{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:08:03Z","timestamp":1792782483646,"version":"4.5.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"FEIOMM","award":["FEIOMM2019"],"award-info":[{"award-number":["FEIOMM2019"]}]},{"name":"AEI","award":["PID2019-107188RB-C21, PID2022-141461OB-I00"],"award-info":[{"award-number":["PID2019-107188RB-C21, PID2022-141461OB-I00"]}]},{"name":"AEI","award":["PID2019109659RB-I00"],"award-info":[{"award-number":["PID2019109659RB-I00"]}]},{"name":"CIBER","award":["CB16\/10\/00245"],"award-info":[{"award-number":["CB16\/10\/00245"]}],"id":[{"id":"https:\/\/ror.org\/02g87qh62","id-type":"ROR","asserted-by":"crossref"}]},{"name":"AGAUR","award":["SGR2021\/1093 and SGR2021\/00043"],"award-info":[{"award-number":["SGR2021\/1093 and SGR2021\/00043"]}],"id":[{"id":"https:\/\/ror.org\/01n4pqe45","id-type":"ROR","asserted-by":"crossref"}]},{"name":"AGAUR","award":["FI (2017FI_B 01107)"],"award-info":[{"award-number":["FI (2017FI_B 01107)"]}],"id":[{"id":"https:\/\/ror.org\/01n4pqe45","id-type":"ROR","asserted-by":"crossref"}]},{"name":"AGAUR","award":["FI-SDU (2020FISDU 00517)"],"award-info":[{"award-number":["FI-SDU (2020FISDU 00517)"]}],"id":[{"id":"https:\/\/ror.org\/01n4pqe45","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Montcelimar Foundation","award":["Montcelimar Foundation"],"award-info":[{"award-number":["Montcelimar Foundation"]}]},{"name":"GEMSTONE-COST Action","award":["GEMSTONE-COST Action"],"award-info":[{"award-number":["GEMSTONE-COST Action"]}]},{"name":"CIBERER","award":["U720"],"award-info":[{"award-number":["U720"]}],"id":[{"id":"https:\/\/ror.org\/01ygm5w19","id-type":"ROR","asserted-by":"crossref"}]},{"name":"ERDF\/EU","award":["ERDF\/EU"],"award-info":[{"award-number":["ERDF\/EU"]}]},{"name":"FEIOMM mobility fellowship","award":["FEIOMM mobility fellowship"],"award-info":[{"award-number":["FEIOMM mobility fellowship"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Calcif Tissue Int"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Gaucher disease (GD) is caused by recessive mutations in the\n                    <jats:italic>GBA1<\/jats:italic>\n                    gene (Glucosylceramidase beta 1) generating lysosomal accumulation of glucosylceramides. Bone phenotypes related to GD include Erlenmeyer flask deformity, osteosclerosis, osteonecrosis, osteopenia, and bone pain. Lysosomes modulate osteoclast differentiation, playing a fundamental role in osteoclastogenesis and bone resorption. However, the role of\n                    <jats:italic>GBA1<\/jats:italic>\n                    mutations in the osteoclast function remains poorly understood. We aimed to generate and characterize an in vitro osteoclast cell model of GD. The\n                    <jats:italic>Gba1<\/jats:italic>\n                    gene was knocked out with CRISPR\/Cas9 in the murine macrophage cell line RAW264.7. One RAW-Gba1KO clone displaying no GBA1 enzymatic activity was selected. Non-edited RAW264.7 cells were used as controls (wt). Expression of osteoclast biomarkers,\n                    <jats:italic>Rank<\/jats:italic>\n                    ,\n                    <jats:italic>Trap<\/jats:italic>\n                    ,\n                    <jats:italic>Nfatc1<\/jats:italic>\n                    , and pro-cathepsin K\/cathepsin K as well as activity of TRAP protein and bone resorption were assessed. RAW-Gba1KO cells showed reduced expression of the osteoclast differentiation markers Rank and Nfatc1, suggesting that osteoclast differentiation is delayed or impaired compared with wt cells. Despite this, KO cells exhibited higher expression of Trap and cathepsin K, indicating enhanced osteoclast activity. Functional assays confirmed this finding, showing significantly increased TRAP activity and bone resorption in KO cells during differentiation. Additionally, KO cells displayed elevated levels of cathepsin K and pro-cathepsin K, particularly before differentiation, which may contribute to the increased TRAP activation. In conclusion, lack of Gba1 activity induced changes in our osteoclast model which enhanced its bone resorption potential, demonstrating a major intrinsic osteoclastic defect in Gaucher disease of bone.\n                  <\/jats:p>","DOI":"10.1007\/s00223-026-01616-5","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:48:47Z","timestamp":1790819327000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Generation and Characterization of an Osteoclastic Cell Model of Gaucher\u2019s Bone Disease"],"prefix":"10.1007","volume":"117","author":[{"given":"Juan-David","family":"Pati\u00f1o-Salazar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Diego","family":"Guti\u00e9rrez-\u00c1vila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Heredero-Jimenez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Mart\u00edn-Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00faria","family":"Mart\u00ednez-Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Cozar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Ovejero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Nogu\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Cinque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Ardura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arancha R.","family":"Gortazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Grinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Balcells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-0147","authenticated-orcid":false,"given":"Natalia","family":"Garcia-Giralt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Rabionet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"1616_CR1","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1002\/humu.20676","volume":"29","author":"KS Hruska","year":"2008","unstructured":"Hruska KS, LaMarca ME, Scott CR, Sidransky E (2008) Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 29:567\u2013583","journal-title":"Hum Mutat"},{"key":"1616_CR2","doi-asserted-by":"publisher","first-page":"441","DOI":"10.3390\/ijms18020441","volume":"18","author":"J Stirnemann","year":"2017","unstructured":"Stirnemann J, Belmatoug N, Camou F et al (2017) A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 18:441. https:\/\/doi.org\/10.3390\/ijms18020441","journal-title":"Int J Mol Sci"},{"key":"1616_CR3","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.ymgme.2021.01.002","volume":"132","author":"EC Daykin","year":"2021","unstructured":"Daykin EC, Ryan E, Sidransky E (2021) Diagnosing neuronopathic Gaucher disease: new considerations and challenges in assigning Gaucher phenotypes. Mol Genet Metab 132:49\u201358","journal-title":"Mol Genet Metab"},{"key":"1616_CR4","doi-asserted-by":"publisher","first-page":"934820","DOI":"10.3389\/fnmol.2022.934820","volume":"15","author":"NB Ar\u00e9valo","year":"2022","unstructured":"Ar\u00e9valo NB, Lamaizon CM, Cavieres VA et al (2022) Neuronopathic Gaucher disease: beyond lysosomal dysfunction. Front Mol Neurosci 15:934820","journal-title":"Front Mol Neurosci"},{"key":"1616_CR5","doi-asserted-by":"publisher","first-page":"2840","DOI":"10.3390\/diagnostics14242840","volume":"14","author":"DA M\u00e9ndez-Cobi\u00e1n","year":"2024","unstructured":"M\u00e9ndez-Cobi\u00e1n DA, Guzm\u00e1n-Silahua S, Garc\u00eda-Hern\u00e1ndez D et al (2024) An overview of Gaucher disease. Diagnostics (Basel) 14:2840. https:\/\/doi.org\/10.3390\/diagnostics14242840","journal-title":"Diagnostics (Basel)"},{"key":"1616_CR6","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s00109-021-02174-z","volume":"100","author":"J Roh","year":"2022","unstructured":"Roh J, Subramanian S, Weinreb NJ, Kartha RV (2022) Gaucher disease - more than just a rare lipid storage disease. J Mol Med (Berl) 100:499\u2013518","journal-title":"J Mol Med (Berl)"},{"key":"1616_CR7","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/j.1365-2141.2006.05978.x","volume":"133","author":"I Magal","year":"2006","unstructured":"Magal I, Lebel E, Altarescu G et al (2006) Serum levels of osteoprotegerin and osteoprotegerin polymorphisms in Gaucher disease. Br J Haematol 133:93\u201397","journal-title":"Br J Haematol"},{"key":"1616_CR8","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1002\/jbmr.3734","volume":"34","author":"D Hughes","year":"2019","unstructured":"Hughes D, Mikosch P, Belmatoug N et al (2019) Gaucher disease in bone: from pathophysiology to practice. J Bone Min Res 34:996\u20131013","journal-title":"J Bone Min Res"},{"key":"1616_CR9","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.berh.2011.10.015","volume":"25","author":"P Mikosch","year":"2011","unstructured":"Mikosch P (2011) Miscellaneous non-inflammatory musculoskeletal conditions. Gaucher disease and bone. Best Pract Res Clin Rheumatol 25:665\u2013681","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"1616_CR10","doi-asserted-by":"publisher","first-page":"1431566","DOI":"10.3389\/fcell.2024.1431566","volume":"12","author":"J Jiang","year":"2024","unstructured":"Jiang J, Ren R, Fang W et al (2024) Lysosomal biogenesis and function in osteoclasts: a comprehensive review. Front Cell Dev Biol 12:1431566","journal-title":"Front Cell Dev Biol"},{"key":"1616_CR11","doi-asserted-by":"publisher","first-page":"11204","DOI":"10.3390\/ijms241311204","volume":"24","author":"ME Ormazabal","year":"2023","unstructured":"Ormazabal ME, Pavan E, Vaena E et al (2023) Exploring the pathophysiologic cascade leading to osteoclastogenic activation in gaucher disease monocytes generated via CRISPR\/Cas9 technology. Int J Mol Sci 24:11204. https:\/\/doi.org\/10.3390\/ijms241311204","journal-title":"Int J Mol Sci 24"},{"key":"1616_CR12","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1038\/nprot.2013.143","volume":"8","author":"FA Ran","year":"2013","unstructured":"Ran FA, Hsu PD, Wright J et al (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281\u20132308","journal-title":"Nat Protoc"},{"key":"1616_CR13","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1182\/blood.V96.5.1969","volume":"96","author":"MT Moran","year":"2000","unstructured":"Moran MT, Schofield JP, Hayman AR et al (2000) Pathologic gene expression in Gaucher disease: up-regulation of cysteine proteinases including osteoclastic cathepsin K. Blood 96:1969\u20131978","journal-title":"Blood"},{"key":"1616_CR14","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.medcli.2014.11.018","volume":"145","author":"J Bobillo Lobato","year":"2015","unstructured":"Bobillo Lobato J, Dur\u00e1n Parejo P, N\u00fa\u00f1ez V\u00e1zquez RJ, Jim\u00e9nez Jim\u00e9nez LM (2015) [Cathepsin K as a biomarker of bone involvement in type 1 Gaucher disease]. Med Clin (Barc) 145:281\u2013287","journal-title":"Med Clin (Barc)"},{"key":"1616_CR15","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/S8756-3282(00)00445-2","volume":"28","author":"DJ Rieman","year":"2001","unstructured":"Rieman DJ, McClung HA, Dodds RA et al (2001) Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone 28:282\u2013289","journal-title":"Bone"},{"key":"1616_CR16","doi-asserted-by":"publisher","first-page":"jcs216267","DOI":"10.1242\/jcs.216267","volume":"131","author":"M Pereira","year":"2018","unstructured":"Pereira M, Petretto E, Gordon S et al (2018) Common signalling pathways in macrophage and osteoclast multinucleation. J Cell Sci 131:jcs216267","journal-title":"J Cell Sci"},{"key":"1616_CR17","first-page":"637","volume":"10","author":"E Fleckenstein","year":"1996","unstructured":"Fleckenstein E, Dirks W, Dehmel U, Drexler HG (1996) Cloning and characterization of the human tartrate-resistant acid phosphatase (TRAP) gene. Leukemia 10:637\u2013643","journal-title":"Leukemia"},{"key":"1616_CR18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12860-020-00253-6","volume":"21","author":"A Reithmeier","year":"2020","unstructured":"Reithmeier A, Norg\u00e5rd M, Ek-Rylander B et al (2020) Cathepsin K regulates localization and secretion of Tartrate-Resistant Acid Phosphatase (TRAP) in TRAP-overexpressing MDA-MB-231 breast cancer cells. BMC Mol Cell Biol 21:15","journal-title":"BMC Mol Cell Biol"},{"key":"1616_CR19","doi-asserted-by":"publisher","first-page":"2217","DOI":"10.3390\/jcm10102217","volume":"10","author":"M Ivanova","year":"2021","unstructured":"Ivanova M, Dao J, Noll L et al (2021) TRAP5b and RANKL\/OPG predict bone pathology in patients with Gaucher disease. J Clin Med 10:2217. https:\/\/doi.org\/10.3390\/jcm10102217","journal-title":"J Clin Med 10"},{"key":"1616_CR20","doi-asserted-by":"publisher","first-page":"e20240002","DOI":"10.1590\/2326-4594-JIEMS-2024-0002","volume":"13","author":"D Arturo-Terranova","year":"2025","unstructured":"Arturo-Terranova D, Moreno Giraldo LJ, Satizabal Soto JM (2025) Exploration of bone alterations in Gaucher disease Type 1: a global and systematic analysis of scientific knowledge. J Inborn Errors Metabolism Screen 13:e20240002. https:\/\/doi.org\/10.1590\/2326-4594-JIEMS-2024-0002","journal-title":"J Inborn Errors Metabolism Screen"}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-026-01616-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-026-01616-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-026-01616-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T01:48:49Z","timestamp":1790819329000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-026-01616-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1616"],"URL":"https:\/\/doi.org\/10.1007\/s00223-026-01616-5","relation":{},"ISSN":["1432-0827"],"issn-type":[{"value":"1432-0827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"assertion":[{"value":"2 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","label":"Competing Interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"154"}}