{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T14:31:56Z","timestamp":1782311516878,"version":"3.54.5"},"reference-count":43,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>The regulation of bone mass by the testis is a well-recognized mechanism, but the role of Leydig-specific marker insulin-like 3 peptide (INSL3) on the most abundant bone cell population, osteocytes, is unknown. In this study, we aimed to investigate the relationship between INSL3 and sclerostin, an osteocyte-specific protein that negatively regulates bone formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Serum sclerostin and INSL3 levels were evaluated in Klinefelter syndrome (KS) and healthy controls. In vitro effect of INSL3 on sclerostin production was evaluated in human cultured osteocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>A total of 103 KS patients and 60 age- and sex-matched controls were recruited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcome Measures<\/jats:title><jats:p>Serum sclerostin and INSL3 levels were assessed by enzyme-linked immunosorbent assay. Osteocytes were isolated by fluorescence-assisted cell sorting. Sclerostin expression was evaluated by western blot, immunofluorescence, and reverse transcription polymerase chain reaction. Measurement of bone mineral density was done by dual-energy X-ray absorptiometry at lumbar spine (L1\u2013L4) and femoral neck.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sclerostin levels were significantly increased in KS subjects, and negatively correlated with INSL3 levels in both cohorts and with bone mineral density in the KS group. Stimulation of cultured osteocytes with INSL3 at 10\u22127 M significantly decreased both sclerostin messenger RNA and protein expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We report a negative association between the testicular hormone INSL3 and the osteocytic negative regulator of bone formation, sclerostin. We further explored this association in vitro and showed that INSL3 was able to reduce sclerostin expression. These results add further knowledge on the emerging role of sclerostin as a therapeutic target for osteoporosis treatment.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2017-02762","type":"journal-article","created":{"date-parts":[[2018,2,14]],"date-time":"2018-02-14T19:06:57Z","timestamp":1518635217000},"page":"2033-2041","source":"Crossref","is-referenced-by-count":19,"title":["Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis\u2013Bone Crosstalk"],"prefix":"10.1210","volume":"103","author":[{"given":"Andrea","family":"Di Nisio","sequence":"first","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"De Toni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Santa","family":"Rocca","sequence":"additional","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Selice","sequence":"additional","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Taglialavoro","sequence":"additional","affiliation":[{"name":"Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Ferlin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Foresta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Operative Unit of Andrology and Medicine of Human Reproduction, University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2018,2,14]]},"reference":[{"issue":"2","key":"2020071623174343400_B1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1530\/JOE-11-0452","article-title":"The mutual dependence between bone and gonads","volume":"213","author":"Karsenty","year":"2012","journal-title":"J Endocrinol"},{"issue":"6","key":"2020071623174343400_B2","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1210\/jc.2011-3045","article-title":"Osteoporosis in men: an Endocrine Society clinical practice guideline","volume":"97","author":"Watts","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2020071623174343400_B3","doi-asserted-by":"crossref","first-page":"5952","DOI":"10.1210\/jc.2004-0575","article-title":"A novel circulating hormone of testis origin in humans","volume":"89","author":"Foresta","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2020071623174343400_B4","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1210\/jc.2004-2257","article-title":"Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis","volume":"90","author":"Bay","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2020071623174343400_B5","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/MED.0b013e3283453fe6","article-title":"Biological role and clinical significance of insulin-like peptide 3","volume":"18","author":"Ivell","year":"2011","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"issue":"9","key":"2020071623174343400_B6","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/nrendo.2013.135","article-title":"Testicular function and bone metabolism--beyond testosterone","volume":"9","author":"Ferlin","year":"2013","journal-title":"Nat Rev Endocrinol"},{"issue":"19","key":"2020071623174343400_B7","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1001\/jama.2008.668","article-title":"Genetic alterations associated with cryptorchidism","volume":"300","author":"Ferlin","year":"2008","journal-title":"JAMA"},{"issue":"1","key":"2020071623174343400_B8","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/gene.1029","article-title":"A transgenic insertion causing cryptorchidism in mice","volume":"30","author":"Overbeek","year":"2001","journal-title":"Genesis"},{"issue":"5","key":"2020071623174343400_B9","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1359\/jbmr.080204","article-title":"Mutations in the insulin-like factor 3 receptor are associated with osteoporosis","volume":"23","author":"Ferlin","year":"2008","journal-title":"J Bone Miner Res"},{"issue":"12","key":"2020071623174343400_B10","doi-asserted-by":"crossref","first-page":"e29733","DOI":"10.1371\/journal.pone.0029733","article-title":"Profiling insulin like factor 3 (INSL3) signaling in human osteoblasts","volume":"6","author":"Ferlin","year":"2011","journal-title":"PLoS One"},{"issue":"6","key":"2020071623174343400_B11","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/j.1365-2605.2006.00714.x","article-title":"Peripheral INSL3 concentrations decline with age in a large population of Australian men","volume":"29","author":"Anand-Ivell","year":"2006","journal-title":"Int J Androl"},{"issue":"6","key":"2020071623174343400_B12","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1093\/molehr\/gaq026","article-title":"Osteoporosis in Klinefelter\u2019s syndrome","volume":"16","author":"Ferlin","year":"2010","journal-title":"Mol Hum Reprod"},{"issue":"1","key":"2020071623174343400_B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1357-2725(03)00241-3","article-title":"The osteocyte","volume":"36","author":"Knothe Tate","year":"2004","journal-title":"Int J Biochem Cell Biol"},{"issue":"23","key":"2020071623174343400_B14","doi-asserted-by":"crossref","first-page":"6267","DOI":"10.1093\/emboj\/cdg599","article-title":"Osteocyte control of bone formation via sclerostin, a novel BMP antagonist","volume":"22","author":"Winkler","year":"2003","journal-title":"EMBO J"},{"issue":"20","key":"2020071623174343400_B15","doi-asserted-by":"crossref","first-page":"19883","DOI":"10.1074\/jbc.M413274200","article-title":"Sclerostin binds to LRP5\/6 and antagonizes canonical Wnt signaling","volume":"280","author":"Li","year":"2005","journal-title":"J Biol Chem"},{"issue":"6","key":"2020071623174343400_B16","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1359\/jbmr.080216","article-title":"Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength","volume":"23","author":"Li","year":"2008","journal-title":"J Bone Miner Res"},{"issue":"12","key":"2020071623174343400_B17","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1002\/jbmr.1718","article-title":"High serum sclerostin predicts the occurrence of osteoporotic fractures in postmenopausal women: the Center of Excellence for Osteoporosis Research Study","volume":"27","author":"Ardawi","year":"2012","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2020071623174343400_B18","doi-asserted-by":"crossref","first-page":"5866","DOI":"10.1074\/jbc.M705092200","article-title":"Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost\/sclerostin","volume":"283","author":"Robling","year":"2008","journal-title":"J Biol Chem"},{"issue":"12","key":"2020071623174343400_B19","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1359\/jbmr.070804","article-title":"Control of the SOST bone enhancer by PTH using MEF2 transcription factors","volume":"22","author":"Leupin","year":"2007","journal-title":"J Bone Miner Res"},{"issue":"15","key":"2020071623174343400_B20","doi-asserted-by":"crossref","first-page":"2450","DOI":"10.1016\/j.febslet.2011.06.019","article-title":"Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4","volume":"585","author":"Galea","year":"2011","journal-title":"FEBS Lett"},{"issue":"2","key":"2020071623174343400_B21","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1172\/JCI40568","article-title":"Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice","volume":"120","author":"Walker","year":"2010","journal-title":"J Clin Invest"},{"issue":"12","key":"2020071623174343400_B22","doi-asserted-by":"crossref","first-page":"4534","DOI":"10.1210\/en.2015-1244","article-title":"Regulation of sclerostin production in human male osteocytes by androgens: Experimental and clinical evidence","volume":"156","author":"Di Nisio","year":"2015","journal-title":"Endocrinology"},{"issue":"2","key":"2020071623174343400_B23","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1210\/jc.2002-021491","article-title":"Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study","volume":"88","author":"Bojesen","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2020071623174343400_B24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1385\/JCD:7:1:1","article-title":"Official positions of the International Society for Clinical Densitometry","volume":"7","author":"Leib","year":"2004","journal-title":"J Clin Densitom"},{"issue":"11","key":"2020071623174343400_B25","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1002\/art.24888","article-title":"Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis","volume":"60","author":"Appel","year":"2009","journal-title":"Arthritis Rheum"},{"issue":"6","key":"2020071623174343400_B26","doi-asserted-by":"crossref","first-page":"361","DOI":"10.2144\/0000113876","article-title":"Isolation and culture of primary osteocytes from the long bones of skeletally mature and aged mice","volume":"52","author":"Stern","year":"2012","journal-title":"Biotechniques"},{"issue":"1","key":"2020071623174343400_B27","doi-asserted-by":"crossref","first-page":"E138","DOI":"10.1152\/ajpendo.00228.2006","article-title":"T222P mutation of the insulin-like 3 hormone receptor LGR8 is associated with testicular maldescent and hinders receptor expression on the cell surface membrane","volume":"292","author":"Bogatcheva","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"41","key":"2020071623174343400_B28","doi-asserted-by":"crossref","first-page":"29809","DOI":"10.1074\/jbc.M113.485938","article-title":"Resorption controls bone anabolism driven by parathyroid hormone (PTH) receptor signaling in osteocytes","volume":"288","author":"Rhee","year":"2013","journal-title":"J Biol Chem"},{"issue":"3","key":"2020071623174343400_B29","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/j.2047-2927.2014.00204.x","article-title":"Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis","volume":"2","author":"Overvad","year":"2014","journal-title":"Andrology"},{"issue":"1","key":"2020071623174343400_B30","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1210\/jc.2011-2152","article-title":"Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults","volume":"97","author":"Amrein","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2020071623174343400_B31","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1002\/jbmr.479","article-title":"Determinants of serum sclerostin in healthy pre- and postmenopausal women","volume":"26","author":"Ardawi","year":"2011","journal-title":"J Bone Miner Res"},{"key":"2020071623174343400_B32","first-page":"1","article-title":"Role of sclerostin and dkk1 in bone remodeling in type 2 diabetic patients","volume":"43","author":"Wang","year":"2017","journal-title":"Endocr Res"},{"issue":"2","key":"2020071623174343400_B33","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00198-012-1978-x","article-title":"Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study","volume":"24","author":"Garnero","year":"2013","journal-title":"Osteoporos Int"},{"issue":"9","key":"2020071623174343400_B34","doi-asserted-by":"crossref","first-page":"3873","DOI":"10.1210\/jc.2013-2113","article-title":"Association of circulating sclerostin with bone mineral mass, microstructure, and turnover biochemical markers in healthy elderly men and women","volume":"98","author":"Durosier","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"2020071623174343400_B35","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1002\/jbmr.1888","article-title":"Correlates of bone microarchitectural parameters and serum sclerostin levels in men: the STRAMBO study","volume":"28","author":"Szulc","year":"2013","journal-title":"J Bone Miner Res"},{"issue":"6","key":"2020071623174343400_B36","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1159\/000446278","article-title":"Sclerostin and bone aging: a mini-review","volume":"62","author":"Hay","year":"2016","journal-title":"Gerontology"},{"key":"2020071623174343400_B37","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.bone.2016.10.012","article-title":"Sclerostin measurement in human disease: Validity and current limitations","volume":"96","author":"Costa","year":"2017","journal-title":"Bone"},{"issue":"4","key":"2020071623174343400_B38","doi-asserted-by":"crossref","first-page":"E739","DOI":"10.1210\/jc.2010-1878","article-title":"Bone mass in subjects with Klinefelter syndrome: role of testosterone levels and androgen receptor gene CAG polymorphism","volume":"96","author":"Ferlin","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2020071623174343400_B39","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s001980170158","article-title":"Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter\u2019s syndrome after long-term testosterone substitution","volume":"12","author":"van den Bergh","year":"2001","journal-title":"Osteoporos Int"},{"issue":"3","key":"2020071623174343400_B40","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1034\/j.1399-0004.2003.00036.x","article-title":"The natural history of sclerosteosis","volume":"63","author":"Hamersma","year":"2003","journal-title":"Clin Genet"},{"issue":"1","key":"2020071623174343400_B41","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1210\/jc.2011-2152","article-title":"Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults","volume":"97","author":"Amrein","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2020071623174343400_B42","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1359\/jbmr.081206","article-title":"Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis","volume":"24","author":"Li","year":"2009","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2020071623174343400_B43","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/jbmr.173","article-title":"Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody","volume":"26","author":"Padhi","year":"2011","journal-title":"J Bone Miner Res"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/103\/5\/2033\/24795122\/jc.2017-02762.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/103\/5\/2033\/24795122\/jc.2017-02762.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,14]],"date-time":"2022-08-14T10:36:26Z","timestamp":1660473386000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/103\/5\/2033\/4857436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,14]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2017-02762","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,5]]},"published":{"date-parts":[[2018,2,14]]}}}