{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T18:42:59Z","timestamp":1785868979859,"version":"3.56.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T00:00:00Z","timestamp":1711497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Societ\u00e0 Italiana dell\u2019Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro, Italy","award":["Premio di Ricerca SIOMMMS Giovani Ricercatori 2021"],"award-info":[{"award-number":["Premio di Ricerca SIOMMMS Giovani Ricercatori 2021"]}]},{"DOI":"10.13039\/100010874","name":"American Society for Bone and Mineral Research","doi-asserted-by":"publisher","award":["ASBMR Fund for Research and Education Grant 2021"],"award-info":[{"award-number":["ASBMR Fund for Research and Education Grant 2021"]}],"id":[{"id":"10.13039\/100010874","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondazione Cariplo and Fondazione Telethon","award":["Joint Grant on rare diseases, GJC21079\/2022-0577"],"award-info":[{"award-number":["Joint Grant on rare diseases, GJC21079\/2022-0577"]}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR2019-12370949"],"award-info":[{"award-number":["GR2019-12370949"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["Investigator Grant 2016 - 18858"],"award-info":[{"award-number":["Investigator Grant 2016 - 18858"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002803","name":"Fondazione Cariplo","doi-asserted-by":"publisher","award":["2018-0541"],"award-info":[{"award-number":["2018-0541"]}],"id":[{"id":"10.13039\/501100002803","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union \u2013 Next Generation EU","award":["National Recovery and Resilience Plan, Investment Partenariato Esteso PE8 \"Conseguenze e sfide dell'invecchiamento\", Project Age-It - Ageing Well in an Ageing Society"],"award-info":[{"award-number":["National Recovery and Resilience Plan, Investment Partenariato Esteso PE8 \"Conseguenze e sfide dell'invecchiamento\", Project Age-It - Ageing Well in an Ageing Society"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bone destruction, a major source of morbidity, is mediated by heightened differentiation and activity of osteoclasts (OC), highly specialized multinucleated myeloid cells endowed with unique bone-resorptive capacity. The molecular mechanisms regulating OC differentiation in the bone marrow are still partly elusive. Here, we aimed to identify new regulatory circuits and actionable targets by comprehensive proteomic characterization of OCgenesis from mouse bone marrow monocytes, adopting two parallel unbiased comparative proteomic approaches. This work disclosed an unanticipated protein signature of OCgenesis, with most gene products currently unannotated in bone-related functions, revealing broad structural and functional cellular reorganization and divergence from macrophagic immune activity. Moreover, we identified the deubiquitinase UCHL1 as the most upregulated cytosolic protein in differentiating OCs. Functional studies proved it essential, as UCHL1 genetic and pharmacologic inhibition potently suppressed OCgenesis. Furthermore, proteomics and mechanistic dissection showed that UCHL1 supports OC differentiation by restricting the anti-OCgenic activity of NRF2, the transcriptional activator of the canonical antioxidant response, through redox-independent stabilization of the NRF2 inhibitor, KEAP1. Besides offering a valuable experimental framework to dissect OC differentiation, our study discloses the essential role of UCHL1, exerted through KEAP1-dependent containment of NRF2 anti-OCgenic activity, yielding a novel potential actionable pathway against bone loss.<\/jats:p>","DOI":"10.1038\/s41598-024-57898-y","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T14:01:54Z","timestamp":1711548114000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A novel proteomic signature of osteoclast differentiation unveils the deubiquitinase UCHL1 as a necessary osteoclastogenic driver"],"prefix":"10.1038","volume":"14","author":[{"given":"Maria","family":"Materozzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Resnati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Facchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Trudu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugo","family":"Orfanelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Perini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Gennari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Milan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Cenci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"57898_CR1","doi-asserted-by":"publisher","first-page":"3553","DOI":"10.3390\/ijms22073553","volume":"22","author":"A Chandra","year":"2021","unstructured":"Chandra, A. & Rajawat, J. Skeletal aging and osteoporosis: Mechanisms and therapeutics. Int. J. Mol. Sci. 22, 3553. https:\/\/doi.org\/10.3390\/ijms22073553 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"57898_CR2","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1002\/jbmr.4665","volume":"37","author":"S Minisola","year":"2022","unstructured":"Minisola, S. et al. Epidemiology, pathophysiology, and genetics of primary hyperparathyroidism. J. Bone Miner. Res Off. J. Am. Soc. Bone Miner. Res. 37, 2315\u20132329. https:\/\/doi.org\/10.1002\/jbmr.4665 (2022).","journal-title":"J. Bone Miner. Res Off. J. Am. Soc. Bone Miner. Res."},{"key":"57898_CR3","doi-asserted-by":"publisher","first-page":"1880","DOI":"10.3390\/genes13101880","volume":"13","author":"N Charoenngam","year":"2022","unstructured":"Charoenngam, N., Nasr, A., Shirvani, A. & Holick, M. F. Hereditary metabolic bone diseases: A review of pathogenesis. Diagn. Manag. Genes 13, 1880. https:\/\/doi.org\/10.3390\/genes13101880 (2022).","journal-title":"Diagn. Manag. Genes"},{"key":"57898_CR4","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41572-020-00216-3","volume":"6","author":"RE Coleman","year":"2020","unstructured":"Coleman, R. E. et al. Bone metastases. Nat. Rev. Dis. Prim. 6, 83. https:\/\/doi.org\/10.1038\/s41572-020-00216-3 (2020).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"57898_CR5","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/S2213-8587(22)00012-2","volume":"10","author":"T Vilaca","year":"2022","unstructured":"Vilaca, T., Eastell, R. & Schini, M. Osteoporosis in men. Lancet Diabetes Endocrinol. 10, 273\u2013283. https:\/\/doi.org\/10.1016\/S2213-8587(22)00012-2 (2022).","journal-title":"Lancet Diabetes Endocrinol."},{"key":"57898_CR6","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S2213-8587(21)00347-8","volume":"10","author":"LC Hofbauer","year":"2022","unstructured":"Hofbauer, L. C. et al. Bone fragility in diabetes: Novel concepts and clinical implications. Lancet Diabetes Endocrinol. 10, 207\u2013220. https:\/\/doi.org\/10.1016\/S2213-8587(21)00347-8 (2022).","journal-title":"Lancet Diabetes Endocrinol."},{"key":"57898_CR7","doi-asserted-by":"publisher","first-page":"4873","DOI":"10.3390\/ijms20194873","volume":"20","author":"CE Murray","year":"2019","unstructured":"Murray, C. E. & Coleman, C. M. Impact of diabetes mellitus on bone health. Int. J. Mol. Sci. 20, 4873. https:\/\/doi.org\/10.3390\/ijms20194873 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"57898_CR8","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s11657-020-0706-y","volume":"15","author":"F Borgstr\u00f6m","year":"2020","unstructured":"Borgstr\u00f6m, F. et al. Fragility fractures in Europe: burden, management and opportunities. Arch. Osteoporos. 15, 59. https:\/\/doi.org\/10.1007\/s11657-020-0706-y (2020).","journal-title":"Arch. Osteoporos."},{"key":"57898_CR9","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1177\/0004563218759371","volume":"55","author":"JS Kenkre","year":"2018","unstructured":"Kenkre, J. S. & Bassett, J. The bone remodelling cycle. Ann. Clin. Biochem. 55, 308\u2013327. https:\/\/doi.org\/10.1177\/0004563218759371 (2018).","journal-title":"Ann. Clin. Biochem."},{"key":"57898_CR10","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-018-2817-9","author":"KH Park-Min","year":"2018","unstructured":"Park-Min, K. H. Mechanisms involved in normal and pathological osteoclastogenesis. Cell. Mol. Life Sci. CMLS https:\/\/doi.org\/10.1007\/s00018-018-2817-9 (2018).","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"57898_CR11","doi-asserted-by":"publisher","first-page":"981487","DOI":"10.3389\/fendo.2022.981487","volume":"13","author":"D Ali","year":"2022","unstructured":"Ali, D., Tencerova, M., Figeac, F., Kassem, M. & Jafari, A. The pathophysiology of osteoporosis in obesity and type 2 diabetes in aging women and men: The mechanisms and roles of increased bone marrow adiposity. Front. Endocrinol. 13, 981487. https:\/\/doi.org\/10.3389\/fendo.2022.981487 (2022).","journal-title":"Front. Endocrinol."},{"key":"57898_CR12","doi-asserted-by":"publisher","DOI":"10.1111\/ecc.12761","author":"E Terpos","year":"2017","unstructured":"Terpos, E., Christoulas, D., Gavriatopoulou, M. & Dimopoulos, M. A. Mechanisms of bone destruction in multiple myeloma. Eur. J. Cancer Care (Engl.) https:\/\/doi.org\/10.1111\/ecc.12761 (2017).","journal-title":"Eur. J. Cancer Care (Engl.)"},{"key":"57898_CR13","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1152\/physrev.00012.2019","volume":"101","author":"P Cl\u00e9zardin","year":"2021","unstructured":"Cl\u00e9zardin, P. et al. Bone metastasis: Mechanisms, therapies, and biomarkers. Physiol. Rev. 101, 797\u2013855. https:\/\/doi.org\/10.1152\/physrev.00012.2019 (2021).","journal-title":"Physiol. Rev."},{"key":"57898_CR14","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1016\/S0140-6736(21)02646-5","volume":"399","author":"IR Reid","year":"2022","unstructured":"Reid, I. R. & Billington, E. O. Drug therapy for osteoporosis in older adults. Lancet Lond. Engl. 399, 1080\u20131092. https:\/\/doi.org\/10.1016\/S0140-6736(21)02646-5 (2022).","journal-title":"Lancet Lond. Engl."},{"key":"57898_CR15","doi-asserted-by":"publisher","DOI":"10.1007\/s11864-019-0623-8","author":"H Goldvaser","year":"2019","unstructured":"Goldvaser, H. & Amir, E. Role of bisphosphonates in breast cancer therapy. Curr. Treat. Options Oncol. https:\/\/doi.org\/10.1007\/s11864-019-0623-8 (2019).","journal-title":"Curr. Treat. Options Oncol."},{"key":"57898_CR16","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1210\/clinem\/dgab888","volume":"107","author":"AD Anastasilakis","year":"2022","unstructured":"Anastasilakis, A. D. et al. Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: A critical review organized by the ECTS. J. Clin. Endocrinol. Metab. 107, 1441\u20131460. https:\/\/doi.org\/10.1210\/clinem\/dgab888 (2022).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"57898_CR17","doi-asserted-by":"publisher","first-page":"182","DOI":"10.7326\/M22-0684","volume":"176","author":"C Ayers","year":"2023","unstructured":"Ayers, C. et al. Effectiveness and safety of treatments to prevent fractures in people with low bone mass or primary osteoporosis: A living systematic review and network meta-analysis for the American College of Physicians. Ann. Intern. Med. 176, 182\u2013195. https:\/\/doi.org\/10.7326\/M22-0684 (2023).","journal-title":"Ann. Intern. Med."},{"key":"57898_CR18","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.semcdb.2021.05.014","volume":"123","author":"V Fischer","year":"2022","unstructured":"Fischer, V. & Haffner-Luntzer, M. Interaction between bone and immune cells: Implications for postmenopausal osteoporosis. Semin. Cell Dev. Biol. 123, 14\u201321. https:\/\/doi.org\/10.1016\/j.semcdb.2021.05.014 (2022).","journal-title":"Semin. Cell Dev. Biol."},{"key":"57898_CR19","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.3389\/fimmu.2019.01408","volume":"10","author":"M-B Madel","year":"2019","unstructured":"Madel, M.-B. et al. Immune function and diversity of osteoclasts in normal and pathological conditions. Front. Immunol. 10, 1408. https:\/\/doi.org\/10.3389\/fimmu.2019.01408 (2019).","journal-title":"Front. Immunol."},{"key":"57898_CR20","doi-asserted-by":"publisher","first-page":"664871","DOI":"10.3389\/fimmu.2021.664871","volume":"12","author":"Y Yao","year":"2021","unstructured":"Yao, Y. et al. The macrophage-osteoclast axis in osteoimmunity and osteo-related diseases. Front. Immunol. 12, 664871. https:\/\/doi.org\/10.3389\/fimmu.2021.664871 (2021).","journal-title":"Front. Immunol."},{"key":"57898_CR21","doi-asserted-by":"publisher","unstructured":"Halper, J., Madel, M.-B. & Blin-Wakkach, C. Differentiation and phenotyping of murine osteoclasts from bone marrow progenitors, monocytes, and dendritic cells. In Methods Molecular Biology, Vol. 2308 21\u201334 (Clifton, 2021). https:\/\/doi.org\/10.1007\/978-1-0716-1425-9_2 (2021).","DOI":"10.1007\/978-1-0716-1425-9_2"},{"key":"57898_CR22","doi-asserted-by":"publisher","first-page":"D981","DOI":"10.1093\/nar\/gkaa1083","volume":"49","author":"JA Blake","year":"2021","unstructured":"Blake, J. A. et al. Mouse genome database (MGD): Knowledgebase for mouse-human comparative biology. Nucleic Acids Res. 49, D981\u2013D987. https:\/\/doi.org\/10.1093\/nar\/gkaa1083 (2021).","journal-title":"Nucleic Acids Res."},{"key":"57898_CR23","doi-asserted-by":"publisher","first-page":"101856","DOI":"10.1016\/j.arr.2023.101856","volume":"86","author":"Z Mi","year":"2023","unstructured":"Mi, Z. & Graham, S. H. Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury. Ageing Res. Rev. 86, 101856. https:\/\/doi.org\/10.1016\/j.arr.2023.101856 (2023).","journal-title":"Ageing Res. Rev."},{"key":"57898_CR24","doi-asserted-by":"publisher","first-page":"eaax4826","DOI":"10.1126\/sciadv.aax4826","volume":"6","author":"H-L Bi","year":"2020","unstructured":"Bi, H.-L. et al. The deubiquitinase UCHL1 regulates cardiac hypertrophy by stabilizing epidermal growth factor receptor. Sci. Adv. 6, eaax4826. https:\/\/doi.org\/10.1126\/sciadv.aax4826 (2020).","journal-title":"Sci. Adv."},{"key":"57898_CR25","doi-asserted-by":"publisher","first-page":"102295","DOI":"10.1016\/j.redox.2022.102295","volume":"52","author":"B Geng","year":"2022","unstructured":"Geng, B. et al. UCHL1 protects against ischemic heart injury via activating HIF-1\u03b1 signal pathway. Redox Biol. 52, 102295. https:\/\/doi.org\/10.1016\/j.redox.2022.102295 (2022).","journal-title":"Redox Biol."},{"key":"57898_CR26","doi-asserted-by":"publisher","first-page":"8379","DOI":"10.1007\/s13277-015-3566-0","volume":"36","author":"Y Gu","year":"2015","unstructured":"Gu, Y. et al. The de-ubiquitinase UCHL1 promotes gastric cancer metastasis via the Akt and Erk1\/2 pathways. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 36, 8379\u20138387. https:\/\/doi.org\/10.1007\/s13277-015-3566-0 (2015).","journal-title":"Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med."},{"key":"57898_CR27","doi-asserted-by":"publisher","first-page":"662","DOI":"10.7150\/jca.6641","volume":"4","author":"C Jin","year":"2013","unstructured":"Jin, C. et al. UCHL1 Is a putative tumor suppressor in ovarian cancer cells and contributes to cisplatin resistance. J. Cancer 4, 662\u2013670. https:\/\/doi.org\/10.7150\/jca.6641 (2013).","journal-title":"J. Cancer"},{"key":"57898_CR28","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1158\/1078-0432.CCR-19-1373","volume":"26","author":"S Liu","year":"2020","unstructured":"Liu, S. et al. Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGF\u03b2-induced breast cancer metastasis. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 26, 1460\u20131473. https:\/\/doi.org\/10.1158\/1078-0432.CCR-19-1373 (2020).","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"57898_CR29","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/labinvest.2013.140","volume":"94","author":"AE Coudert","year":"2014","unstructured":"Coudert, A. E. et al. Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology. Lab. Investig. J. Tech. Methods Pathol. 94, 275\u2013285. https:\/\/doi.org\/10.1038\/labinvest.2013.140 (2014).","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"57898_CR30","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1016\/j.chembiol.2003.08.010","volume":"10","author":"Y Liu","year":"2003","unstructured":"Liu, Y. et al. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. Chem. Biol. 10, 837\u2013846. https:\/\/doi.org\/10.1016\/j.chembiol.2003.08.010 (2003).","journal-title":"Chem. Biol."},{"key":"57898_CR31","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3181\/00379727-187-42656","volume":"187","author":"K Yamazaki","year":"1988","unstructured":"Yamazaki, K. et al. Gracile axonal dystrophy (GAD), a new neurological mutant in the mouse. Proc. Soc. Exp. Biol. Med. 187, 209\u2013215. https:\/\/doi.org\/10.3181\/00379727-187-42656 (1988).","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"57898_CR32","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1093\/hmg\/ddw391","volume":"26","author":"SL Rydning","year":"2017","unstructured":"Rydning, S. L. et al. Novel UCHL1 mutations reveal new insights into ubiquitin processing. Hum. Mol. Genet. 26, 1031\u20131040. https:\/\/doi.org\/10.1093\/hmg\/ddw391 (2017).","journal-title":"Hum. Mol. Genet."},{"key":"57898_CR33","doi-asserted-by":"publisher","first-page":"7963","DOI":"10.1073\/pnas.1812413116","volume":"116","author":"AT Reinicke","year":"2019","unstructured":"Reinicke, A. T. et al. Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks. Proc. Natl. Acad. Sci. U.S.A. 116, 7963\u20137972. https:\/\/doi.org\/10.1073\/pnas.1812413116 (2019).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"57898_CR34","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1016\/j.gim.2022.07.006","volume":"24","author":"J Park","year":"2022","unstructured":"Park, J. et al. Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy. Genet. Med. Off. J. Am. Coll. Med. Genet. 24, 2079\u20132090. https:\/\/doi.org\/10.1016\/j.gim.2022.07.006 (2022).","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"57898_CR35","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1093\/hmg\/ddg211","volume":"12","author":"H Osaka","year":"2003","unstructured":"Osaka, H. et al. Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum. Mol. Genet. 12, 1945\u20131958. https:\/\/doi.org\/10.1093\/hmg\/ddg211 (2003).","journal-title":"Hum. Mol. Genet."},{"key":"57898_CR36","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20017","author":"DM Maraganore","year":"2004","unstructured":"Maraganore, D. M. et al. UCHL1 is a Parkinson\u2019s disease susceptibility gene. Ann. Neurol. https:\/\/doi.org\/10.1002\/ana.20017 (2004).","journal-title":"Ann. Neurol."},{"key":"57898_CR37","doi-asserted-by":"publisher","first-page":"23731","DOI":"10.1074\/jbc.M801918200","volume":"283","author":"T Kabuta","year":"2008","unstructured":"Kabuta, T., Furuta, A., Aoki, S., Furuta, K. & Wada, K. Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J. Biol. Chem. 283, 23731\u201323738. https:\/\/doi.org\/10.1074\/jbc.M801918200 (2008).","journal-title":"J. Biol. Chem."},{"key":"57898_CR38","doi-asserted-by":"publisher","first-page":"3269","DOI":"10.1172\/JCI76765","volume":"125","author":"T Tohmonda","year":"2015","unstructured":"Tohmonda, T. et al. IRE1\u03b1\/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis. J. Clin. Invest. 125, 3269\u20133279. https:\/\/doi.org\/10.1172\/JCI76765 (2015).","journal-title":"J. Clin. Invest."},{"key":"57898_CR39","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1146\/annurev-cancerbio-030518-055627","volume":"4","author":"WL Wu","year":"2020","unstructured":"Wu, W. L. & Papagiannakopoulos, T. The pleiotropic role of the KEAP1\/NRF2 pathway in cancer. Annu. Rev. Cancer Biol. 4, 413\u2013435. https:\/\/doi.org\/10.1146\/annurev-cancerbio-030518-055627 (2020).","journal-title":"Annu. Rev. Cancer Biol."},{"key":"57898_CR40","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.tibs.2014.02.002","volume":"39","author":"JD Hayes","year":"2014","unstructured":"Hayes, J. D. & Dinkova-Kostova, A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199\u2013218. https:\/\/doi.org\/10.1016\/j.tibs.2014.02.002 (2014).","journal-title":"Trends Biochem. Sci."},{"key":"57898_CR41","doi-asserted-by":"publisher","first-page":"813057","DOI":"10.3389\/fendo.2022.813057","volume":"13","author":"J Han","year":"2022","unstructured":"Han, J. et al. The role of NRF2 in bone metabolism\u2014Friend or foe?. Front. Endocrinol. 13, 813057 (2022).","journal-title":"Front. Endocrinol."},{"key":"57898_CR42","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1002\/jps.2600680727","volume":"68","author":"SA Eigebaly","year":"1979","unstructured":"Eigebaly, S. A. et al. Antitumor agents. XXXV: Effects of brusatol, bruceoside A, and bruceantin on P-388 lymphocytic leukemia cell respiration. J. Pharm. Sci. 68, 887\u2013890. https:\/\/doi.org\/10.1002\/jps.2600680727 (1979).","journal-title":"J. Pharm. Sci."},{"key":"57898_CR43","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1073\/pnas.1014275108","volume":"108","author":"D Ren","year":"2011","unstructured":"Ren, D. et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc. Natl. Acad. Sci. U.S.A. 108, 1433\u20131438. https:\/\/doi.org\/10.1073\/pnas.1014275108 (2011).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"57898_CR44","doi-asserted-by":"publisher","first-page":"13561","DOI":"10.1073\/pnas.1121572109","volume":"109","author":"K Taguchi","year":"2012","unstructured":"Taguchi, K. et al. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc. Natl. Acad. Sci. 109, 13561\u201313566. https:\/\/doi.org\/10.1073\/pnas.1121572109 (2012).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"57898_CR45","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1002\/jbm4.10058","volume":"2","author":"AY Ng","year":"2018","unstructured":"Ng, A. Y. et al. Comparative characterization of osteoclasts derived from murine bone marrow macrophages and RAW 264.7 cells using quantitative proteomics. JBMR Plus 2, 328\u2013340. https:\/\/doi.org\/10.1002\/jbm4.10058 (2018).","journal-title":"JBMR Plus"},{"key":"57898_CR46","doi-asserted-by":"publisher","first-page":"141","DOI":"10.5483\/BMBRep.2014.47.3.270","volume":"47","author":"J-H Lee","year":"2014","unstructured":"Lee, J.-H. & Cho, J.-Y. Proteomics approaches for the studies of bone metabolism. BMB Rep. 47, 141\u2013148. https:\/\/doi.org\/10.5483\/BMBRep.2014.47.3.270 (2014).","journal-title":"BMB Rep."},{"key":"57898_CR47","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.1074\/mcp.M113.034371","volume":"13","author":"E An","year":"2014","unstructured":"An, E., Narayanan, M., Manes, N. P. & Nita-Lazar, A. Characterization of functional reprogramming during osteoclast development using quantitative proteomics and mRNA profiling. Mol. Cell. Proteom. MCP 13, 2687\u20132704. https:\/\/doi.org\/10.1074\/mcp.M113.034371 (2014).","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"57898_CR48","doi-asserted-by":"publisher","first-page":"3868","DOI":"10.1002\/pmic.200402059","volume":"5","author":"C Czupalla","year":"2005","unstructured":"Czupalla, C., Mansukoski, H., Pursche, T., Krause, E. & Hoflack, B. Comparative study of protein and mRNA expression during osteoclastogenesis. Proteomics 5, 3868\u20133875. https:\/\/doi.org\/10.1002\/pmic.200402059 (2005).","journal-title":"Proteomics"},{"key":"57898_CR49","doi-asserted-by":"publisher","first-page":"916","DOI":"10.3390\/genes14040916","volume":"14","author":"S Rashid","year":"2023","unstructured":"Rashid, S. et al. Identification of differentially expressed genes and molecular pathways involved in osteoclastogenesis using RNA-seq. Genes 14, 916. https:\/\/doi.org\/10.3390\/genes14040916 (2023).","journal-title":"Genes"},{"key":"57898_CR50","doi-asserted-by":"publisher","first-page":"37808","DOI":"10.1074\/jbc.M112.385369","volume":"287","author":"T Miyazaki","year":"2012","unstructured":"Miyazaki, T. et al. Intracellular and extracellular ATP coordinately regulate the inverse correlation between osteoclast survival and bone resorption. J. Biol. Chem. 287, 37808\u201337823. https:\/\/doi.org\/10.1074\/jbc.M112.385369 (2012).","journal-title":"J. Biol. Chem."},{"key":"57898_CR51","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.biocel.2016.08.034","volume":"79","author":"S Lemma","year":"2016","unstructured":"Lemma, S. et al. Energy metabolism in osteoclast formation and activity. Int. J. Biochem. Cell Biol. 79, 168\u2013180. https:\/\/doi.org\/10.1016\/j.biocel.2016.08.034 (2016).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"57898_CR52","first-page":"363","volume":"122","author":"R Baron","year":"1986","unstructured":"Baron, R., Neff, L., Van Tran, P., Nefussi, J. R. & Vignery, A. Kinetic and cytochemical identification of osteoclast precursors and their differentiation into multinucleated osteoclasts. Am. J. Pathol. 122, 363\u2013378 (1986).","journal-title":"Am. J. Pathol."},{"key":"57898_CR53","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/s0092-8674(02)01012-7","volume":"111","author":"Y Liu","year":"2002","unstructured":"Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z. & Lansbury, P. T. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson\u2019s disease susceptibility. Cell 111, 209\u2013218. https:\/\/doi.org\/10.1016\/s0092-8674(02)01012-7 (2002).","journal-title":"Cell"},{"key":"57898_CR54","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1292\/jvms.70.649","volume":"70","author":"S Shim","year":"2008","unstructured":"Shim, S., Kwon, Y.-B., Yoshikawa, Y. & Kwon, J. Ubiquitin C-terminal hydrolase L1 deficiency decreases bone mineralization. J. Vet. Med. Sci. 70, 649\u2013651. https:\/\/doi.org\/10.1292\/jvms.70.649 (2008).","journal-title":"J. Vet. Med. Sci."},{"key":"57898_CR55","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1007\/s00774-017-0871-2","volume":"36","author":"S-H Kim","year":"2018","unstructured":"Kim, S.-H. et al. Bortezomib prevents ovariectomy-induced osteoporosis in mice by inhibiting osteoclast differentiation. J. Bone Miner. Metab. 36, 537\u2013546. https:\/\/doi.org\/10.1007\/s00774-017-0871-2 (2018).","journal-title":"J. Bone Miner. Metab."},{"key":"57898_CR56","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.7150\/ijbs.82152","volume":"19","author":"Z Feng","year":"2023","unstructured":"Feng, Z. et al. The deubiquitinase UCHL1 negatively controls osteoclastogenesis by regulating TAZ\/NFATC1 signalling. Int. J. Biol. Sci. 19, 2319\u20132332. https:\/\/doi.org\/10.7150\/ijbs.82152 (2023).","journal-title":"Int. J. Biol. Sci."},{"key":"57898_CR57","doi-asserted-by":"publisher","first-page":"4011","DOI":"10.1096\/fj.201700177R","volume":"31","author":"E Sakai","year":"2017","unstructured":"Sakai, E. et al. Effects of deficiency of Kelch-like ECH-associated protein 1 on skeletal organization: a mechanism for diminished nuclear factor of activated T cells cytoplasmic 1 during osteoclastogenesis. FASEB. J. Off. Publ. Fed. Am. Soc. Exp. Biol. 31, 4011\u20134022. https:\/\/doi.org\/10.1096\/fj.201700177R (2017).","journal-title":"J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"57898_CR58","doi-asserted-by":"publisher","first-page":"14033","DOI":"10.1038\/boneres.2014.33","volume":"2","author":"J-H Kim","year":"2014","unstructured":"Kim, J.-H., Singhal, V., Biswal, S., Thimmulappa, R. K. & DiGirolamo, D. J. Nrf2 is required for normal postnatal bone acquisition in mice. Bone Res. 2, 14033. https:\/\/doi.org\/10.1038\/boneres.2014.33 (2014).","journal-title":"Bone Res."},{"key":"57898_CR59","doi-asserted-by":"publisher","first-page":"23009","DOI":"10.1074\/jbc.M113.478545","volume":"288","author":"H Kanzaki","year":"2013","unstructured":"Kanzaki, H., Shinohara, F., Kajiya, M. & Kodama, T. The Keap1\/Nrf2 protein axis plays a role in osteoclast differentiation by regulating intracellular reactive oxygen species signaling. J. Biol. Chem. 288, 23009\u201323020. https:\/\/doi.org\/10.1074\/jbc.M113.478545 (2013).","journal-title":"J. Biol. Chem."},{"key":"57898_CR60","doi-asserted-by":"publisher","first-page":"726590","DOI":"10.1155\/2014\/726590","volume":"2014","author":"L Ib\u00e1\u00f1ez","year":"2014","unstructured":"Ib\u00e1\u00f1ez, L. et al. Effects of Nrf2 deficiency on bone microarchitecture in an experimental model of osteoporosis. Oxid. Med. Cell. Longev. 2014, 726590. https:\/\/doi.org\/10.1155\/2014\/726590 (2014).","journal-title":"Oxid. Med. Cell. Longev."},{"key":"57898_CR61","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.3390\/cells9092133","volume":"9","author":"PSU Park","year":"2020","unstructured":"Park, P. S. U. et al. NRF2 is an upstream regulator of MYC-mediated osteoclastogenesis and pathological bone erosion. Cells 9, 2133. https:\/\/doi.org\/10.3390\/cells9092133 (2020).","journal-title":"Cells"},{"key":"57898_CR62","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.1172\/JCI89935","volume":"127","author":"S Bae","year":"2017","unstructured":"Bae, S. et al. MYC-dependent oxidative metabolism regulates osteoclastogenesis via nuclear receptor ERR\u03b1. J. Clin. Invest. 127, 2555\u20132568. https:\/\/doi.org\/10.1172\/JCI89935 (2017).","journal-title":"J. Clin. Invest."},{"key":"57898_CR63","doi-asserted-by":"publisher","first-page":"100228","DOI":"10.1016\/j.bonr.2019.100228","volume":"11","author":"T Narimiya","year":"2019","unstructured":"Narimiya, T. et al. Nrf2 activation in osteoblasts suppresses osteoclastogenesis via inhibiting IL-6 expression. Bone Rep. 11, 100228. https:\/\/doi.org\/10.1016\/j.bonr.2019.100228 (2019).","journal-title":"Bone Rep."},{"key":"57898_CR64","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.bone.2014.01.025","volume":"63","author":"CK Park","year":"2014","unstructured":"Park, C. K. et al. Nrf2 is a novel regulator of bone acquisition. Bone 63, 36\u201346. https:\/\/doi.org\/10.1016\/j.bone.2014.01.025 (2014).","journal-title":"Bone"},{"key":"57898_CR65","doi-asserted-by":"publisher","first-page":"376","DOI":"10.3969\/j.issn.1673-5374.2012.05.009","volume":"7","author":"X Chen","year":"2012","unstructured":"Chen, X., Guo, C. & Kong, J. Oxidative stress in neurodegenerative diseases. Neural Regen. Res. 7, 376\u2013385. https:\/\/doi.org\/10.3969\/j.issn.1673-5374.2012.05.009 (2012).","journal-title":"Neural Regen. Res."},{"key":"57898_CR66","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn115","author":"E Kyratzi","year":"2008","unstructured":"Kyratzi, E., Pavlaki, M. & Stefanis, L. The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells. Hum. Mol. Genet. https:\/\/doi.org\/10.1093\/hmg\/ddn115 (2008).","journal-title":"Hum. Mol. Genet."},{"key":"57898_CR67","doi-asserted-by":"publisher","first-page":"030006052110206","DOI":"10.1177\/03000605211020641","volume":"49","author":"S Liu","year":"2021","unstructured":"Liu, S. et al. Long-term inhibition of UCHL1 decreases hypertension and retinopathy in spontaneously hypertensive rats. J. Int. Med. Res. 49, 03000605211020641. https:\/\/doi.org\/10.1177\/03000605211020641 (2021).","journal-title":"J. Int. Med. Res."},{"key":"57898_CR68","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-017-3907-z","author":"A Namani","year":"2018","unstructured":"Namani, A., Rahaman, M. M., Chen, M. & Tang, X. Gene-expression signature regulated by the KEAP1-NRF2-CUL3 axis is associated with a poor prognosis in head and neck squamous cell cancer. BMC Cancer https:\/\/doi.org\/10.1186\/s12885-017-3907-z (2018).","journal-title":"BMC Cancer"},{"key":"57898_CR69","doi-asserted-by":"publisher","first-page":"166879","DOI":"10.1016\/j.jmb.2021.166879","volume":"433","author":"S Puri","year":"2021","unstructured":"Puri, S. & Hsu, S.-T.D. Cross-over loop cysteine C152 acts as an antioxidant to maintain the folding stability and deubiquitinase activity of UCH-L1 under oxidative stress. J. Mol. Biol. 433, 166879. https:\/\/doi.org\/10.1016\/j.jmb.2021.166879 (2021).","journal-title":"J. Mol. Biol."},{"key":"57898_CR70","doi-asserted-by":"publisher","first-page":"108162","DOI":"10.1016\/j.celrep.2020.108162","volume":"32","author":"C Fucci","year":"2020","unstructured":"Fucci, C. et al. The interaction of the tumor suppressor FAM46C with p62 and FNDC3 proteins integrates protein and secretory homeostasis. Cell Rep. 32, 108162. https:\/\/doi.org\/10.1016\/j.celrep.2020.108162 (2020).","journal-title":"Cell Rep."},{"key":"57898_CR71","doi-asserted-by":"publisher","first-page":"14272","DOI":"10.1038\/s41598-019-50718-8","volume":"9","author":"M Barbariga","year":"2019","unstructured":"Barbariga, M. et al. The role of extracellular matrix in mouse and human corneal neovascularization. Sci. Rep. 9, 14272. https:\/\/doi.org\/10.1038\/s41598-019-50718-8 (2019).","journal-title":"Sci. Rep."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57898-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57898-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57898-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T14:09:41Z","timestamp":1711548581000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-57898-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,27]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["57898"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-57898-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,27]]},"assertion":[{"value":"16 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7290"}}