{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T04:11:34Z","timestamp":1792987894392,"version":"4.5.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chronic kidney disease-mineral bone disorder is the irreversible loss of kidney function leading to altered mineral homeostasis and bone loss, commonly referred to as renal osteodystrophy. Bone marrow adipose tissue (BMAT) accumulates in clinical CKD and animal models of this disease, but the mechanism(s) responsible are unclear. This study sought to determine the relationship between BMAT distribution and bone structure and to establish whether disease progression directly affected: 1) the commitment of bone marrow mesenchymal stromal cells (BMSCs) to osteoblastic (OPC) and adipogenic (APC) precursor cells, and 2) the differentiation of BMSCs to mature adipocytes and osteoblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eight-week-old male C57BL\/6J mice received a diet supplemented with 0.2% adenine for \u22645 weeks to induce CKD. Control mice received the same diet without adenine. Serum biochemistries were quantified using a biochemistry analyzer and plasma hormone levels by ELISA. Bone phenotypes were evaluated by \u00b5CT. The same bones were decalcified and stained with 1% osmium tetroxide and BMAT quantified using \u00b5CT. Precursor cell populations in bone marrow were quantified by flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The development of CKD during the early stages of the disease was confirmed by elevated serum concentrations of blood urea nitrogen and creatinine from 3-weeks\u2019 induction. After 5-weeks\u2019 induction, trabecular bone microarchitecture including bone mineral density was compromised whereas cortical bone area and thickness were decreased in CKD tibiae after 3- and 5-weeks\u2019 induction. Compared to age-matched controls, proximal tibial BMAT tended to increase in CKD mice by 3 weeks\u2019 induction and this reached statistical significance after 5-weeks where there was a negative correlation between regulated BMAT accumulation and trabecular bone loss. BMAT accumulation was not due to calorie deficiency and was positively correlated with circulating adiponectin, but not with circulating leptin or corticosterone. During CKD onset (weeks 1-2) of CKD, BMSCs from CKD mice had enhanced adipogenic potential but the proportions of OPCs and APCs within the bone marrow were unchanged.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In experimental CKD, BMAT expansion depends on CKD duration and does not appear to be driven by hypoleptinemia or hypercorticosteronemia, or by altered precursor cell differentiation during CKD onset.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1666681","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T04:12:17Z","timestamp":1758514337000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Bone marrow adipose tissue expansion and bone loss in experimental chronic kidney disease is independent of altered bone marrow stromal cell lineage determination"],"prefix":"10.3389","volume":"16","author":[{"given":"Worachet","family":"Promruk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Cawthorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie E.","family":"Bourne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soher N.","family":"Jayash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aine","family":"Pears","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Staines","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise A.","family":"Stephen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Farquharson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.kisu.2021.11.003","article-title":"Epidemiology of chronic kidney disease: an update 2022","volume":"12","author":"Kovesdy","year":"2022","journal-title":"Kidney Int Suppl"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30045-3","article-title":"Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"395","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.271","article-title":"Early chronic kidney disease-mineral bone disorder stimulates vascular calcification","volume":"85","author":"Fang","year":"2014","journal-title":"Kidney Int"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms21186846","article-title":"Osteoporosis in patients with chronic kidney diseases: A systemic review","volume":"21","author":"Hsu","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3094","article-title":"Serum phosphate is associated with fracture risk: the rotterdam study and mrOS","volume":"32","author":"Campos-Obando","year":"2017","journal-title":"J Bone Mineral Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.kint.2016.01.024","article-title":"Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease","volume":"90","author":"Carrillo-L\u00f3pez","year":"2016","journal-title":"Kidney Int"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.04.024","article-title":"Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function","volume":"90","author":"Dhayat","year":"2016","journal-title":"Kidney Int"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5001754","article-title":"Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study","volume":"70","author":"Jadoul","year":"2006","journal-title":"Kidney Int"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1916","article-title":"Rapid cortical bone loss in patients with chronic kidney disease","volume":"28","author":"Nickolas","year":"2013","journal-title":"J Bone Mineral Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1242\/dev.102210","article-title":"Skeletal stem cells","volume":"142","author":"Bianco","year":"2015","journal-title":"Development"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.21037\/qims-23-530","article-title":"Assessment of bone marrow fat by 3-Tesla magnetic resonance spectroscopy in patients with chronic kidney disease","volume":"13","author":"Borelli","year":"2023","journal-title":"Quant Imaging Med Surg"},{"key":"B12","doi-asserted-by":"publisher","first-page":"3073","DOI":"10.1038\/s41598-017-03059-3","article-title":"Knee subchondral bone perfusion and its relationship to marrow fat and trabeculation on multi-parametric MRI and micro-CT in experimental CKD","volume":"7","author":"Wang","year":"2017","journal-title":"Sci Rep"},{"key":"B13","doi-asserted-by":"publisher","first-page":"312","DOI":"10.21037\/atm.2019.06.44","article-title":"Cinacalcet attenuated bone loss via inhibiting parathyroid hormone-induced endothelial-to-adipocyte transition in chronic kidney disease rats","volume":"7","author":"Ni","year":"2019","journal-title":"Ann Transl Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2016.03.001","article-title":"Bone marrow adipose tissue: formation, function and regulation","volume":"28","author":"Suchacki","year":"2016","journal-title":"Curr Opin Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2019.03.038","article-title":"Inverse correlation between trabecular bone volume and bone marrow adipose tissue in rats treated with osteoanabolic agents","volume":"123","author":"Costa","year":"2019","journal-title":"Bone"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.04.011","article-title":"Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk","volume":"23","author":"Stern","year":"2016","journal-title":"Cell Metab"},{"key":"B17","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1515\/hmbci-2016-0012","article-title":"Bone marrow adipose tissue as an endocrine organ: close to the bone","author":"Sulston","year":"2016","journal-title":"Horm Mol Biol Clin Investig"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.01.001","article-title":"Parathyroid hormone directs bone marrow mesenchymal cell fate","volume":"25","author":"Fan","year":"2017","journal-title":"Cell Metab"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1477","article-title":"Expansion of bone marrow adipose tissue during caloric restriction is associated with increased circulating glucocorticoids and not with hypoleptinemia","volume":"157","author":"Cawthorn","year":"2016","journal-title":"Endocrinology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-22-0097","article-title":"Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy","volume":"254","author":"Hsu","year":"2022","journal-title":"J Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20190329","article-title":"Conditional deletion of E11\/Podoplanin in bone protects against ovariectomy-induced increases in osteoclast formation and activity","volume":"40","author":"Staines","year":"2020","journal-title":"Biosci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e10439","DOI":"10.1002\/jbm4.10439","article-title":"Ablation of enpp6 results in transient bone hypomineralization","volume":"5","author":"Dillon","year":"2021","journal-title":"JBMR Plus"},{"key":"B23","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s13293-024-00626-y","article-title":"Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton","volume":"15","author":"Bourne","year":"2024","journal-title":"Biol Sex Differ"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-411619-1.00007-0","article-title":"Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo","volume":"537","author":"Scheller","year":"2014","journal-title":"Methods Enzymol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"7808","DOI":"10.1038\/ncomms8808","article-title":"Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues","volume":"6","author":"Scheller","year":"2015","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/jbmr\/zjae104","article-title":"Calorie restriction in mice impairs cortical but not trabecular peak bone mass by suppressing bone remodeling","volume":"39","author":"Liu","year":"2024","journal-title":"J Bone Miner Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1007\/s00223-021-00882-9","article-title":"Proton pump inhibitors inhibit PHOSPHO1 activity and matrix mineralisation in vitro","volume":"109","author":"Staines","year":"2021","journal-title":"Calcif Tissue Int"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66063","article-title":"Distinct skeletal stem cell types orchestrate long bone skeletogenesis","volume":"10","author":"Ambrosi","year":"2021","journal-title":"Elife"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5","DOI":"10.2174\/1874303X02013010005","article-title":"Prevalence of osteopenia and osteoporosis among chronic kidney disease patients: A systematic review","volume":"13","author":"Tariq","year":"2020","journal-title":"Open Urol Nephrol J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1053\/ajkd.2000.19812","article-title":"Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone","volume":"36","author":"Coco","year":"2000","journal-title":"Am J Kidney Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2025.01.022","article-title":"Mitochondrial dysfunction and mitophagy blockade contribute to renal osteodystrophy in chronic kidney disease-mineral bone disorder","volume":"107","author":"Hsu","year":"2025","journal-title":"Kidney Int"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-015-3064-7","article-title":"Bone marrow fat is increased in chronic kidney disease by magnetic resonance spectroscopy","volume":"26","author":"Moorthi","year":"2015","journal-title":"Osteoporos Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3562","article-title":"Chronic kidney disease is associated with greater bone marrow adiposity","volume":"33","author":"Woods","year":"2018","journal-title":"J Bone Miner Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/jmri.20367","article-title":"Osteoporosis is associated with increased marrow fat content and decreased marrow fat unsaturation: a proton MR spectroscopy study","volume":"22","author":"Yeung","year":"2005","journal-title":"J Magn Reson Imaging"},{"key":"B35","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.csbj.2023.12.029","article-title":"A novel deep learning method for large-scale analysis of bone marrow adiposity using UK Biobank Dixon MRI data","volume":"24","author":"Morris","year":"2024","journal-title":"Comput Struct Biotechnol J"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00198-006-0285-9","article-title":"MRI-measured bone marrow adipose tissue is inversely related to DXA-measured bone mineral in Caucasian women","volume":"18","author":"Shen","year":"2007","journal-title":"Osteoporos Int"},{"key":"B37","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/s41467-024-55422-4","article-title":"Deep learning and genome-wide association meta-analyses of bone marrow adiposity in the UK Biobank","volume":"16","author":"Xu","year":"2025","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/j.stem.2017.02.009","article-title":"Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration","volume":"20","author":"Ambrosi","year":"2017","journal-title":"Cell Stem Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3949","article-title":"Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults","volume":"98","author":"Schwartz","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.31434","article-title":"Interplay between bone marrow adiposity and bone resorption in RANKL-mediated modelled osteoporosis","volume":"239","author":"Rinotas","year":"2024","journal-title":"J Cell Physiol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"101104","DOI":"10.1016\/j.bonr.2021.101104","article-title":"Bone marrow adiposity inversely correlates with bone turnover in pediatric renal osteodystrophy","volume":"15","author":"Sirimongkolchaiyakul","year":"2021","journal-title":"Bone Rep"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2010.155","article-title":"PPARgamma: a circadian transcription factor in adipogenesis and osteogenesis","volume":"6","author":"Kawai","year":"2010","journal-title":"Nat Rev Endocrinol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.78496.sa2","article-title":"Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits","volume":"11","author":"Li","year":"2022","journal-title":"ELife"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevEukarGeneExpr.v19.i2.20","article-title":"Marrow fat and the bone microenvironment: developmental, functional, and pathological implications","volume":"19","author":"Rosen","year":"2009","journal-title":"Crit Rev Eukaryot Gene Expr"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/j.stem.2021.01.010","article-title":"Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging","volume":"28","author":"Deng","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.54695","article-title":"Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment","volume":"9","author":"Zhong","year":"2020","journal-title":"Elife"},{"key":"B47","doi-asserted-by":"publisher","first-page":"5598","DOI":"10.1038\/s41598-020-62465-2","article-title":"High serum adiponectin as a biomarker of renal dysfunction: Results from the KNOW-CKD study","volume":"10","author":"Song","year":"2020","journal-title":"Sci Rep"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M400373-JLR200","article-title":"Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation","volume":"46","author":"Fu","year":"2005","journal-title":"J Lipid Res"},{"key":"B49","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.cell.2017.12.001","article-title":"Leptin mediates a glucose-fatty acid cycle to maintain glucose homeostasis in starvation","volume":"172","author":"Perry","year":"2018","journal-title":"Cell"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2003.11.020","article-title":"Leptin deficiency produces contrasting phenotypes in bones of the limb and spine","volume":"34","author":"Hamrick","year":"2004","journal-title":"Bone"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2018.01.008","article-title":"Development, regulation, metabolism and function of bone marrow adipose tissues","volume":"110","author":"Li","year":"2018","journal-title":"Bone"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1095550","article-title":"Basal corticosterone levels of young og\/ob mice","volume":"9","author":"Dubuc","year":"1977","journal-title":"Horm Metab Res"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-3123","article-title":"Body composition and cardiovascular risk markers after remission of Cushing\u2019s disease: a prospective study using whole-body MRI","volume":"97","author":"Geer","year":"2012","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1666681\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T04:12:18Z","timestamp":1758514338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1666681\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,22]]},"references-count":53,"alternative-id":["10.3389\/fendo.2025.1666681"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1666681","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,22]]},"article-number":"1666681"}}