Dataset Information

OMIC analyses identified senescence activation in osteogenesis imperfecta osteoblasts that is rescued by 4-PBA treatment

ABSTRACT: Mutations in collagen I account for the most frequent cause of the skeletal disease osteogenesis imperfecta (OI) and are responsible for delay in protein folding and synthesis of molecules with abnormal structure. A fraction of aberrant collagen molecules is secreted in the extracellular matrix (ECM) where they impair the bone quality, while others are intracellularly retained in the endoplasmic reticulum where they perturb osteoblast homeostasis. The chemical chaperone 4-phenylbutyrate (4-PBA) improves OI osteoblast activity ameliorating ECM composition. To evaluate the consequences of intracellular malfunctioning in OI and to elucidate the mechanism responsible for the described positive effect of 4-PBA in OI, omics techniques were applied to analyze osteoblasts secretome and transcriptome in two well characterized murine models of dominant OI, the Col1a1+/G349C and the Col1a2+/G610C mice. Analyses of the cell culture media by nano LC-ESI-MS/MS and bioinformatic tools identified several senescence associated secretory proteins together with changes in cytoskeletal and cell adhesion proteins. Bioinformatic analyses of transcriptomic data revealed p53 as hub gene supporting a premature senescence activation in both models. Increased senescence-associated β-galactosidase activity, as well as increased gene expression of the cyclin-dependent kinase-inhibitor p16, and a decreased expression of Ki67, indicating a permanent exit from the cell cycle in both mutants confirmed the ainduction of cellular senescence. Senescence proteins were undetectable in secretome collected following 4-PBA incubation that also modified the cytoskeletal and adhesion protein expression. Furthermore, the drug normalized the senescence markers expression and the number of senescent cells. Our study identified senescence as OI osteoblasts hallmark and discover a new positive contribution of 4-PBA to osteoblasts homeostasis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Simona Nonnis

LAB HEAD: Elisa Maffioli

PROVIDER: PXD059591 | Pride | 2026-04-13

REPOSITORIES: Pride

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	20-08-24-20P36-Amish10-het-pba1-01.raw	Raw
	20-08-24-20P36-Amish10-het-pba1-02.raw	Raw
	20-08-24-20P36-Amish10-het-pba1-03.raw	Raw
	20-08-24-20P36-Amish10-het1-01.raw	Raw
	20-08-24-20P36-Amish10-het1-02.raw	Raw

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OMICS Profiling Identifies Signatures of Senescence in Osteogenesis Imperfecta Osteoblasts Counteracted by 4-PBA.

Besio Roberta R Maffioli Elisa E Palladino Erika E Sala Alessandra A Garibaldi Nadia N Izzi Valerio V Forlino Antonella A Tedeschi Gabriella G

Journal of cellular and molecular medicine 20260401 7

Mutations in collagen I are the most common cause of osteogenesis imperfecta (OI), leading to delayed protein folding and structurally abnormal molecules. While some aberrant collagen is secreted into the extracellular matrix (ECM), impairing bone quality, a significant fraction is retained intracellularly, disrupting osteoblast homeostasis. 4-phenylbutyrate (4-PBA) has been shown to improve osteoblast function and ECM composition in OI models. To investigate the intracellular consequences of mu ...[more]

PMID: 41937492

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