Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis–Bone Crosstalk
Abstract Context 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 an...
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| Veröffentlicht in: | The journal of clinical endocrinology and metabolism 2018-05, Vol.103 (5), p.2033-2041 |
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| creator | Di Nisio, Andrea De Toni, Luca Rocca, Maria Santa Ghezzi, Marco Selice, Riccardo Taglialavoro, Giuseppe Ferlin, Alberto Foresta, Carlo |
| description | Abstract
Context
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.
Design
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.
Patients
A total of 103 KS patients and 60 age- and sex-matched controls were recruited.
Main Outcome Measures
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–L4) and femoral neck.
Results
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 10−7 M significantly decreased both sclerostin messenger RNA and protein expression.
Conclusions
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.
We report a negative association between INSL3 and sclerostin in vivo and in vitro, suggesting new pathways in the emerging role of testis in the regulation of bone metabolism. |
| doi_str_mv | 10.1210/jc.2017-02762 |
| format | Article |
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Context
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.
Design
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.
Patients
A total of 103 KS patients and 60 age- and sex-matched controls were recruited.
Main Outcome Measures
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–L4) and femoral neck.
Results
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 10−7 M significantly decreased both sclerostin messenger RNA and protein expression.
Conclusions
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.
We report a negative association between INSL3 and sclerostin in vivo and in vitro, suggesting new pathways in the emerging role of testis in the regulation of bone metabolism.</description><identifier>ISSN: 0021-972X</identifier><identifier>EISSN: 1945-7197</identifier><identifier>DOI: 10.1210/jc.2017-02762</identifier><identifier>PMID: 29452406</identifier><language>eng</language><publisher>Washington, DC: Endocrine Society</publisher><subject>Adult ; Bone density ; Bone growth ; Bone mass ; Bone mineral density ; Bone Morphogenetic Proteins - blood ; Bone Morphogenetic Proteins - genetics ; Bone Morphogenetic Proteins - metabolism ; Bone turnover ; Case-Control Studies ; Cells, Cultured ; Dual energy X-ray absorptiometry ; Energy measurement ; Enzyme-linked immunosorbent assay ; Female ; Femur ; Fluorescence ; Gene expression ; Gene Expression - drug effects ; Genetic Markers - genetics ; Humans ; Immunofluorescence ; Insulin ; Insulin - blood ; Insulin - metabolism ; Insulin - pharmacology ; Klinefelter Syndrome - blood ; Klinefelter Syndrome - genetics ; Klinefelter Syndrome - metabolism ; Klinefelter Syndrome - pathology ; Klinefelter's syndrome ; Male ; Metabolism ; Middle Aged ; Osteocytes ; Osteocytes - drug effects ; Osteocytes - metabolism ; Osteocytes - pathology ; Osteogenesis ; Osteoporosis ; Parathyroid Hormone - pharmacology ; Polymerase chain reaction ; Proteins - metabolism ; Proteins - pharmacology ; Retrospective Studies ; Reverse transcription ; SOST protein ; Spine ; Spine (lumbar) ; Therapeutic applications ; Young Adult</subject><ispartof>The journal of clinical endocrinology and metabolism, 2018-05, Vol.103 (5), p.2033-2041</ispartof><rights>Copyright © 2018 Endocrine Society 2018</rights><rights>Copyright © Oxford University Press 2015</rights><rights>Copyright © 2018 Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4382-38a8b1dbf4d509f3cadaefd526b0dfc8d68f682a32f39bf3c21475adebdb59593</citedby><cites>FETCH-LOGICAL-c4382-38a8b1dbf4d509f3cadaefd526b0dfc8d68f682a32f39bf3c21475adebdb59593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2036652155?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,21388,21389,27924,27925,33530,33531,33744,33745,43659,43805,64385,64387,64389,72469,73123,73128,73129,73131</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29452406$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Nisio, Andrea</creatorcontrib><creatorcontrib>De Toni, Luca</creatorcontrib><creatorcontrib>Rocca, Maria Santa</creatorcontrib><creatorcontrib>Ghezzi, Marco</creatorcontrib><creatorcontrib>Selice, Riccardo</creatorcontrib><creatorcontrib>Taglialavoro, Giuseppe</creatorcontrib><creatorcontrib>Ferlin, Alberto</creatorcontrib><creatorcontrib>Foresta, Carlo</creatorcontrib><title>Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis–Bone Crosstalk</title><title>The journal of clinical endocrinology and metabolism</title><addtitle>J Clin Endocrinol Metab</addtitle><description>Abstract
Context
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.
Design
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.
Patients
A total of 103 KS patients and 60 age- and sex-matched controls were recruited.
Main Outcome Measures
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–L4) and femoral neck.
Results
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 10−7 M significantly decreased both sclerostin messenger RNA and protein expression.
Conclusions
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.
We report a negative association between INSL3 and sclerostin in vivo and in vitro, suggesting new pathways in the emerging role of testis in the regulation of bone metabolism.</description><subject>Adult</subject><subject>Bone density</subject><subject>Bone growth</subject><subject>Bone mass</subject><subject>Bone mineral density</subject><subject>Bone Morphogenetic Proteins - blood</subject><subject>Bone Morphogenetic Proteins - genetics</subject><subject>Bone Morphogenetic Proteins - metabolism</subject><subject>Bone turnover</subject><subject>Case-Control Studies</subject><subject>Cells, Cultured</subject><subject>Dual energy X-ray absorptiometry</subject><subject>Energy measurement</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Female</subject><subject>Femur</subject><subject>Fluorescence</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Genetic Markers - genetics</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Insulin</subject><subject>Insulin - blood</subject><subject>Insulin - metabolism</subject><subject>Insulin - pharmacology</subject><subject>Klinefelter Syndrome - blood</subject><subject>Klinefelter Syndrome - genetics</subject><subject>Klinefelter Syndrome - metabolism</subject><subject>Klinefelter Syndrome - pathology</subject><subject>Klinefelter's syndrome</subject><subject>Male</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Osteocytes</subject><subject>Osteocytes - drug effects</subject><subject>Osteocytes - metabolism</subject><subject>Osteocytes - pathology</subject><subject>Osteogenesis</subject><subject>Osteoporosis</subject><subject>Parathyroid Hormone - pharmacology</subject><subject>Polymerase chain reaction</subject><subject>Proteins - metabolism</subject><subject>Proteins - pharmacology</subject><subject>Retrospective Studies</subject><subject>Reverse transcription</subject><subject>SOST protein</subject><subject>Spine</subject><subject>Spine (lumbar)</subject><subject>Therapeutic applications</subject><subject>Young Adult</subject><issn>0021-972X</issn><issn>1945-7197</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kstuEzEUhkcIRNPCki2yxIbNFF_Gc2HXRpREROkiRWJneexjOqljB9tDlB2vgHhDngSnKSAhYcmyj_zpP5ffRfGC4HNCCX6zVucUk6bEtKnpo2JCuoqXDemax8UEY0rKrqGfTorTGNcYk6ri7GlxQjNEK1xPiu9L-CzT8BXQRYxeDfnuHbqEtANwaKUsBB_T4JB0Gs2XqwVDOZhHb2UCjWbjRjp0HRN4tU8Q77EMfLCDAwM2QUCrvdPBb-AtWsIOzQaXIjI-oBvIwvHntx-X3gGa5jwxSXv3rHhipI3w_OE8Kz5evbuZzsrF9fv59GJRqoq1tGStbHuie1NpjjvDlNQSjOa07rE2qtV1a-qWSkYN6_r8TknVcKmh1z3veMfOitdH3W3wX8Zci9gMUYG10oEfo6AYM5zH1LUZffUPuvZjcLm6TLG65pRwnqnySKlDKwGM2IZhI8NeECwOXom1EgevxL1XmX_5oDr2G9B_6N_mZKA6Ajt_GGS8s-MOgrgFadOtwHlVddOWWbLFPEdl3oz-bcyP2_-VcPwu7Bf_N61V</recordid><startdate>201805</startdate><enddate>201805</enddate><creator>Di Nisio, Andrea</creator><creator>De Toni, Luca</creator><creator>Rocca, Maria Santa</creator><creator>Ghezzi, Marco</creator><creator>Selice, Riccardo</creator><creator>Taglialavoro, Giuseppe</creator><creator>Ferlin, Alberto</creator><creator>Foresta, Carlo</creator><general>Endocrine Society</general><general>Copyright Oxford University Press</general><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>201805</creationdate><title>Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis–Bone Crosstalk</title><author>Di Nisio, Andrea ; De Toni, Luca ; Rocca, Maria Santa ; Ghezzi, Marco ; Selice, Riccardo ; Taglialavoro, Giuseppe ; Ferlin, Alberto ; Foresta, Carlo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4382-38a8b1dbf4d509f3cadaefd526b0dfc8d68f682a32f39bf3c21475adebdb59593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Bone density</topic><topic>Bone growth</topic><topic>Bone mass</topic><topic>Bone mineral density</topic><topic>Bone Morphogenetic Proteins - blood</topic><topic>Bone Morphogenetic Proteins - genetics</topic><topic>Bone Morphogenetic Proteins - metabolism</topic><topic>Bone turnover</topic><topic>Case-Control Studies</topic><topic>Cells, Cultured</topic><topic>Dual energy X-ray absorptiometry</topic><topic>Energy measurement</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Female</topic><topic>Femur</topic><topic>Fluorescence</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Genetic Markers - genetics</topic><topic>Humans</topic><topic>Immunofluorescence</topic><topic>Insulin</topic><topic>Insulin - blood</topic><topic>Insulin - metabolism</topic><topic>Insulin - pharmacology</topic><topic>Klinefelter Syndrome - blood</topic><topic>Klinefelter Syndrome - genetics</topic><topic>Klinefelter Syndrome - metabolism</topic><topic>Klinefelter Syndrome - pathology</topic><topic>Klinefelter's syndrome</topic><topic>Male</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Osteocytes</topic><topic>Osteocytes - drug effects</topic><topic>Osteocytes - metabolism</topic><topic>Osteocytes - pathology</topic><topic>Osteogenesis</topic><topic>Osteoporosis</topic><topic>Parathyroid Hormone - pharmacology</topic><topic>Polymerase chain reaction</topic><topic>Proteins - metabolism</topic><topic>Proteins - pharmacology</topic><topic>Retrospective Studies</topic><topic>Reverse transcription</topic><topic>SOST protein</topic><topic>Spine</topic><topic>Spine (lumbar)</topic><topic>Therapeutic applications</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Nisio, Andrea</creatorcontrib><creatorcontrib>De Toni, Luca</creatorcontrib><creatorcontrib>Rocca, Maria Santa</creatorcontrib><creatorcontrib>Ghezzi, Marco</creatorcontrib><creatorcontrib>Selice, Riccardo</creatorcontrib><creatorcontrib>Taglialavoro, Giuseppe</creatorcontrib><creatorcontrib>Ferlin, Alberto</creatorcontrib><creatorcontrib>Foresta, Carlo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of clinical endocrinology and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Nisio, Andrea</au><au>De Toni, Luca</au><au>Rocca, Maria Santa</au><au>Ghezzi, Marco</au><au>Selice, Riccardo</au><au>Taglialavoro, Giuseppe</au><au>Ferlin, Alberto</au><au>Foresta, Carlo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis–Bone Crosstalk</atitle><jtitle>The journal of clinical endocrinology and metabolism</jtitle><addtitle>J Clin Endocrinol Metab</addtitle><date>2018-05</date><risdate>2018</risdate><volume>103</volume><issue>5</issue><spage>2033</spage><epage>2041</epage><pages>2033-2041</pages><issn>0021-972X</issn><eissn>1945-7197</eissn><abstract>Abstract
Context
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.
Design
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.
Patients
A total of 103 KS patients and 60 age- and sex-matched controls were recruited.
Main Outcome Measures
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–L4) and femoral neck.
Results
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 10−7 M significantly decreased both sclerostin messenger RNA and protein expression.
Conclusions
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.
We report a negative association between INSL3 and sclerostin in vivo and in vitro, suggesting new pathways in the emerging role of testis in the regulation of bone metabolism.</abstract><cop>Washington, DC</cop><pub>Endocrine Society</pub><pmid>29452406</pmid><doi>10.1210/jc.2017-02762</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| issn | 0021-972X 1945-7197 |
| language | eng |
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| source | ProQuest One Community College; MEDLINE; ProQuest Central (Alumni Edition); Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete; Oxford University Press Journals All Titles (1996-Current); ProQuest Central UK/Ireland; Alma/SFX Local Collection; ProQuest Central |
| subjects | Adult Bone density Bone growth Bone mass Bone mineral density Bone Morphogenetic Proteins - blood Bone Morphogenetic Proteins - genetics Bone Morphogenetic Proteins - metabolism Bone turnover Case-Control Studies Cells, Cultured Dual energy X-ray absorptiometry Energy measurement Enzyme-linked immunosorbent assay Female Femur Fluorescence Gene expression Gene Expression - drug effects Genetic Markers - genetics Humans Immunofluorescence Insulin Insulin - blood Insulin - metabolism Insulin - pharmacology Klinefelter Syndrome - blood Klinefelter Syndrome - genetics Klinefelter Syndrome - metabolism Klinefelter Syndrome - pathology Klinefelter's syndrome Male Metabolism Middle Aged Osteocytes Osteocytes - drug effects Osteocytes - metabolism Osteocytes - pathology Osteogenesis Osteoporosis Parathyroid Hormone - pharmacology Polymerase chain reaction Proteins - metabolism Proteins - pharmacology Retrospective Studies Reverse transcription SOST protein Spine Spine (lumbar) Therapeutic applications Young Adult |
| title | Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis–Bone Crosstalk |
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