eprintid: 10204558 rev_number: 9 eprint_status: archive userid: 699 dir: disk0/10/20/45/58 datestamp: 2025-02-11 10:21:29 lastmod: 2025-02-11 10:21:29 status_changed: 2025-02-11 10:21:29 type: article metadata_visibility: show sword_depositor: 699 creators_name: Corcelli, Michelangelo creators_name: Sagar, Rachel creators_name: Petzendorfer, Ellen creators_name: Hasan, Mohammad Mehedi creators_name: van Dijk, Fleur S creators_name: David, Anna L creators_name: Guillot, Pascale V title: Pleiotropic effects of a recessive Col1a2 mutation occurring in a mouse model of severe osteogenesis imperfecta ispublished: pub divisions: UCL divisions: B02 divisions: D11 divisions: G12 keywords: Osteoblasts, Osteogenesis imperfecta, Bone and mineral metabolism, Collagens, Bone fracture, Osteoblast differentiation, Bone imaging, Bone density note: Copyright: © 2025 Corcelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. http://creativecommons.org/licenses/by/4.0/ abstract: In Europe, approximately 85–90% of individuals with Osteogenesis Imperfecta (OI) have dominant pathogenic variants in the Col1a1 or Col1a2 genes whilst for Asian, especially Indian and Chinese cohorts, this ratio is much lower. This leads to decreased or abnormal Collagen type I production. Subsequently, bone formation is strongly reduced, causing bone fragility and liability to fractures throughout life. OI is clinically heterogeneous, with the severity ranging from mild to lethal depending on the gene and the type and location of the OI-causative variant and the subsequent effect on (pro) collagen type I synthesis. However, the specific effects on the phenotype and function of osteoblasts are not fully understood. To investigate this, one of the OI murine models was used, i.e. the oim/oim (OIM) mice, which closest resembling severely deforming OI in humans. We showed that in OIM, the Col1a2 mutation results in a multifactorial inhibition of the osteogenic differentiation and maturation as well as inhibition of osteoclastogenesis. The phenotype of differentiated OIM osteoblasts also differs from that of wild type mature osteoblasts, with upregulated oxidative cell stress and autophagy pathways. The extracellular accumulation of defective type I collagen fibres contributes to activation of the TGF-β signalling pathway and activates the inflammatory pathway. These effects combine to destabilise the balance of bone turnover, increasing bone fragility. Together, these findings identify the complex mechanisms underlying OI bone fragility in the OIM model of severe OI and can potentially enable identification of clinically relevant endpoints to assess the efficacy of innovative pro-osteogenic treatment for patients with OI. date: 2025-02-05 date_type: published publisher: Public Library of Science (PLoS) official_url: https://doi.org/10.1371/journal.pone.0309801 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2358865 doi: 10.1371/journal.pone.0309801 medium: Electronic-eCollection pii: PONE-D-24-09480 lyricists_name: David, Anna lyricists_name: Guillot, Pascale lyricists_name: Petzendorfer, Ellen lyricists_id: ADAVI52 lyricists_id: PVGUI46 lyricists_id: EPETZ05 actors_name: Guillot, Pascale actors_id: PVGUI46 actors_role: owner funding_acknowledgements: PVG received funding from the United Kingdom Medical Research Council (https://www.ukri.org/councils/mrc/) award 179068) and The Rosetrees Trust (https://rosetrees.org.uk/) award CM935. The sponsors did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. full_text_status: public publication: PLoS One volume: 20 number: 2 article_number: e0309801 event_location: United States issn: 1932-6203 editors_name: van Wijnen, Andre citation: Corcelli, Michelangelo; Sagar, Rachel; Petzendorfer, Ellen; Hasan, Mohammad Mehedi; van Dijk, Fleur S; David, Anna L; Guillot, Pascale V; (2025) Pleiotropic effects of a recessive Col1a2 mutation occurring in a mouse model of severe osteogenesis imperfecta. PLoS One , 20 (2) , Article e0309801. 10.1371/journal.pone.0309801 <https://doi.org/10.1371/journal.pone.0309801>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10204558/1/Guillot_Pleiotropic%20effects%20of%20a%20recessive%20Col1a2-journal.pone.0309801.pdf