{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T22:44:47Z","timestamp":1782168287948,"version":"3.54.5"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fonds voor Wetenschappelijk Onderzoek Vlaanderen","award":["OZ8346"],"award-info":[{"award-number":["OZ8346"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Renal osteodystrophy (ROD) is a complex and serious complication of chronic kidney disease (CKD), a major global health problem caused by loss of renal function. Currently, the gold standard to accurately diagnose ROD is based on quantitative histomorphometric analysis of trabecular bone. Although this analysis encompasses the evaluation of osteoblast and osteoclast number\/activity, tfigurehe interest in osteocytes remains almost nihil. Nevertheless, this cell type is evidenced to perform a key role in bone turnover, particularly through its production of various bone proteins, such as sclerostin. In this study, we aim to investigate, in the context of ROD, to which extent an association exists between bone turnover and the abundance of osteocytes and osteocytic sclerostin expression in both the trabecular and cortical bone compartments. Additionally, the effect of parathyroid hormone (PTH) on bone sclerostin expression was examined in parathyroidectomized rats. Our results indicate that PTH exerts a direct inhibitory function on sclerostin, which in turn negatively affects bone turnover and mineralization. Moreover, this study emphasizes the functional differences between cortical and trabecular bone, as the number of (sclerostin-positive) osteocytes is dependent on the respective bone compartment. Finally, we evaluated the potential of sclerostin as a marker for CKD and found that the diagnostic performance of circulating sclerostin is limited and that changes in skeletal sclerostin expression occur more rapidly and more pronounced. The inclusion of osteocytic sclerostin expression and cortical bone analysis could be relevant when performing bone histomorphometric analysis for diagnostic purposes and to unravel pathological mechanisms of bone disease.<\/jats:p>","DOI":"10.3390\/nu15030598","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T01:59:03Z","timestamp":1674525543000},"page":"598","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Osteocytic Sclerostin Expression as an Indicator of Altered Bone Turnover"],"prefix":"10.3390","volume":"15","author":[{"given":"Yentl","family":"Huybrechts","sequence":"first","affiliation":[{"name":"Laboratory of Pathophysiology, University of Antwerp, 2610 Antwerp, Belgium"},{"name":"Center of Medical Genetics, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Evenepoel","sequence":"additional","affiliation":[{"name":"Laboratory of Nephrology, Department of Immunology and Microbiology, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8274-6356","authenticated-orcid":false,"given":"Mathias","family":"Haarhaus","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Campus Flemingsberg, 141 52 Stockholm, Sweden"},{"name":"Diaverum AB, 215 37 Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Cavalier","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, CHU de Li\u00e8ge, Universit\u00e9 de Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Dams","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5065-7858","authenticated-orcid":false,"given":"Wim","family":"Van Hul","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1463-6571","authenticated-orcid":false,"given":"Patrick C.","family":"D\u2019Haese","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4533-443X","authenticated-orcid":false,"given":"Anja","family":"Verhulst","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41413-020-0099-y","article-title":"Molecular mechanosensors in osteocytes","volume":"8","author":"Qin","year":"2020","journal-title":"Bone Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.bone.2007.12.224","article-title":"Osteocytes, mechanosensing and Wnt signaling","volume":"42","author":"Bonewald","year":"2008","journal-title":"Bone"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ecl.2016.09.003","article-title":"The Role of the Osteocyte in Bone and Nonbone Disease","volume":"46","author":"Bonewald","year":"2017","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3389\/fendo.2020.00165","article-title":"WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders","volume":"11","author":"Huybrechts","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_5","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."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"222","DOI":"10.5414\/CN109650","article-title":"Serum bone markers in ROD patients across the spectrum of decreases in GFR: Activin A increases before all other markers","volume":"91","author":"Lima","year":"2019","journal-title":"Clin. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1210\/jc.2013-2786","article-title":"Renal elimination of sclerostin increases with declining kidney function","volume":"99","author":"Cejka","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.bone.2017.01.023","article-title":"The chronic kidney disease\u2014Mineral bone disorder (CKD-MBD): Advances in pathophysiology","volume":"100","author":"Hruska","year":"2017","journal-title":"Bone"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s11914-017-0367-y","article-title":"Renal Osteodystrophy-Time for Common Nomenclature","volume":"15","author":"Ott","year":"2017","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1038\/sj.ki.5000414","article-title":"Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)","volume":"69","author":"Moe","year":"2006","journal-title":"Kidney Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1007\/s00223-021-00838-z","article-title":"The Role of Bone Biopsy in the Management of CKD-MBD","volume":"108","author":"Ferreira","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_12","first-page":"1608","article-title":"Bone biopsy practice patterns across Europe: The European renal osteodystrophy initiative-a position paper","volume":"32","author":"Evenepoel","year":"2017","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Dalle Carbonare, L., Valenti, M.T., Giannini, S., Gallieni, M., Stefani, F., Ciresa, R., Politi, C., and Fusaro, M.J.J.o.C.M. (2021). Bone Biopsy for Histomorphometry in Chronic Kidney Disease (CKD): State-of-the-Art and New Perspectives. J. Clin. Med., 10.","DOI":"10.3390\/jcm10194617"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1053\/j.ajkd.2015.06.023","article-title":"Diagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis","volume":"67","author":"Sprague","year":"2016","journal-title":"Am. J. Kidney Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15269","DOI":"10.1096\/fj.202000596R","article-title":"Relationship between GFR, intact PTH, oxidized PTH, non-oxidized PTH as well as FGF23 in patients with CKD","volume":"34","author":"Zeng","year":"2020","journal-title":"FASEB J."},{"key":"ref_16","unstructured":"Kopple, J.D., Massry, S.G., Kalantar-Zadeh, K., and Fouque, D. (2022). Nutritional Management of Renal Disease, Academic Press. [4th ed.]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/ki.2011.146","article-title":"Three feedback loops precisely regulating serum phosphate concentration","volume":"80","author":"Torres","year":"2011","journal-title":"Kidney Int."},{"key":"ref_18","unstructured":"Khan, M., Jose, A., and Sharma, S. (2022). StatPearls, StatPearls Publishing."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/nep.13014","article-title":"The use of bone turnover markers in chronic kidney disease-mineral and bone disorders","volume":"22","author":"Chiang","year":"2017","journal-title":"Nephrology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s40620-017-0408-8","article-title":"Circulating markers of bone turnover","volume":"30","author":"Vervloet","year":"2017","journal-title":"J. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1053\/j.ajkd.2021.07.027","article-title":"Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy","volume":"79","author":"Behets","year":"2022","journal-title":"Am. J. Kidney Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1097\/MNH.0000000000000798","article-title":"Clinical utility of bone turnover markers in patients with chronic kidney disease","volume":"31","author":"Smout","year":"2022","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/sdi.12844","article-title":"PTH determination in hemodialyzed patients\u2014A laboratory perspective","volume":"32","author":"Cavalier","year":"2019","journal-title":"Semin. Dial."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1007\/s00223-020-00781-5","article-title":"The Non-invasive Diagnosis of Bone Disorders in CKD","volume":"108","author":"Bover","year":"2021","journal-title":"Calcif. Tissue Int."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Behets, G.J., Viaene, L., Meijers, B., Blocki, F., Brandenburg, V.M., Verhulst, A., D\u2019Haese, P.C., and Evenepoel, P. (2017). Circulating levels of sclerostin but not DKK1 associate with laboratory parameters of CKD-MBD. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176411"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1002\/jbmr.4636","article-title":"Evaluation of Renal Osteodystrophy and Serum Bone-Related Biomarkers in a Peritoneal Dialysis Population","volume":"37","author":"Pereira","year":"2022","journal-title":"J. Bone Miner. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1681\/ASN.2017050584","article-title":"Diagnostic accuracy of biomarkers and imaging for bone turnover in renal osteodystrophy","volume":"29","author":"Salam","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1681\/ASN.2018060609","article-title":"Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance","volume":"30","author":"Opdebeeck","year":"2019","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s12325-020-01568-8","article-title":"Burden of chronic kidney disease by KDIGO categories of glomerular filtration rate and albuminuria: A systematic review","volume":"38","author":"Murton","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/ki.2014.349","article-title":"Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism","volume":"87","author":"Behets","year":"2015","journal-title":"Kidney Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1093\/clinchem\/36.2.271","article-title":"Immunoradiometric assay of parathyrin with polyclonal and monoclonal region-specific antibodies","volume":"36","author":"Bouillon","year":"1990","journal-title":"Clin. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee","volume":"28","author":"Dempster","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1002\/jbmr.345","article-title":"Sclerostin is a locally acting regulator of late-osteoblast\/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism","volume":"26","author":"Atkins","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.bone.2012.09.016","article-title":"Effects of PTH on osteocyte function","volume":"54","author":"Bellido","year":"2013","journal-title":"Bone"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bone.2016.10.007","article-title":"Role and mechanism of action of sclerostin in bone","volume":"96","author":"Sato","year":"2017","journal-title":"Bone"},{"key":"ref_36","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."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1097\/TP.0000000000001311","article-title":"Decreased Circulating Sclerostin Levels in Renal Transplant Recipients With Persistent Hyperparathyroidism","volume":"100","author":"Evenepoel","year":"2016","journal-title":"Transplantation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4577","DOI":"10.1210\/en.2005-0239","article-title":"Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: A novel mechanism for hormonal control of osteoblastogenesis","volume":"146","author":"Bellido","year":"2005","journal-title":"Endocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bone.2019.01.029","article-title":"Effects of parathyroidectomy on the biology of bone tissue in patients with chronic kidney disease and secondary hyperparathyroidism","volume":"121","author":"Pires","year":"2019","journal-title":"Bone"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1093\/ckj\/sfab081","article-title":"Sclerostin and DKK1 circulating levels associate with low bone turnover in patients with chronic kidney disease Stages 3 and 4","volume":"14","author":"Neto","year":"2021","journal-title":"Clin. Kidney J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1002\/jbmr.474","article-title":"Patients with sclerosteosis and disease carriers: Human models of the effect of sclerostin on bone turnover","volume":"26","author":"Hamdy","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/jor.23339","article-title":"Different bone remodeling levels of trabecular and cortical bone in response to changes in Wnt\/\u03b2-catenin signaling in mice","volume":"35","author":"Li","year":"2017","journal-title":"J. Orthop. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1159\/000489672","article-title":"Cortical or Trabecular Bone: What\u2019s the Difference?","volume":"47","author":"Ott","year":"2018","journal-title":"Am. J. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s00223-018-0491-4","article-title":"Association of Serum Sclerostin with Bone Sclerostin in Chronic Kidney Disease is Lost in Glucocorticoid Treated Patients","volume":"104","author":"Qureshi","year":"2019","journal-title":"Calcif. Tissue Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1159\/000511658","article-title":"Circulating Levels of Dickkopf-Related Protein 1 Decrease as Measured GFR Declines and Are Associated with PTH Levels","volume":"51","author":"Forster","year":"2020","journal-title":"Am. J. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s00223-021-00900-w","article-title":"Relationship Between Changes in Serum Levels of Intact Parathyroid Hormone and Sclerostin After a Single Dose of Zoledronic Acid: Results of a Phase 1 Pharmacokinetic Study","volume":"110","author":"Kuroda","year":"2022","journal-title":"Calcif. Tissue Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.32867\/inakidney.v1i1.3","article-title":"Hypertension. Sclerostin serum concentration in patients with predialysis CKD stage 3-5","volume":"1","author":"Pura","year":"2018","journal-title":"Indones. J. Kidney Hypertens."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/jbmr.1630","article-title":"Repression of osteocyte Wnt\/\u03b2-catenin signaling is an early event in the progression of renal osteodystrophy","volume":"27","author":"Sabbagh","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/j.kint.2016.12.029","article-title":"The complexity of chronic kidney disease\u2013mineral and bone disorder across stages of chronic kidney disease","volume":"91","author":"Graciolli","year":"2017","journal-title":"Kidney Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1373\/clinchem.2016.259085","article-title":"Bone Turnover Markers in the Diagnosis and Monitoring of Metabolic Bone Disease","volume":"63","author":"Greenblatt","year":"2017","journal-title":"Clin. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S2213-8587(18)30308-5","article-title":"Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): A prospective study","volume":"7","author":"Samelson","year":"2019","journal-title":"Lancet. Diabetes Endocrinol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/3\/598\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:14:25Z","timestamp":1760120065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/3\/598"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,23]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["nu15030598"],"URL":"https:\/\/doi.org\/10.3390\/nu15030598","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,23]]}}}