{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T02:30:14Z","timestamp":1770085814699,"version":"3.49.0"},"reference-count":85,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. Specifically, decreased BMP2 and increased BMP13 have been linked to impaired osteogenesis and cartilage-like shifts in bone progenitors. A human in vitro system that recapitulates this hepatic BMP imbalance is needed to dissect mechanisms and identify targets. To address this, we established a long-term human three-dimensional liver\u2013bone co-culture model that integrates hepatocytes (HepaRG), hepatic stellate cells (LX-2), and human umbilical vein endothelial cells (HUVECs) with bone scaffolds seeded with osteoblast precursors (SCP-1) and osteoclast precursors (THP-1). This study aimed to characterize the effects of chronic 50 mM alcohol exposure on hepatic fibrogenic activation and BMP ligand secretion, and to investigate the associated BMP-responsive signaling involved in bone cell lineage differentiation and functional activity. The results demonstrated alcohol-induced hepatic CYP2E1 activation and fibrogenic remodeling with EMT signatures, as well as a decrease in BMP2 and an increase in BMP13, without affecting BMP9. Liver-derived factors activated both canonical and non-canonical BMP signaling in bone progenitors, reduced osteoblast activity and mineralization, preserved osteoclast TRAP activity, and shifted the lineage toward chondrogenesis (SOX9\u2191, RUNX2\u2193). Notably, this BMP profile and skeletal phenotype reflect clinical observations in chronic liver disease, indicating that the model recapitulates key in vivo pathological features. This human liver micro-organoid co-culture reproduces alcohol-induced hepatic BMP dysregulation and downstream bone defects, offering an organoid-centric, microengineered platform for mechanistic studies and BMP-targeted therapeutic screening in HOD.<\/jats:p>","DOI":"10.3390\/cells15030274","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:49:44Z","timestamp":1770036584000},"page":"274","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Three-Dimensional Human Liver Micro Organoids and Bone Co-Culture Mimics Alcohol-Induced BMP Dysregulation and Bone Remodeling Defects"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4865-8787","authenticated-orcid":false,"given":"Yuxuan","family":"Xin","sequence":"first","affiliation":[{"name":"Department of Traumatology, Siegfried Weller Institute, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"},{"name":"Department of Orthopaedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7860-8154","authenticated-orcid":false,"given":"Guanqiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Traumatology, Siegfried Weller Institute, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6679-2495","authenticated-orcid":false,"given":"Mohammad Majd","family":"Hammour","sequence":"additional","affiliation":[{"name":"Department of Traumatology, Siegfried Weller Institute, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Traumatology, Siegfried Weller Institute, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian","family":"Springer","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology, University Hospital T\u00fcbingen, Hoppe-Seyler-Str. 3, 72076 T\u00fcbingen, Germany"},{"name":"Department of Radiology, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8724-9009","authenticated-orcid":false,"given":"Elke","family":"Maurer","sequence":"additional","affiliation":[{"name":"Department Traumatology and Reconstructive Surgery BG-Clinic T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Lumedis Orthopedics, Kirchstr. 12, 60311 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-6791","authenticated-orcid":false,"given":"Andreas K.","family":"N\u00fcssler","sequence":"additional","affiliation":[{"name":"Department of Traumatology, Siegfried Weller Institute, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5160-2111","authenticated-orcid":false,"given":"Romina H.","family":"Aspera-Werz","sequence":"additional","affiliation":[{"name":"Department of Traumatology, Siegfried Weller Institute, BG-Klinik T\u00fcbingen, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ehnert, S., Aspera-Werz, R.H., Ruo\u00df, M., Dooley, S., Hengstler, J.G., Nadalin, S., Relja, B., Badke, A., and Nussler, A.K. (2019). Hepatic Osteodystrophy-Molecular Mechanisms Proposed to Favor Its Development. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102555"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1002\/hep.21852","article-title":"Bone disorders in chronic liver disease","volume":"46","author":"Collier","year":"2007","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.cmet.2022.02.006","article-title":"Defects in a liver-bone axis contribute to hepatic osteodystrophy disease progression","volume":"34","author":"Lu","year":"2022","journal-title":"Cell Metab."},{"key":"ref_4","first-page":"217","article-title":"Emerging role of liver-bone axis in osteoporosis","volume":"48","author":"Gao","year":"2024","journal-title":"J. Orthop. Transl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.35946\/arcr.v38.2.01","article-title":"Alcoholic Liver Disease: Pathogenesis and Current Management","volume":"38","author":"Osna","year":"2017","journal-title":"Alcohol Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.gande.2025.01.003","article-title":"Alcohol-associated liver disease: A review","volume":"3","author":"Nagarjuna","year":"2025","journal-title":"Gastroenterol. Endosc."},{"key":"ref_7","unstructured":"World Health Organization. Regional Office for Europe (2024). Alcohol Taxation and Pricing Policies and Their Impact on Alcohol Consumption in Ukraine from 2011\u20132021: Country Report, World Health Organization."},{"key":"ref_8","unstructured":"World Health Organization (2026, January 22). Global Information System on Alcohol and Health. Levels of Consumption. Available online: https:\/\/www.who.int\/data\/gho\/data\/themes\/topics\/topic-details\/GHO\/levels-of-consumption."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.jhep.2014.09.033","article-title":"Alcohol directly stimulates epigenetic modifications in hepatic stellate cells","volume":"62","author":"Page","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112938","DOI":"10.1016\/j.intimp.2024.112938","article-title":"Key regulators of hepatic stellate cell activation in alcohol liver Disease: A comprehensive review","volume":"141","author":"Patidar","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1038\/s41374-018-0069-9","article-title":"BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-\u03b21 signaling","volume":"98","author":"Chung","year":"2018","journal-title":"Lab. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1002\/hep.30655","article-title":"Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis","volume":"70","author":"Tillet","year":"2019","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1002\/jcb.30248","article-title":"Bone morphogenetic protein 13 in hepatic stellate cells and hepatic fibrosis","volume":"123","author":"Peschl","year":"2022","journal-title":"J. Cell. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bordukalo-Nik\u0161i\u0107, T., Kufner, V., and Vuki\u010devi\u0107, S. (2022). The Role Of BMPs in the Regulation of Osteoclasts Resorption and Bone Remodeling: From Experimental Models to Clinical Applications. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.869422"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/jcmm.12373","article-title":"BMP-9 regulates the osteoblastic differentiation and calcification of vascular smooth muscle cells through an ALK1 mediated pathway","volume":"19","author":"Zhu","year":"2015","journal-title":"J. Cell. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"192","DOI":"10.7150\/ijbs.5.192","article-title":"BMP-13 emerges as a potential inhibitor of bone formation","volume":"5","author":"Shen","year":"2009","journal-title":"Int. J. Biol. Sci."},{"key":"ref_17","first-page":"93","article-title":"Modeling alcohol\u2019s effects on organs in animal models","volume":"24","author":"Ponnappa","year":"2000","journal-title":"Alcohol Res. Health"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1159\/000075032","article-title":"Different effects of BMP-2 on marrow stromal cells from human and rat bone","volume":"176","author":"Osyczka","year":"2004","journal-title":"Cells Tissues Organs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00204-024-03899-9","article-title":"Establishment of a human 3D in vitro liver-bone model as a potential system for drug toxicity screening","volume":"99","author":"Chen","year":"2025","journal-title":"Arch. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1016\/j.cgh.2019.07.060","article-title":"Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis","volume":"18","author":"Moon","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0140-6736(21)01701-3","article-title":"The EASL\u2013Lancet Liver Commission: Protecting the next generation of Europeans against liver disease complications and premature mortality","volume":"399","author":"Karlsen","year":"2022","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1007\/s40265-023-01939-9","article-title":"Alcohol-Associated Liver Disease: Evolving Concepts and Treatments","volume":"83","author":"Prince","year":"2023","journal-title":"Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/term.2802","article-title":"Differentiation of the human liver progenitor cell line (HepaRG) on a microfluidic-based biochip","volume":"13","author":"Jang","year":"2019","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9232","DOI":"10.1038\/s41598-018-27686-6","article-title":"In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A","volume":"8","author":"Hong","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10931","DOI":"10.1038\/s41598-021-90263-x","article-title":"Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model","volume":"11","author":"Song","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1111\/j.1582-4934.2008.00299.x","article-title":"Introducing a single-cell-derived human mesenchymal stem cell line expressing hTERT after lentiviral gene transfer","volume":"12","author":"Yin","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1007\/s12015-021-10266-z","article-title":"Improved Differentiation of hESC-Derived Pancreatic Progenitors by Using Human Fetal Pancreatic Mesenchymal Cells in a Micro-scalable Three-Dimensional Co-culture System","volume":"18","author":"Ghezelayagh","year":"2022","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1007\/s00204-022-03265-7","article-title":"In vitro modeling of liver fibrosis in 3D microtissues using scalable micropatterning system","volume":"96","author":"Zahmatkesh","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"H\u00e4ussling, V., Deninger, S., Vidoni, L., Rinderknecht, H., Ruo\u00df, M., Arnscheidt, C., Athanasopulu, K., Kemkemer, R., Nussler, A.K., and Ehnert, S. (2019). Impact of Four Protein Additives in Cryogels on Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells. Bioengineering, 6.","DOI":"10.3390\/bioengineering6030067"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Weng, W., H\u00e4ussling, V., Aspera-Werz, R.H., Springer, F., Rinderknecht, H., Braun, B., K\u00fcper, M.A., Nussler, A.K., and Ehnert, S. (2020). Material-Dependent Formation and Degradation of Bone Matrix-Comparison of Two Cryogels. Bioengineering, 7.","DOI":"10.3390\/bioengineering7020052"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"H\u00e4ussling, V., Aspera-Werz, R.H., Rinderknecht, H., Springer, F., Arnscheidt, C., Menger, M.M., Histing, T., Nussler, A.K., and Ehnert, S. (2021). 3D Environment Is Required In Vitro to Demonstrate Altered Bone Metabolism Characteristic for Type 2 Diabetics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062925"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1007\/s00204-022-03329-8","article-title":"Optimisation of the HepaRG cell line model for drug toxicity studies using two different cultivation conditions: Advantages and limitations","volume":"96","author":"Hammour","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3172480","DOI":"10.1155\/2018\/3172480","article-title":"Nicotine and Cotinine Inhibit Catalase and Glutathione Reductase Activity Contributing to the Impaired Osteogenesis of SCP-1 Cells Exposed to Cigarette Smoke","volume":"2018","author":"Ehnert","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Guo, H., Weng, W., Zhang, S., Rinderknecht, H., Braun, B., Breinbauer, R., Gupta, P., Kumar, A., Ehnert, S., and Histing, T. (2022). Maqui Berry and Ginseng Extracts Reduce Cigarette Smoke-Induced Cell Injury in a 3D Bone Co-Culture Model. Antioxidants, 11.","DOI":"10.3390\/antiox11122460"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhu, S., H\u00e4ussling, V., Aspera-Werz, R.H., Chen, T., Braun, B., Weng, W., Histing, T., and Nussler, A.K. (2021). Bisphosphonates Reduce Smoking-Induced Osteoporotic-Like Alterations by Regulating RANKL\/OPG in an Osteoblast and Osteoclast Co-Culture Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22010053"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Godel, M., Morena, D., Ananthanarayanan, P., Buondonno, I., Ferrero, G., Hattinger, C.M., Di Nicolantonio, F., Serra, M., Taulli, R., and Cordero, F. (2020). Small Nucleolar RNAs Determine Resistance to Doxorubicin in Human Osteosarcoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124500"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Aspera-Werz, R.H., Chen, T., Ehnert, S., Zhu, S., Fr\u00f6hlich, T., and Nussler, A.K. (2019). Cigarette Smoke Induces the Risk of Metabolic Bone Diseases: Transforming Growth Factor Beta Signaling Impairment via Dysfunctional Primary Cilia Affects Migration, Proliferation, and Differentiation of Human Mesenchymal Stem Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20122915"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1161\/STROKEAHA.120.030046","article-title":"Mesenchymal Behavior of the Endothelium Promoted by SMAD6 Downregulation Is Associated with Brain Arteriovenous Malformation Microhemorrhage","volume":"51","author":"Fu","year":"2020","journal-title":"Stroke"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1520\/JFS2002420","article-title":"Comparison of blood-ethanol concentration in deaths attributed to acute alcohol poisoning and chronic alcoholism","volume":"48","author":"Jones","year":"2003","journal-title":"J. Forensic Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Herrera, B., Addante, A., and S\u00e1nchez, A. (2018). BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010039"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chen, H., Li, Y.Y., Nio, K., and Tang, H. (2024). Unveiling the Impact of BMP9 in Liver Diseases: Insights into Pathogenesis and Therapeutic Potential. Biomolecules, 14.","DOI":"10.3390\/biom14081013"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"125","DOI":"10.3892\/mmr.2020.11764","article-title":"BMP2 induces hMSC osteogenesis and matrix remodeling","volume":"23","author":"Cai","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1097\/01.blo.0000063602.67412.83","article-title":"Alcohol-Induced Adipogenesis in Bone and Marrow: A Possible Mechanism for Osteonecrosis","volume":"410","author":"Wang","year":"2003","journal-title":"Clin. Orthop. Relat. Res.\u00ae"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1016\/j.stemcr.2023.08.001","article-title":"Integrated single cell analysis shows chronic alcohol drinking disrupts monocyte differentiation in the bone marrow","volume":"18","author":"Lewis","year":"2023","journal-title":"Stem Cell Rep."},{"key":"ref_45","first-page":"148","article-title":"Alcohol-induced adipogenesis in a cloned bone-marrow stem cell","volume":"88","author":"Cui","year":"2006","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cmet.2015.09.010","article-title":"A Liver-Bone Endocrine Relay by IGFBP1 Promotes Osteoclastogenesis and Mediates FGF21-Induced Bone Resorption","volume":"22","author":"Wang","year":"2015","journal-title":"Cell Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41413-025-00424-1","article-title":"Bone-derived factors mediate crosstalk between skeletal and extra-skeletal organs","volume":"13","author":"He","year":"2025","journal-title":"Bone Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1124\/dmd.122.000870","article-title":"HepaRG cells adopt zonal-like drug-metabolizing phenotypes under physiologically relevant oxygen tensions and Wnt\/\u03b2-catenin signaling","volume":"50","author":"DiProspero","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"10512","DOI":"10.3748\/wjg.v22.i48.10512","article-title":"Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets","volume":"22","author":"Zhang","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kocherova, I., Bryja, A., Mozdziak, P., Angelova Volponi, A., Dyszkiewicz-Konwi\u0144ska, M., Piotrowska-Kempisty, H., Antosik, P., Bukowska, D., Bruska, M., and I\u017cycki, D. (2019). Human Umbilical Vein Endothelial Cells (HUVECs) Co-Culture with Osteogenic Cells: From Molecular Communication to Engineering Prevascularised Bone Grafts. J. Clin. Med., 8.","DOI":"10.3390\/jcm8101602"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1124\/dmd.109.030155","article-title":"CYP2C9-CYP3A4 protein-protein interactions: Role of the hydrophobic N terminus","volume":"38","author":"Subramanian","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1124\/dmd.114.057901","article-title":"Altered CYP2C9 activity following modulation of CYP3A4 levels in human hepatocytes: An example of protein-protein interactions","volume":"42","author":"Ramsden","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hong, X., Huang, S., Jiang, H., Ma, Q., Qiu, J., Luo, Q., Cao, C., Xu, Y., Chen, F., and Chen, Y. (2024). Alcohol-related liver disease (ALD): Current perspectives on pathogenesis, therapeutic strategies, and animal models. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1432480"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s00204-013-1191-5","article-title":"Chronic CCl4 intoxication causes liver and bone damage similar to the human pathology of hepatic osteodystrophy: A mouse model to analyse the liver-bone axis","volume":"88","author":"Nussler","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"22211","DOI":"10.1074\/jbc.M110.119982","article-title":"Chronic alcohol exposure increases circulating bioactive oxidized phospholipids","volume":"285","author":"Yang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jhep.2022.08.030","article-title":"Alcohol consumption and metabolic syndrome: Clinical and epidemiological impact on liver disease","volume":"78","author":"Byrne","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Fujii, T., Fuchs, B.C., Yamada, S., Lauwers, G.Y., Kulu, Y., Goodwin, J.M., Lanuti, M., and Tanabe, K.K. (2010). Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol., 10.","DOI":"10.1186\/1471-230X-10-79"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1172\/JCI10483","article-title":"Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice","volume":"106","author":"Dai","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"de Almeida, J.M., Pazmino, V.F.C., Novaes, V.C.N., Bomfim, S.R.M., Nagata, M.J.H., Oliveira, F.L.P., Matheus, H.R., and Ervolino, E. (2020). Chronic consumption of alcohol increases alveolar bone loss. PLoS ONE, 15.","DOI":"10.1101\/2020.04.22.055186"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S0741-8329(98)00025-1","article-title":"Alcohol consumption inhibits osteoblastic cell proliferation and activity in vivo","volume":"16","author":"Dyer","year":"1998","journal-title":"Alcohol"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3027954","DOI":"10.1155\/2021\/3027954","article-title":"Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis","volume":"2021","author":"Guo","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1359\/jbmr.090806","article-title":"Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts","volume":"25","author":"Kamiya","year":"2010","journal-title":"J. Bone Miner. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e657","DOI":"10.1002\/mco2.657","article-title":"Regulation of bone homeostasis: Signaling pathways and therapeutic targets","volume":"5","author":"Wu","year":"2024","journal-title":"MedComm"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"32","DOI":"10.4236\/jbise.2013.68A1004","article-title":"BMP signaling in mesenchymal stem cell differentiation and bone formation","volume":"6","author":"Beederman","year":"2013","journal-title":"J. Biomed. Sci. Eng."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1089\/scd.2008.0130","article-title":"A comprehensive analysis of the dual roles of BMPs in regulating adipogenic and osteogenic differentiation of mesenchymal progenitor cells","volume":"18","author":"Kang","year":"2009","journal-title":"Stem Cells Dev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ydbio.2005.05.009","article-title":"BMP signaling and stem cell regulation","volume":"284","author":"Zhang","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"459278","DOI":"10.1155\/2012\/459278","article-title":"Alcohol Activates TGF-Beta but Inhibits BMP Receptor-Mediated Smad Signaling and Smad4 Binding to Hepcidin Promoter in the Liver","volume":"2012","author":"Gerjevic","year":"2012","journal-title":"Int. J. Hepatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1074\/jbc.M111.253187","article-title":"BMP2 protein regulates osteocalcin expression via Runx2-mediated Atf6 gene transcription","volume":"287","author":"Jang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3109\/08977194.2011.593178","article-title":"Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities","volume":"29","author":"Berasi","year":"2011","journal-title":"Growth Factors"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16005","DOI":"10.1038\/boneres.2016.5","article-title":"The biological function of type I receptors of bone morphogenetic protein in bone","volume":"4","author":"Lin","year":"2016","journal-title":"Bone Res."},{"key":"ref_71","first-page":"17","article-title":"The role of bone morphogenetic proteins in liver fibrosis","volume":"12","author":"Yang","year":"2021","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Kersten, V., Seitz, T., Sommer, J., Thasler, W.E., Bosserhoff, A., and Hellerbrand, C. (2023). Bone Morphogenetic Protein 13 Has Protumorigenic Effects on Hepatocellular Carcinoma Cells In Vitro. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311059"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Gaither, K.A., Yue, G., Singh, D.K., Trudeau, J., Ponraj, K., Davydova, N.Y., Lazarus, P., Davydov, D.R., and Prasad, B. (2025). Effects of Chronic Alcohol Intake on the Composition of the Ensemble of Drug-Metabolizing Enzymes and Transporters in the Human Liver. J. Xenobiotics, 15.","DOI":"10.3390\/jox15010020"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41421-024-00689-6","article-title":"Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis","volume":"10","author":"Zhu","year":"2024","journal-title":"Cell Discov."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1177\/1535370219828694","article-title":"Bone morphogenetic protein signaling in inflammation","volume":"244","author":"Wu","year":"2019","journal-title":"Exp. Biol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1186\/s13018-019-1505-2","article-title":"The regulatory mechanism of p38\/MAPK in the chondrogenic differentiation from bone marrow mesenchymal stem cells","volume":"14","author":"Ma","year":"2019","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s13238-017-0385-7","article-title":"The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells","volume":"8","author":"Li","year":"2017","journal-title":"Protein Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e0534","DOI":"10.1097\/HC9.0000000000000534","article-title":"Mitochondrial quality control in alcohol-associated liver disease","volume":"8","author":"Thoudam","year":"2024","journal-title":"Hepatol. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"207","DOI":"10.2174\/1874467208666150817111114","article-title":"Role of CYP2E1 in Mitochondrial Dysfunction and Hepatic Injury by Alcohol and Non-Alcoholic Substances","volume":"10","author":"Abdelmegeed","year":"2017","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3956","DOI":"10.1210\/endo.141.11.7739","article-title":"Inhibition of osteoblast differentiation by tumor necrosis factor-alpha","volume":"141","author":"Gilbert","year":"2000","journal-title":"Endocrinology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1007\/s11684-018-0625-0","article-title":"Cytokines and inflammation in adipogenesis: An updated review","volume":"13","author":"Jiang","year":"2019","journal-title":"Front. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.actbio.2021.12.006","article-title":"The immune microenvironment in cartilage injury and repair","volume":"140","author":"Li","year":"2022","journal-title":"Acta Biomater."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"19004","DOI":"10.1073\/pnas.0605170103","article-title":"Dominance of SOX9 function over RUNX2 during skeletogenesis","volume":"103","author":"Zhou","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","first-page":"92","article-title":"Osteoporosis: A Review of Treatment Options","volume":"43","author":"Tu","year":"2018","journal-title":"Pharm. Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4234061","DOI":"10.1155\/2016\/4234061","article-title":"Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases","volume":"2016","author":"Li","year":"2016","journal-title":"Oxidative Med. Cell. Longev."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/274\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:54:00Z","timestamp":1770036840000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/3\/274"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,1]]},"references-count":85,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cells15030274"],"URL":"https:\/\/doi.org\/10.3390\/cells15030274","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,1]]}}}