{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:00:36Z","timestamp":1783422036429,"version":"3.54.6"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Education, University and Research","award":["3776\/202000"],"award-info":[{"award-number":["3776\/202000"]}]},{"name":"Finanziato dall\u2019Unione Europea\u2014Next Generation","award":["20223C8C5B"],"award-info":[{"award-number":["20223C8C5B"]}]},{"name":"Michael Geisman Research Fellowship-Osteogenesis Imperfecta Foundation","award":["2019-2021"],"award-info":[{"award-number":["2019-2021"]}]},{"DOI":"10.13039\/100013124","name":"Brittle Bone Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013124","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Osteogenesis imperfecta (OI) is a family of heritable collagen I\u2013related skeletal disorders for which, to date, no definitive cure is available. Individuals with OI are mainly treated with bisphosphonates that enhance bone mass by inhibiting bone resorption. However, new strategies combining antiresorptive molecules with bone anabolic drugs are likely to provide valid alternatives for skeletal health, protecting physiological bone turnover. Recently, cellular stress has been identified as a therapeutic target in both dominant and recessive forms of OI characterized by overmodified collagen I. The chemical chaperone 4-phenylbutyrate (4PBA) successfully ameliorated cell homeostasis in both in vitro and in vivo OI models. In this study, dominant Chihuahua (Chi\/+) and recessive p3h1\u2212\/\u2212 zebrafish OI models were treated for 2 mo either with the bisphosphonate alendronate (ALN) or with 4PBA or with a combination of the two. The treatment effect at the tissue level was evaluated by microCT analysis of the vertebral body, while histology and gene expression analyses allowed to dissect the consequences at a cellular level. Only ALN administration improved the vertebral thickness in the dominant Chi\/+ model. The combined therapy synergistically improved osteoblast homeostasis and promoted the formation of mature extracellular collagen fibers in both models. All treatment conditions reduced osteoclast TRAP activity in Chi\/+, whereas 4PBA and 4PBA\u2009+\u2009ALN had the opposite effect on p3h1\u2212\/\u2212. Finally, 4PBA and the combination of ALN and 4PBA reduced osteocyte apoptosis only in p3h1\u2212\/\u2212. Our data demonstrated for the first time in vivo a differential effect of the combination of an antiresorptive and a new anabolic compound in dominant and recessive OI zebrafish models, stressing the importance of identifying the specific causative molecular defect to define the best treatment option.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf112","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T08:01:15Z","timestamp":1751443275000},"source":"Crossref","is-referenced-by-count":1,"title":["Combined antiresorptive and new anabolic drug approach in osteogenesis imperfecta zebrafish models"],"prefix":"10.1093","volume":"9","author":[{"given":"Cecilia","family":"Masiero","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Tonelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Aresi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Filibian","sequence":"additional","affiliation":[{"name":"Centro Grandi Strumenti, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Larionova","sequence":"additional","affiliation":[{"name":"Evolutionary Developmental Biology Group, Department of Biology, Ghent University , 9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5143-5563","authenticated-orcid":false,"given":"Silvia","family":"Cotti","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1308-1060","authenticated-orcid":false,"given":"Filippo","family":"Doria","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Torriani","sequence":"additional","affiliation":[{"name":"Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2002-0127","authenticated-orcid":false,"given":"Paola","family":"Bertuccio","sequence":"additional","affiliation":[{"name":"Department of Public Health and Experimental and Forensic Medicine, Unit of Hygiene, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Odone","sequence":"additional","affiliation":[{"name":"Department of Public Health and Experimental and Forensic Medicine, Unit of Hygiene, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Villani","sequence":"additional","affiliation":[{"name":"Department of Public Health and Experimental and Forensic Medicine, Unit of Biostatistics and Clinical Epidemiology, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul Eckhard","family":"Witten","sequence":"additional","affiliation":[{"name":"Evolutionary Developmental Biology Group, Department of Biology, Ghent University , 9000 Ghent ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-1182","authenticated-orcid":false,"given":"Antonella","family":"Forlino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit, University of Pavia , 27100 Pavia ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"issue":"1","key":"2025081514214567900_ref1","doi-asserted-by":"publisher","first-page":"17052","DOI":"10.1038\/nrdp.2017.52","article-title":"Osteogenesis imperfecta","volume":"3","author":"Marini","year":"2017","journal-title":"Nat Rev Dis Primers"},{"issue":"10028","key":"2025081514214567900_ref2","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1016\/S0140-6736(15)00728-X","article-title":"Osteogenesis imperfecta","volume":"387","author":"Forlino","year":"2016","journal-title":"Lancet"},{"issue":"6","key":"2025081514214567900_ref3","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.038521","article-title":"Cellular stress due to impairment of collagen prolyl hydroxylation complex is rescued by the chaperone 4-phenylbutyrate","volume":"12","author":"Besio","year":"2019","journal-title":"Dis Model Mech"},{"key":"2025081514214567900_ref4","doi-asserted-by":"publisher","first-page":"489","DOI":"10.3389\/fendo.2020.00489","article-title":"Zebrafish: a resourceful vertebrate model to investigate skeletal disorders","volume":"11","author":"Tonelli","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"6","key":"2025081514214567900_ref5","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1007\/s00223-024-01282-5","article-title":"Zebrafish models for skeletal and extraskeletal osteogenesis imperfecta features: unveiling pathophysiology and paving the way for drug discovery","volume":"115","author":"Masiero","year":"2024","journal-title":"Calcif Tissue Int"},{"issue":"8","key":"2025081514214567900_ref6","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1002\/jbmr.3445","article-title":"Severely impaired bone material quality in Chihuahua zebrafish resembles classical dominant human osteogenesis imperfecta","volume":"33","author":"Fiedler","year":"2018","journal-title":"J Bone Miner Res"},{"issue":"15","key":"2025081514214567900_ref7","doi-asserted-by":"publisher","first-page":"2897","DOI":"10.1093\/hmg\/ddx171","article-title":"The chaperone activity of 4PBA ameliorates the skeletal phenotype of Chihuahua, a zebrafish model for dominant osteogenesis imperfecta","volume":"26","author":"Gioia","year":"2017","journal-title":"Hum Mol Genet"},{"issue":"34","key":"2025081514214567900_ref8","doi-asserted-by":"publisher","first-page":"E8037","DOI":"10.1073\/pnas.1722200115","article-title":"Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies","volume":"115","author":"Gistelinck","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025081514214567900_ref9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.matbio.2020.03.004","article-title":"Crtap and p3h1 knock out zebrafish support defective collagen chaperoning as the cause of their osteogenesis imperfecta phenotype","volume":"90","author":"Tonelli","year":"2020","journal-title":"Matrix Biol"},{"issue":"2","key":"2025081514214567900_ref10","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1517\/21678707.2015.1006197","article-title":"Treatment options for osteogenesis imperfecta","volume":"3","author":"Besio","year":"2015","journal-title":"Taylor & Francis Online"},{"key":"2025081514214567900_ref11","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.addr.2015.04.009","article-title":"Recent advances in the treatment of hyperammonemia","volume":"90","author":"Matoori","year":"2015","journal-title":"Adv Drug Deliv Rev"},{"issue":"5 Pt A, 5","key":"2025081514214567900_ref12","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1016\/j.bbadis.2018.02.002","article-title":"4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion","volume":"1864","author":"Besio","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2025081514214567900_ref13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.matbio.2021.03.001","article-title":"Targeting cellular stress in vitro improves osteoblast homeostasis, matrix collagen content and mineralization in two murine models of osteogenesis imperfecta","volume":"98","author":"Garibaldi","year":"2021","journal-title":"Matrix Biol"},{"key":"2025081514214567900_ref14","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.matbio.2023.06.003","article-title":"Cell differentiation and matrix organization are differentially affected during bone formation in osteogenesis imperfecta zebrafish models with different genetic defects impacting collagen type I structure","volume":"121","author":"Daponte","year":"2023","journal-title":"Matrix Biol"},{"issue":"4","key":"2025081514214567900_ref15","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1002\/jbmr.4501","article-title":"4-PBA treatment improves bone phenotypes in the Aga2 mouse model of osteogenesis imperfecta","volume":"37","author":"Duran","year":"2022","journal-title":"J Bone Miner Res"},{"issue":"1","key":"2025081514214567900_ref16","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/s0012-1606(03)00399-3","article-title":"Radiographic analysis of zebrafish skeletal defects","volume":"264","author":"Fisher","year":"2003","journal-title":"Dev Biol"},{"key":"2025081514214567900_ref17","doi-asserted-by":"publisher","author":"Organization for Economic Co-operation and Development","DOI":"10.1787\/9789264203709-en"},{"issue":"1","key":"2025081514214567900_ref18","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1471-213X-12-28","article-title":"Distinct patterns of notochord mineralization in zebrafish coincide with the localization of osteocalcin isoform 1 during early vertebral centra formation","volume":"12","author":"Bensimon-Brito","year":"2012","journal-title":"BMC Dev Biol"},{"key":"2025081514214567900_ref19","doi-asserted-by":"publisher","first-page":"851879","DOI":"10.3389\/fendo.2022.851879","article-title":"Compression fractures and partial phenotype rescue with a low phosphorus diet in the Chihuahua zebrafish osteogenesis imperfecta model","volume":"13","author":"Cotti","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025081514214567900_ref20","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/978-1-0716-1847-9_17","article-title":"High-resolution histology for craniofacial studies on zebrafish and other teleost models","volume":"2403","author":"Huysseune","year":"2022","journal-title":"Methods Mol Biol"},{"issue":"3","key":"2025081514214567900_ref21","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.149636","article-title":"4PBA reduces growth deficiency in osteogenesis imperfecta by enhancing transition of hypertrophic chondrocytes to osteoblasts","volume":"7","author":"Scheiber","year":"2022","journal-title":"JCI Insight"},{"issue":"2","key":"2025081514214567900_ref22","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/s0945-053x(01)00125-1","article-title":"Extracellular matrix in development of the intervertebral disc","volume":"20","author":"Hayes","year":"2001","journal-title":"Matrix Biol"},{"issue":"1","key":"2025081514214567900_ref23","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1186\/s13075-018-1701-1","article-title":"Osteoporosis of the vertebra and osteochondral remodeling of the endplate causes intervertebral disc degeneration in ovariectomized mice","volume":"20","author":"Xiao","year":"2018","journal-title":"Arthritis Res Ther"},{"issue":"1","key":"2025081514214567900_ref24","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1038\/s41413-021-00156-y","article-title":"3D assessment of intervertebral disc degeneration in zebrafish identifies changes in bone density that prime disc disease","volume":"9","author":"Kague","year":"2021","journal-title":"Bone Res"},{"issue":"7","key":"2025081514214567900_ref25","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1002\/stem.1107","article-title":"Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy","volume":"30","author":"Gioia","year":"2012","journal-title":"Stem Cells"},{"key":"2025081514214567900_ref26","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.cej.2019.02.202","article-title":"Strengthening the potential of biomineralized microspheres in enhancing osteogenesis via incorporating alendronate","volume":"368","author":"Wei","year":"2019","journal-title":"Chem Eng J"},{"issue":"34","key":"2025081514214567900_ref27","doi-asserted-by":"publisher","first-page":"6941","DOI":"10.1016\/j.biomaterials.2005.04.059","article-title":"Effects of bisphosphonates on proliferation and osteoblast differentiation of human bone marrow stromal cells","volume":"26","author":"von Knoch","year":"2005","journal-title":"Biomaterials"},{"issue":"1","key":"2025081514214567900_ref28","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/iep.12106","article-title":"Alendronate rescued osteoporotic phenotype in a model of glucocorticoid-induced osteoporosis in adult zebrafish scale","volume":"96","author":"Pasqualetti","year":"2015","journal-title":"Int J Exp Pathol"},{"issue":"6","key":"2025081514214567900_ref29","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/s8756-3282(00)00269-6","article-title":"Static and dynamic bone histomorphometry in children with osteogenesis imperfecta","volume":"26","author":"Rauch","year":"2000","journal-title":"Bone"},{"issue":"12","key":"2025081514214567900_ref30","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1359\/jbmr.080804","article-title":"Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors","volume":"23","author":"Uveges","year":"2008","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2025081514214567900_ref31","doi-asserted-by":"publisher","first-page":"3516","DOI":"10.1210\/jc.2016-1334","article-title":"Non-lethal type VIII osteogenesis imperfecta has elevated bone matrix mineralization","volume":"101","author":"Fratzl-Zelman","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2025081514214567900_ref32","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.bone.2016.01.018","article-title":"Bone matrix hypermineralization in prolyl-3 hydroxylase 1 deficient mice","volume":"85","author":"Fratzl-Zelman","year":"2016","journal-title":"Bone"},{"issue":"2","key":"2025081514214567900_ref33","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1111\/j.1469-185X.2009.00077.x","article-title":"A comparative view on mechanisms and functions of skeletal remodelling in teleost fish, with special emphasis on osteoclasts and their function","volume":"84","author":"Witten","year":"2009","journal-title":"Biol Rev Camb Philos Soc"},{"issue":"3","key":"2025081514214567900_ref34","first-page":"292","article-title":"Physiological and pathological osteocytic osteolysis","volume":"18","author":"Tsourdi","year":"2018","journal-title":"J Musculoskelet Neuronal Interact"},{"issue":"9","key":"2025081514214567900_ref35","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1002\/jbmr.3180","article-title":"Hypermineralization and high osteocyte lacunar density in osteogenesis imperfecta type V bone indicate exuberant primary bone formation","volume":"32","author":"Blouin","year":"2017","journal-title":"J Bone Miner Res"},{"issue":"9","key":"2025081514214567900_ref36","doi-asserted-by":"publisher","first-page":"4508","DOI":"10.3390\/ijms22094508","article-title":"Increased osteocyte lacunae density in the hypermineralized bone matrix of children with osteogenesis imperfecta type I","volume":"22","author":"M\u00e4hr","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2025081514214567900_ref37","doi-asserted-by":"publisher","first-page":"100734","DOI":"10.1016\/j.bonr.2020.100734","article-title":"Histopathology of osteogenesis imperfecta bone. Supramolecular assessment of cells and matrices in the context of woven and lamellar bone formation using light, polarization and ultrastructural microscopy","volume":"14","author":"Shapiro","year":"2021","journal-title":"Bone Rep"},{"key":"2025081514214567900_ref38","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.bone.2014.12.023","article-title":"Unique micro- and nano-scale mineralization pattern of human osteogenesis imperfecta type VI bone","volume":"73","author":"Fratzl-Zelman","year":"2015","journal-title":"Bone"},{"issue":"10","key":"2025081514214567900_ref39","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1136\/jcp.2003.015032","article-title":"The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis","volume":"57","author":"Greijer","year":"2004","journal-title":"J Clin Pathol"},{"key":"2025081514214567900_ref40","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.bone.2017.04.016","article-title":"Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta","volume":"101","author":"Little","year":"2017","journal-title":"Bone"},{"issue":"7","key":"2025081514214567900_ref41","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1002\/jbmr.3421","article-title":"Low dose of bisphosphonate enhances sclerostin antibody-induced trabecular bone mass gains in Brtl\/+ osteogenesis imperfecta mouse model","volume":"33","author":"Olvera","year":"2018","journal-title":"J Bone Miner Res"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziaf112\/63645593\/ziaf112.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/9\/9\/ziaf112\/63645593\/ziaf112.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/9\/9\/ziaf112\/63645593\/ziaf112.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T18:21:51Z","timestamp":1755282111000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziaf112\/8182085"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,2]]},"references-count":41,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziaf112","relation":{},"ISSN":["2473-4039"],"issn-type":[{"value":"2473-4039","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,7,2]]},"article-number":"ziaf112"}}