\/mend-3-12-2079","article-title":"Opposing influences of glucocorticoid and retinoic acid on transcriptional control in preosteoblasts","volume":"3","author":"Ng","year":"1989","journal-title":"Mol Endocrinol."},{"key":"2024020319173151700_jbmr2378-bib-0036","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1007\/BF02555904","article-title":"Diverse forms of stress result in changes in cellular levels of osteonectin\/SPARC without altering mRNA levels in osteoligament cells","volume":"49","author":"Sauk","year":"1991","journal-title":"Calcif Tissue Int."},{"key":"2024020319173151700_jbmr2378-bib-0037","first-page":"2482","article-title":"Mutational screening of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus","volume":"17","author":"De Bonis","year":"2011","journal-title":"Mol Vis."},{"key":"2024020319173151700_jbmr2378-bib-0038","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1093\/rheumatology\/keh460","article-title":"Single-nucleotide polymorphisms in the SPARC gene are not associated with susceptibility to scleroderma","volume":"44","author":"Lagan","year":"2005","journal-title":"Rheumatology."},{"key":"2024020319173151700_jbmr2378-bib-0039","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1111\/j.1440-1746.2009.06009.x","article-title":"Secreted protein acidic and rich in cysteine (SPARC) gene polymorphism association with hepatocellular carcinoma in Italian patients","volume":"24","author":"Segat","year":"2009","journal-title":"J Gastroenterol Hepatol."},{"key":"2024020319173151700_jbmr2378-bib-0040","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1002\/art.10601","article-title":"Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to scleroderma","volume":"46","author":"Zhou","year":"2002","journal-title":"Arthritis Rheum."},{"key":"2024020319173151700_jbmr2378-bib-0041","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1093\/nar\/29.1.308","article-title":"dbSNP: the NCBI database of genetic variation","volume":"29","author":"Sherry","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"2024020319173151700_jbmr2378-bib-0042","first-page":"305","article-title":"Racial differences in bone strength","volume":"118","author":"Hochberg","year":"2007","journal-title":"Trans Am Clin Climatol Assoc."},{"key":"2024020319173151700_jbmr2378-bib-0043","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1359\/jbmr.2003.18.12.2238","article-title":"Racial differences in bone mineral density in older men","volume":"18","author":"George","year":"2003","journal-title":"J Bone Miner Res."},{"issue":"7","key":"2024020319173151700_jbmr2378-bib-0044","first-page":"1102","article-title":"Bone mineral density-affecting genes in Africans","volume":"98","author":"Gong","year":"2006","journal-title":"J Natl Med Assoc."},{"key":"2024020319173151700_jbmr2378-bib-0045","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrg3118","article-title":"Rare and common variants: twenty arguments","volume":"13","author":"Gibson","year":"2012","journal-title":"Nat Rev Genet."},{"key":"2024020319173151700_jbmr2378-bib-0046","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1007\/s11914-012-0113-4","article-title":"Genetics and the individualized prediction of fracture","volume":"10","author":"Nguyen","year":"2012","journal-title":"Curr Osteoporos Rep."},{"key":"2024020319173151700_jbmr2378-bib-0047","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2147\/TACG.S52047","article-title":"Clinical impact of recent genetic discoveries in osteoporosis","volume":"6","author":"Mitchell","year":"2013","journal-title":"Appl Clin Genet."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2378","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/30\/4\/723\/56568596\/jbmr2378.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/30\/4\/723\/56568596\/jbmr2378.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:53:05Z","timestamp":1710341585000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/30\/4\/723-732\/7599288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,29]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2014,9,29]]},"published-print":{"date-parts":[[2015,4,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2378","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,4,1]]},"published":{"date-parts":[[2014,9,29]]}}}