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While some aberrant collagen is secreted into the extracellular matrix (ECM), impairing bone quality, a significant fraction is retained intracellularly, disrupting osteoblast homeostasis. 4\u2010phenylbutyrate (4\u2010PBA) has been shown to improve osteoblast function and ECM composition in OI models. To investigate the intracellular consequences of mutant collagen retention and the mechanisms of 4\u2010PBA, we analysed the secretome and transcriptome of two dominant OI mouse models,\n                    <jats:italic>Col1a1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/G349C<\/jats:italic>\n                    <\/jats:sup>\n                    and\n                    <jats:italic>Col1a2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/G610C<\/jats:italic>\n                    <\/jats:sup>\n                    . MS\/MS proteomic analysis of conditioned media revealed senescence\u2010associated secretory phenotype proteins, together with components linked to altered cytoskeletal organization and cell adhesion. Transcriptomic analysis identified\n                    <jats:italic>P53<\/jats:italic>\n                    as a central hub gene, supporting premature senescence activation. Increased senescence\u2010associated \u03b2\u2010galactosidase activity, elevated expression of the cyclin\u2010dependent kinase inhibitor\n                    <jats:italic>P16<\/jats:italic>\n                    , and reduced\n                    <jats:italic>Ki67<\/jats:italic>\n                    levels further supported a senescent phenotype. Notably, senescence\u2010associated proteins were absent from the secretome following 4\u2010PBA treatment, which also modulated cytoskeletal and adhesion\u2010related protein expression. Moreover, 4\u2010PBA significantly reduced senescence marker expression and decreased the number of senescent cells. Overall, these findings indicate that cellular senescence underlies osteoblast dysfunction in OI and uncover a novel contribution of 4\u2010PBA to osteoblast homeostasis.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71120","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T07:07:22Z","timestamp":1775459242000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["OMICS Profiling Identifies Signatures of Senescence in Osteogenesis Imperfecta Osteoblasts Counteracted by 4\u2010PBA"],"prefix":"10.1111","volume":"30","author":[{"given":"Roberta","family":"Besio","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Biochemistry Unit University of Pavia  Pavia Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Maffioli","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine and Animal Sciences 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