{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:50:36Z","timestamp":1790142636129,"version":"4.0.1"},"reference-count":130,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"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. Cell Dev. Biol."],"abstract":"<jats:p>E3 ubiquitin ligases are key determinants of substrate specificity within the ubiquitin\u2013proteasome system and have emerged as important regulators of skeletal biology. Although traditionally classified into RING-, HECT-, and RBR-type families based on structural features, their roles in bone homeostasis are more clearly understood when examined in the context of specific skeletal regulatory processes. In this review, we briefly outline major E3 ligase families and the updated human E3 ligase landscape, and then discuss how representative E3 ligases regulate osteoblast differentiation, osteoclast differentiation, cartilage homeostasis, and bone remodeling. A central concept emerging from current evidence is that E3 ligases converge on critical regulatory nodes that govern skeletal cell fate and tissue-level remodeling. In osteogenesis, multiple E3 ligases control RUNX2 stability, transcriptional activity, and associated signaling pathways, including the BMP\/SMAD and PI3K\/Akt pathways. In osteoclast differentiation, E3 ligases primarily modulate TRAF6-dependent signaling and NF-\u03baB activation, thereby influencing bone resorption. Beyond these lineage-specific roles, E3 ligases also participate in higher-order processes such as osteoblast\u2013osteoclast coupling, osteoimmune regulation, mitochondrial quality control, and cartilage matrix homeostasis, highlighting their roles as process-level regulators of skeletal homeostasis. We further summarize how dysregulation of E3 ligase\u2013mediated pathways contributes to common skeletal disorders, including osteoporosis, inflammatory bone loss, degenerative diseases, and therapy-associated complications. Finally, we discuss emerging pharmacological strategies targeting E3 ligases and E3-dependent pathways, including modulation of ubiquitination signaling and targeted protein degradation. Collectively, this review underscores the central roles of E3 ubiquitin ligases in integrating skeletal regulation and highlights their potential as therapeutic targets in bone-related diseases.<\/jats:p>","DOI":"10.3389\/fcell.2026.1825526","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:44:06Z","timestamp":1779083046000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["E3 ubiquitin ligases in bone homeostasis: from regulatory mechanisms to skeletal diseases and therapeutic targeting"],"prefix":"10.3389","volume":"14","author":[{"given":"Yutong","family":"Zhao","sequence":"first","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanjue","family":"Cao","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1007\/s00784-014-1193-6","article-title":"Six-month results following treatment of aggressive periodontitis with antimicrobial photodynamic therapy or amoxicillin and metronidazole","volume":"18","author":"Arweiler","year":"2014","journal-title":"Clin. Oral Invest."},{"key":"B2","doi-asserted-by":"publisher","first-page":"7656","DOI":"10.1038\/s41467-023-43326-8","article-title":"BioE3 identifies specific substrates of ubiquitin E3 ligases","volume":"14","author":"Barroso-Gomila","year":"2023","journal-title":"Nat. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/nrm.2016.91","article-title":"Structural insights into the catalysis and regulation of E3 ubiquitin ligases","volume":"17","author":"Buetow","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.molimm.2023.11.010","article-title":"Silencing of STUB1 relieves osteoarthritis via inducing NRF2-mediated M2 macrophage polarization","volume":"164","author":"Cao","year":"2023","journal-title":"Mol. Immunology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.str.2016.01.007","article-title":"Linkage via K27 bestows ubiquitin chains with unique properties among polyubiquitins","volume":"24","author":"Casta\u00f1eda","year":"2016","journal-title":"Structure"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.3390\/biom11101512","article-title":"A promising intracellular protein-degradation strategy: TRIMbody-away technique based on nanobody fragment","volume":"11","author":"Chen","year":"2021","journal-title":"Biomolecules"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e23373","DOI":"10.1002\/jbt.23373","article-title":"CUL4A-mediated ZEB1\/microRNA-340-5p\/HMGB1 axis promotes the development of osteoporosis","volume":"37","author":"Chen","year":"2023","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41368-025-00360-0","article-title":"Dimethyl fumarate modulates M1\/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy","volume":"17","author":"Chen","year":"2025","journal-title":"Int. J. Oral Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"157146","DOI":"10.1016\/j.phymed.2025.157146","article-title":"Quercetin attenuates chondrocyte anoikis via modulation of mesenchymal stromal cell-derived small extracellular vesicles to promote cartilage repair in osteoarthritis","volume":"146","author":"Cheng","year":"2025","journal-title":"Phytomedicine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"6421","DOI":"10.3390\/ijms23126421","article-title":"Identification of novel genes for cell fusion during osteoclast formation","volume":"23","author":"Cho","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1016\/j.cell.2026.01.029","article-title":"The E3-ome gene-centric compendium reveals the human E3 ligase landscape","volume":"189","author":"Chua","year":"2026","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e2201490119","DOI":"10.1073\/pnas.2201490119","article-title":"IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation","volume":"119","author":"Deepak","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1038\/s41413-024-00363-3","article-title":"IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1\/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1\/2","volume":"12","author":"Deng","year":"2024","journal-title":"Bone Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/s41420-025-02482-0","article-title":"The E3 ligase c-Cbl modulates microglial phenotypes and contributes to Parkinson\u2019s disease pathology","volume":"11","author":"Deng","year":"2025","journal-title":"Cell Death Discov."},{"key":"B15","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1146\/annurev.biochem.78.101807.093809","article-title":"RING domain E3 ubiquitin ligases","volume":"78","author":"Deshaies","year":"2009","journal-title":"Annu. Rev. Biochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"4639","DOI":"10.1016\/j.jmb.2016.09.018","article-title":"Role of E2-RING interactions in governing RNF4-mediated substrate ubiquitination","volume":"428","author":"DiBello","year":"2016","journal-title":"J. Mol. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1002\/jbmr.4800","article-title":"Higenamine promotes osteogenesis via IQGAP1\/SMAD4 signaling pathway and prevents age- and Estrogen-dependent bone loss in mice","volume":"38","author":"Dong","year":"2023","journal-title":"J. Bone Miner. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41413-024-00394-w","article-title":"Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2","volume":"13","author":"Dong","year":"2025","journal-title":"Bone Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e2405265121","DOI":"10.1073\/pnas.2405265121","article-title":"REG\u03b3 is essential to maintain bone homeostasis by degrading TRAF6, preventing osteoporosis","volume":"121","author":"Du","year":"2024","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B20","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41467-018-03124-z","article-title":"Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin","volume":"9","author":"Duchamp de Lageneste","year":"2018","journal-title":"Nat. Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.str.2013.04.019","article-title":"Structure of HHARI, a RING-IBR-RING ubiquitin ligase: autoinhibition of an Ariadne-family E3 and insights into ligation mechanism","volume":"21","author":"Duda","year":"2013","journal-title":"Structure"},{"key":"B22","doi-asserted-by":"publisher","first-page":"11382","DOI":"10.1038\/s41467-025-67450-9","article-title":"Multi-scale classification decodes the complexity of the human E3 ligome","volume":"16","author":"Dutta","year":"2025","journal-title":"Nat. Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/j.tibs.2025.07.009","article-title":"E3 ubiquitin ligases in signaling, disease, and therapeutics","volume":"50","author":"Ebadi","year":"2025","journal-title":"Trends Biochem. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"9661200","DOI":"10.1155\/2021\/9661200","article-title":"Bortezomib rescues ovariectomy-induced bone loss via SMURF-mediated ubiquitination pathway","volume":"2021","author":"Fang","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"155890","DOI":"10.1016\/j.phymed.2024.155890","article-title":"Active fraction of polyrhachis vicina (Rogers) inhibits osteoclastogenesis by targeting Trim38 mediated proteasomal degradation of TRAF6","volume":"132","author":"Feng","year":"2024","journal-title":"Phytomedicine"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1080\/15548627.2025.2472586","article-title":"Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion","volume":"21","author":"Fogo","year":"2025","journal-title":"Autophagy"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1038\/s41467-024-47289-2","article-title":"Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis","volume":"15","author":"Fu","year":"2024","journal-title":"Nat. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"117725","DOI":"10.1016\/j.ejmech.2025.117725","article-title":"Mechanisms underlying altered ubiquitin-proteasome system activity during heart failure and pharmacological interventions","volume":"292","author":"Gao","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3945","DOI":"10.1016\/j.cell.2023.07.01","article-title":"Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation","volume":"186","author":"Geffen","year":"2023","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e2411162","DOI":"10.1002\/advs.202411162","article-title":"SPP1-ITG\u03b15\/\u03b21 accelerates calcification of nucleus pulposus cells by inhibiting mitophagy via Ubiquitin-dependent PINK1\/PARKIN pathway blockade","volume":"12","author":"Gu","year":"2025","journal-title":"Adv. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.3390\/genes15081085","article-title":"Genome-wide identification, characterization, and transcriptional profile of the HECT E3 ubiquitin ligase gene family in the hard-shelled mussel Mytilus coruscus gould","volume":"15","author":"Guo","year":"2024","journal-title":"Genes (Basel)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"5980","DOI":"10.4049\/jimmunol.177.9.5980","article-title":"Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells","volume":"177","author":"Gustin","year":"2006","journal-title":"J. Immunology (Baltimore, Md, 1950)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1002\/1097-4644(20010501)81:2<284::aid-jcb1043>3.0.co;2-d","article-title":"BMP-2 induction and TGF-beta 1 modulation of rat periosteal cell chondrogenesis","volume":"81","author":"Hanada","year":"2001","journal-title":"J. Cell. Biochem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"5254","DOI":"10.7150\/ijbs.101507","article-title":"Amlexanox enforces osteogenic differentiation and bone homeostasis through inhibiting ubiquitin-dependent degradation of \u03b2-Catenin","volume":"20","author":"He","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"679","DOI":"10.3390\/biom15050679","article-title":"Regulatory roles of E3 ubiquitin ligases and deubiquitinases in bone","volume":"15","author":"He","year":"2025","journal-title":"Biomolecules"},{"key":"B36","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1002\/acr.21596","article-title":"American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee","volume":"64","author":"Hochberg","year":"2012","journal-title":"Arthritis Care Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.ygeno.2004.10.006","article-title":"The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects","volume":"85","author":"Hochrainer","year":"2005","journal-title":"Genomics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1083\/jcb.200311015","article-title":"Smad6\/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia","volume":"165","author":"Horiki","year":"2004","journal-title":"J. Cell Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"133411","DOI":"10.1016\/j.jhazmat.2023.133411","article-title":"Calcium supplementation attenuates fluoride-induced bone injury via PINK1\/Parkin-mediated mitophagy and mitochondrial apoptosis in mice","volume":"465","author":"Hu","year":"2024","journal-title":"J. Hazard Mater"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1038\/s41589-024-01590-9","article-title":"Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates","volume":"20","author":"Huang","year":"2024","journal-title":"Nat. Chem. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s11658-019-0156-y","article-title":"C-Cbl negatively regulates TRAF6-mediated NF-\u03baB activation by promoting K48-linked polyubiquitination of TRAF6","volume":"24","author":"Jang","year":"2019","journal-title":"Cell Mol. Biol. Lett."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e2415626","DOI":"10.1002\/advs.202415626","article-title":"Development of MDM2-Targeting PROTAC for advancing bone regeneration","volume":"12","author":"Jeong","year":"2025","journal-title":"Adv. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"103215","DOI":"10.1016\/j.redox.2024.103215","article-title":"FOXO1 regulates RUNX2 ubiquitination through SMURF2 in calcific aortic valve disease","volume":"73","author":"Jiang","year":"","journal-title":"Redox Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"156163","DOI":"10.1016\/j.phymed.2024.156163","article-title":"Eupalinolide A attenuates trauma-induced heterotopic ossification of tendon in mice by promoting YAP degradation through TOLLIP-mediated selective autophagy","volume":"135","author":"Jiang","year":"","journal-title":"Phytomedicine"},{"key":"B45","doi-asserted-by":"publisher","first-page":"11449","DOI":"10.1038\/s41467-025-66285-8","article-title":"Pla2g7 regulates bone homeostasis via Alox12\/12-HETE\/Gpr31 signaling axis","volume":"16","author":"Jin","year":"2025","journal-title":"Nat. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s10020-025-01204-7","article-title":"Tripartite motif-containing 27 negatively regulates NF-\u03baB activation in bone remodeling","volume":"31","author":"Kim","year":"2025","journal-title":"Mol. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41413-020-00115-z","article-title":"A novel negative regulatory mechanism of Smurf2 in BMP\/Smad signaling in bone","volume":"8","author":"Kushioka","year":"2020","journal-title":"Bone Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1038\/sj.onc.1209924","article-title":"Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1","volume":"26","author":"Laine","year":"2007","journal-title":"Oncogene"},{"key":"B49","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/s41467-020-20527-z","article-title":"circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity","volume":"12","author":"Li","year":"2021","journal-title":"Nat. Commun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"121555","DOI":"10.1016\/j.lfs.2023.121555","article-title":"Accumulation of NCOA1 dependent on HERC3 deficiency transactivates matrix metallopeptidases and promotes extracellular matrix degradation in intervertebral disc degeneration","volume":"320","author":"Li","year":"2023","journal-title":"Life Sci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s00394-025-03685-y","article-title":"Vitamin D deficiency promotes intervertebral disc degeneration via p38\/NCoR2-mediated extracellular matrix degradation","volume":"64","author":"Li","year":"","journal-title":"Eur. J. Nutr."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1550309","DOI":"10.3389\/fbioe.2025.1550309","article-title":"Selective laser melting fabrication of functionally graded macro-porous Ti-6Al-4V scaffold for cavity bone defect reconstruction","volume":"13","author":"Li","year":"","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s10020-025-01098-5","article-title":"Mechanism of histone demethylase KDM5A in osteoporotic fracture healing through epigenetic regulation of the miR-495\/SKP2\/Runx2 axis","volume":"31","author":"Li","year":"","journal-title":"Mol. Med."},{"key":"B54","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1038\/s41419-023-06322-w","article-title":"HECW1 induces NCOA4-regulated ferroptosis in glioma through the ubiquitination and degradation of ZNF350","volume":"14","author":"Lin","year":"2023","journal-title":"Cell Death Dis."},{"key":"B55","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1302\/2046-3758.63.BJR-2016-0237.R1","article-title":"Ubiquitin E3 ligase Itch negatively regulates osteoblast function by promoting proteasome degradation of osteogenic proteins","volume":"6","author":"Liu","year":"2017","journal-title":"Bone Jt. Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41413-023-00296-3","article-title":"Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1\/\u03b2-catenin signaling","volume":"11","author":"Liu","year":"2023","journal-title":"Bone Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1080\/15548627.2021.1956105","article-title":"TRIM44 links the UPS to SQSTM1\/p62-dependent aggrephagy and removing misfolded proteins","volume":"18","author":"Lyu","year":"2022","journal-title":"Autophagy"},{"key":"B58","doi-asserted-by":"publisher","first-page":"7228","DOI":"10.1038\/s41467-025-61938-0","article-title":"Targeting Msx2 as a brake in the fusion fate of osteoclasts and an anabolic therapy in pre-clinical models of osteoporosis","volume":"16","author":"Ma","year":"2025","journal-title":"Nat. Commun."},{"key":"B59","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13024-024-00701-3","article-title":"Mitochondrial CISD1\/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1\/parkin models","volume":"19","author":"Martinez","year":"2024","journal-title":"Mol. Neurodegeneration"},{"key":"B60","doi-asserted-by":"publisher","first-page":"e1009275","DOI":"10.1371\/journal.pgen.1009275","article-title":"Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis","volume":"17","author":"Mellis","year":"2021","journal-title":"PLoS Genet."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1016\/j.joca.2008.03.003","article-title":"Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells","volume":"16","author":"Miljkovic","year":"2008","journal-title":"Osteoarthr. Cartilage"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1002\/jbmr.4410","article-title":"The diverse origin of bone-forming osteoblasts","volume":"36","author":"Mizoguchi","year":"2021","journal-title":"J. Bone Min. Res."},{"key":"B63","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.cell.2016.03.003","article-title":"Types of ubiquitin ligases","volume":"165","author":"Morreale","year":"2016","journal-title":"Cell"},{"key":"B64","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1002\/stem.1890","article-title":"TGF-\u03b21, GDF-5, and BMP-2 stimulation induces chondrogenesis in expanded human articular chondrocytes and marrow-derived stromal cells","volume":"33","author":"Murphy","year":"2015","journal-title":"Stem Cells (Dayton, Ohio)"},{"key":"B65","doi-asserted-by":"publisher","first-page":"7972","DOI":"10.1038\/s41467-024-52075-1","article-title":"Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP","volume":"15","author":"Nadel","year":"2024","journal-title":"Nat. Commun."},{"key":"B66","doi-asserted-by":"publisher","first-page":"63","DOI":"10.3390\/cells14020063","article-title":"CUL4-Based ubiquitin ligases in chromatin regulation: an evolutionary perspective","volume":"14","author":"Nakagawa","year":"2025","journal-title":"Cells"},{"key":"B67","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/s41419-022-05262-1","article-title":"RNF4\u223cRGMb\u223cBMP6 axis required for osteogenic differentiation and cancer cell survival","volume":"13","author":"Novak","year":"2022","journal-title":"Cell Death Dis."},{"key":"B68","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1038\/nsb906","article-title":"Structural insights into the U-box, a domain associated with multi-ubiquitination","volume":"10","author":"Ohi","year":"2003","journal-title":"Nat. Struct. Biol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.molcel.2018.03.012","article-title":"Dynamics of PARKIN-dependent mitochondrial ubiquitylation in induced neurons and model systems revealed by digital snapshot proteomics","volume":"70","author":"Ordureau","year":"2018","journal-title":"Mol. Cell"},{"key":"B70","doi-asserted-by":"publisher","first-page":"1033223","DOI":"10.3389\/fcell.2022.1033223","article-title":"Ubiquitin modification in osteogenic differentiation and bone formation: from mechanisms to clinical significance","volume":"10","author":"Pan","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41586-018-0026-1","article-title":"Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity","volume":"556","author":"Pao","year":"2018","journal-title":"Nature"},{"key":"B72","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41419-023-05549-x","article-title":"HERC1 deficiency causes osteopenia through transcriptional program dysregulation during bone remodeling","volume":"14","author":"Pedrazza","year":"2023","journal-title":"Cell Death Dis."},{"key":"B73","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/s13075-025-03624-6","article-title":"Trim21 deficiency alleviates osteoporosis by inhibiting osteoclast differentiation through regulating Txnip","volume":"27","author":"Peng","year":"2025","journal-title":"Arthritis Res. Ther."},{"key":"B74","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.semcdb.2021.11.017","article-title":"The HERC proteins and the nervous system","volume":"132","author":"P\u00e9rez-Villegas","year":"2022","journal-title":"Semin. Cell Dev. Biol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"101981","DOI":"10.1016\/j.jbc.2022.101981","article-title":"E3 ligase HUWE1 promotes PDGF D-mediated osteoblastic differentiation of mesenchymal stem cells by effecting polyubiquitination of \u03b2-PDGFR","volume":"298","author":"Pham","year":"2022","journal-title":"J. Biol. Chem."},{"key":"B76","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/nature17657","article-title":"Ubiquitination independent of E1 and E2 enzymes by bacterial effectors","volume":"533","author":"Qiu","year":"2016","journal-title":"Nature"},{"key":"B77","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1038\/s41374-022-00786-8","article-title":"PAQR3 depletion accelerates diabetic wound healing by promoting angiogenesis through inhibiting STUB1-mediated PPAR\u03b3 degradation","volume":"102","author":"Qiu","year":"2022","journal-title":"Lab. Invest."},{"key":"B78","doi-asserted-by":"publisher","first-page":"9166","DOI":"10.1093\/nar\/gkad631","article-title":"The HDAC6-RNF168 axis regulates H2A\/H2A.X ubiquitination to enable double-strand break repair","volume":"51","author":"Qiu","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1038\/ncomms2982","article-title":"Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases","volume":"4","author":"Riley","year":"2013","journal-title":"Nat. Commun."},{"key":"B80","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s41580-020-00279-w","article-title":"Mechanisms of bone development and repair","volume":"21","author":"Salhotra","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B130","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/s41418-020-00707-6","article-title":"Adaptors as the regulators of HECT ubiquitin ligases","volume":"28","author":"Shah","year":"2021","journal-title":"Cell Death Differ."},{"key":"B81","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41413-024-00344-6","article-title":"PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function","volume":"12","author":"Shao","year":"2024","journal-title":"Bone Res."},{"key":"B82","doi-asserted-by":"publisher","first-page":"e14902","DOI":"10.1002\/advs.202414902","article-title":"PSMD14 stabilizes SLC7A11 to ameliorate glucocorticoid-induced osteoporosis by suppressing osteocyte ferroptosis","volume":"12","author":"Shi","year":"2025","journal-title":"Adv. Sci."},{"key":"B83","doi-asserted-by":"publisher","first-page":"116422","DOI":"10.1016\/j.biopha.2024.116422","article-title":"Icariin ameliorates osteoporosis in ovariectomized rats by targeting Cullin 3\/Nrf2\/OH pathway for osteoclast inhibition","volume":"173","author":"Si","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B84","doi-asserted-by":"publisher","first-page":"19934","DOI":"10.1074\/jbc.RA119.010327","article-title":"Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro","volume":"294","author":"Singh","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B85","doi-asserted-by":"publisher","first-page":"3833","DOI":"10.1038\/emboj.2012.217","article-title":"The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension","volume":"31","author":"Smit","year":"2012","journal-title":"EMBO J."},{"key":"B86","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12943-023-01806-x","article-title":"A novel polypeptide CAPG-171aa encoded by circCAPG plays a critical role in triple-negative breast cancer","volume":"22","author":"Song","year":"2023","journal-title":"Mol. Cancer"},{"key":"B87","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/j.stem.2019.12.006","article-title":"Hematopoietic stem and progenitor cells exhibit stage-specific translational programs via mTOR- and CDK1-Dependent mechanisms","volume":"26","author":"Spevak","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B88","doi-asserted-by":"publisher","first-page":"BSR20202384","DOI":"10.1042\/BSR20202384","article-title":"Integrated analysis of DNA methylation and gene expression profiles identified S100A9 as a potential biomarker in ulcerative colitis","volume":"40","author":"Su","year":"2020","journal-title":"Biosci. Rep."},{"key":"B89","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s13046-024-03062-3","article-title":"PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling","volume":"43","author":"Su","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1610931","DOI":"10.3389\/pore.2023.1610931","article-title":"Emerging roles of the HECT E3 ubiquitin ligases in gastric cancer","volume":"29","author":"Sun","year":"2023","journal-title":"Pathol. Oncol. Res."},{"key":"B91","doi-asserted-by":"publisher","first-page":"542","DOI":"10.7150\/ijbs.24303","article-title":"Generation of Smurf2 conditional knockout mice","volume":"14","author":"Tang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"B92","doi-asserted-by":"publisher","first-page":"e51182","DOI":"10.15252\/embr.202051182","article-title":"ENTREP\/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer","volume":"23","author":"Tsunoda","year":"2022","journal-title":"EMBO Rep."},{"key":"B93","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1007\/s00774-016-0757-8","article-title":"MiR-142-5p promotes bone repair by maintaining osteoblast activity","volume":"35","author":"Tu","year":"2017","journal-title":"J. Bone Min. Metab."},{"key":"B94","first-page":"92","article-title":"Osteoporosis: a review of treatment options","volume":"43","author":"Tu","year":"2018","journal-title":"P T"},{"key":"B95","doi-asserted-by":"publisher","first-page":"e31388","DOI":"10.1002\/jcp.31388","article-title":"Hakai, a novel Runx2 interacting protein, augments osteoblast differentiation by rescuing Runx2 from Smurf2-mediated proteasome degradation","volume":"239","author":"Upadhyay","year":"2024","journal-title":"J. Cell Physiol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"2400","DOI":"10.3390\/cells12192400","article-title":"c-Cbl regulates murine subventricular zone-derived neural progenitor cells in dependence of the epidermal growth factor receptor","volume":"12","author":"Vogt","year":"2023","journal-title":"Cells"},{"key":"B97","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/s41413-020-0088-1","article-title":"Mitigating osteonecrosis of the jaw (ONJ) through preventive dental care and understanding of risk factors","volume":"8","author":"Wan","year":"2020","journal-title":"Bone Res."},{"key":"B98","doi-asserted-by":"publisher","first-page":"5378","DOI":"10.1002\/jcp.29424","article-title":"CHIP regulates skeletal development and postnatal bone growth","volume":"235","author":"Wang","year":"2020","journal-title":"J. Cell Physiol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1016\/j.str.2023.03.010","article-title":"Structure of the human UBR5 E3 ubiquitin ligase","volume":"31","author":"Wang","year":"","journal-title":"Structure"},{"key":"B100","doi-asserted-by":"publisher","first-page":"3585","DOI":"10.1093\/plcell\/koad159","article-title":"PUB25 and PUB26 dynamically modulate ICE1 stability via differential ubiquitination during cold stress in Arabidopsis","volume":"35","author":"Wang","year":"","journal-title":"Plant Cell"},{"key":"B101","doi-asserted-by":"publisher","first-page":"00611","DOI":"10.1016\/j.jare.2024.12.033","article-title":"Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss","author":"Wang","year":"","journal-title":"J. Adv. Res."},{"key":"B102","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1038\/s41467-024-47586-w","article-title":"Structural insights into the functional mechanism of the ubiquitin ligase E6AP","volume":"15","author":"Wang","year":"","journal-title":"Nat. Commun."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1543929","DOI":"10.3389\/fcell.2025.1543929","article-title":"lncRNA Ubr5 promotes BMSCs apoptosis and inhibits their proliferation and osteogenic differentiation in weightless bone loss","volume":"13","author":"Wang","year":"2025","journal-title":"Front. Cell Dev. Biol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"8870","DOI":"10.3390\/ijms25168870","article-title":"The discovery of a specific CKIP-1 ligand for the potential treatment of disuse osteoporosis","volume":"25","author":"Wei","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.3390\/cells10051262","article-title":"A potential role for HUWE1 in modulating Cisplatin sensitivity","volume":"10","author":"Wenmaekers","year":"2021","journal-title":"Cells"},{"key":"B106","doi-asserted-by":"publisher","first-page":"116","DOI":"10.3171\/2016.11.SPINE16901","article-title":"Ectopic expression of Smurf2 and acceleration of age-related intervertebral disc degeneration in a mouse model","volume":"27","author":"Wu","year":"2017","journal-title":"J. Neurosurgery. Spine"},{"key":"B107","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1002\/jor.20563","article-title":"Regulation of embryonic endochondral ossification by Smurf2","volume":"26","author":"Wu","year":"2008","journal-title":"J. Orthopaedic Res."},{"key":"B108","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.jot.2025.01.001","article-title":"JP4-039 protects chondrocytes from ferroptosis to attenuate osteoarthritis progression by promoting Pink1\/Parkin-dependent mitophagy","volume":"51","author":"Xie","year":"2025","journal-title":"J. Orthopaedic Transl."},{"key":"B109","doi-asserted-by":"publisher","first-page":"22622","DOI":"10.1021\/jacs.2c09255","article-title":"Bridged proteolysis targeting chimera (PROTAC) enables degradation of undruggable targets","volume":"144","author":"Xiong","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"B110","doi-asserted-by":"publisher","first-page":"577","DOI":"10.3390\/biom14050577","article-title":"NEDD4 and NEDD4L: Ubiquitin ligases closely related to digestive diseases","volume":"14","author":"Xu","year":"2024","journal-title":"Biomolecules"},{"key":"B111","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.jtcme.2025.02.003","article-title":"Salvianic acid A promotes osteogenic differentiation of bone marrow mesenchymal stem cells in senile osteoporosis through bromodomain-containing protein 4\/Ariadne RBR E3 ubiquitin-protein ligase 1\/Rubicon axis","volume":"15","author":"Xu","year":"2025","journal-title":"J. Tradit. Complement. Med."},{"key":"B112","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1002\/jbmr.3285","article-title":"SIRT1\/HERC4 locus associated with bisphosphonate-induced osteonecrosis of the jaw: an exome-wide Association analysis","volume":"33","author":"Yang","year":"2018","journal-title":"J. Bone Min. Res."},{"key":"B113","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1093\/stmcls\/sxae031","article-title":"Cortactin controls bone homeostasis through regulating the differentiation of osteoblasts and osteoclasts","volume":"42","author":"Yang","year":"2024","journal-title":"Stem Cells"},{"key":"B114","doi-asserted-by":"publisher","first-page":"102009","DOI":"10.1016\/j.mtbio.2025.102009","article-title":"A biomimetic multimodal nanoplatform combining neutrophil-coated two-dimensional metalloporphyrinic framework nanosheet and exendin-4 to treat obesity-related osteoporosis","volume":"33","author":"Yang","year":"2025","journal-title":"Mater Today Bio"},{"key":"B115","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/s41413-024-00352-6","article-title":"Hydroxychloroquine and a low antiresorptive activity bisphosphonate conjugate prevent and reverse ovariectomy-induced bone loss in mice through dual antiresorptive and anabolic effects","volume":"12","author":"Yao","year":"2024","journal-title":"Bone Res."},{"key":"B116","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41413-023-00263-y","article-title":"CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C\/EBP\u03b4","volume":"11","author":"Yu","year":"2023","journal-title":"Bone Res."},{"key":"B117","doi-asserted-by":"publisher","first-page":"22359","DOI":"10.1074\/jbc.M112.442459","article-title":"Ubiquitin E3 ligase Itch negatively regulates osteoclast formation by promoting deubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6","volume":"288","author":"Zhang","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B118","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1111\/odi.13888","article-title":"Trim14 promotes osteoclastogenesis and noncanonical NF-\u03baB activation by targeting p100\/p52 in chronic periodontitis","volume":"28","author":"Zhang","year":"2022","journal-title":"Oral Dis."},{"key":"B119","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13018-023-04494-x","article-title":"Mechanism of Circ_HECW2 regulating osteoblast apoptosis in osteoporosis by attenuating the maturation of miR-1224-5p","volume":"19","author":"Zhang","year":"","journal-title":"J. Orthop. Surg. Res."},{"key":"B120","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s10020-024-00904-w","article-title":"BMSC-derived exosomes promote osteoporosis alleviation via M2 macrophage polarization","volume":"30","author":"Zhang","year":"","journal-title":"Mol. Med."},{"key":"B121","doi-asserted-by":"publisher","first-page":"122893","DOI":"10.1016\/j.lfs.2024.122893","article-title":"RNF31-mediated IKK\u03b1 ubiquitination aggravates inflammation and intestinal injury through regulating NF-\u03baB activation in human and mouse neonates","volume":"352","author":"Zhang","year":"","journal-title":"Life Sci."},{"key":"B122","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1186\/s13018-025-05834-9","article-title":"USP2-induced upregulation of LEF1 through deubiquitination relieves osteoporosis development by promoting the osteogenic differentiation of bone marrow mesenchymal stem cells","volume":"20","author":"Zhang","year":"2025","journal-title":"J. Orthop. Surg. Res."},{"key":"B123","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1002\/stem.703","article-title":"Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1","volume":"29","author":"Zhao","year":"2011","journal-title":"Stem Cells"},{"key":"B124","doi-asserted-by":"publisher","first-page":"625105","DOI":"10.3389\/fcell.2020.625105","article-title":"TRIM16 promotes osteogenic differentiation of human periodontal ligament stem cells by modulating CHIP-mediated degradation of RUNX2","volume":"8","author":"Zhao","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B125","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1038\/s42003-024-07127-z","article-title":"STUB1 suppresses paclitaxel resistance in ovarian cancer through mediating HOXB3 ubiquitination to inhibit PARK7 expression","volume":"7","author":"Zhao","year":"","journal-title":"Commun. Biol."},{"key":"B126","doi-asserted-by":"publisher","first-page":"2303134","DOI":"10.1002\/adhm.202303134","article-title":"Electrospun biomimetic periosteum capable of controlled release of multiple agents for programmed promoting bone regeneration","volume":"13","author":"Zhao","year":"","journal-title":"Adv. Healthc. Mater."},{"key":"B127","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1146\/annurev-biochem-060815-014922","article-title":"Ubiquitin ligases: structure, function, and regulation","volume":"86","author":"Zheng","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"B128","doi-asserted-by":"publisher","first-page":"e2308786","DOI":"10.1002\/advs.202308786","article-title":"Inhibition of METTL3 alleviates NLRP3 inflammasome activation via increasing ubiquitination of NEK7","volume":"11","author":"Zhou","year":"2024","journal-title":"Adv. Sci."},{"key":"B129","doi-asserted-by":"publisher","first-page":"e14294","DOI":"10.1111\/acel.14294","article-title":"\u03b2-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2\/AMPK\/PINK1\/Parkin pathway","volume":"23","author":"Zhuang","year":"2024","journal-title":"Aging Cell"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1825526\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:44:11Z","timestamp":1779083051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1825526\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":130,"alternative-id":["10.3389\/fcell.2026.1825526"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1825526","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"article-number":"1825526"}}