The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Comparative whole-genome analyses of articular chondrocytes and skin fibroblasts reveal distinct genome instability landscapes in mesenchymal cell types
Open accessPreprint — published as 10.1371/journal.pgen.1012156 · Paper page
Abstract
DNA damage lesions can result in mutations and genome rearrangements that are associated with cellular aging and diseases. The landscape of somatic mutations in individual tissue and cell types are dictated by their unique physiological states, cellular functions, mutagenic exposures, and efficiency of DNA repair. Articular chondrocytes and skin fibroblasts are two cell types of mesodermal origin with distinct exposure to internal and external sources of DNA damage. While somatic genome instability features of skin fibroblasts have been well detailed, knowledge about mechanisms underlying genome changes in chondrocytes is scarce. Here, we took a whole-genome sequencing approach to evaluate the load, sources, and patterns of genome changes in 18 primary human chondrocyte clones from donors with and without osteoarthritis (OA). Findings in chondrocyte clones largely agreed with a recent study of 100 single-cell sequenced chondrocytes. We compared genome changes in chondrocytes with clonally-expanded human skin fibroblasts sequenced in our previous studies. We demonstrated that skin fibroblasts show a higher burden of somatic mutations, with an increased rate of mutation accumulation per cell division. Motif-centered analyses of mutation catalogues identified only endogenous sources of mutations in chondrocytes, as opposed to skin fibroblasts which also showed a heavy burden of UV-induced mutations. Spontaneous deamination of meCpG and mutagenesis by exposure to small epoxides and S N 2 electrophiles showed higher mutagenic activities in chondrocytes compared to skin fibroblasts. Chondrocytes showed ubiquitous prevalence of indels in homonucleotide runs of ≥5 bases, while skin fibroblasts showed high contributions of UV-associated deletions of ≥5bp not in repeats. Structural variants in rearrangement hotspots colocalized with human common fragile sites in skin fibroblasts, but not in chondrocytes. Together, our study comprehensively recorded genome instability features in chondrocytes and highlighted the unique mutagenesis landscapes of two mesenchymal cell types.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The central role of DNA damage in the ageing process
Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. J. (2021) · Nature · doi:10.1038/s41586-021-03307-7 · Cited by 907
Flagged first, then by citations
Research works printed but not linked: 85
- 10.1371/journal.pgen.1007108 · DOI
- 10.1038/nature12477 · DOI · Paper page
- Lodato MA , Walsh CA . Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms. Hum Mol Genet. 2019. · DOI · Paper page
- 10.1056/NEJMra2101920 · DOI
- 10.1126/science.aan4673 · DOI · Paper page
- 10.1038/s41586-020-1943-3 · DOI · Paper page
- 10.1038/nrc3816 · DOI
- 10.1073/pnas.1221068110 · DOI
- 10.1093/nar/gkab914 · DOI
- Sauty SM , Hsiao Y-C , Klimczak LJ , Gordenin DA . Motif-Centered Analyses Elucidate Mutagenic Mechanisms Operating in Normal Human Tissues. bioRxiv. 2025:2025.10.07.681015. · DOI
- 10.1126/science.aab4082 · DOI · Paper page
- 10.1038/nature19768 · DOI · Paper page
- 2003, The chondrocyte, The International Journal of Biochemistry & Cell Biology, 35, 401, 10.1016/S1357-2725(02)00301-1 · DOI
- 10.1016/j.joca.2023.11.018 · DOI
- Guo P , Alhaskawi A , Adel Abdo Moqbel S , Pan Z. Recent development of mitochondrial metabolism and dysfunction in osteoarthritis. Front Pharmacol. 2025;16:1538662. · DOI
- 10.1016/j.joca.2015.05.016 · DOI · Paper page
- 2025, Epidemiological trends of osteoarthritis at the global, regional, and national levels from 1990 to 2021 and projections to 2050, Arthritis Res Ther, 27, 199, 10.1186/s13075-025-03658-w · DOI
- 2008, Oxidative DNA damage in osteoarthritic porcine articular cartilage, J Cell Physiol, 217, 828, 10.1002/jcp.21562 · DOI
- 10.1111/acel.13698 · DOI
- 2023, Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes, Aging (Albany NY, 15, 13628
- 2025, Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis, Nature Aging, 5, 2417, 10.1038/s43587-025-01011-z · DOI · Paper page
- 2016, Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound, Adv Wound Care (New Rochelle, 5, 119, 10.1089/wound.2014.0561 · DOI · Paper page
- 10.1038/jid.2010.10 · DOI
- 10.1016/j.mad.2008.04.010 · DOI
- 2012, Aging and photo-aging DNA repair phenotype of skin cells-evidence toward an effect of chronic sun-exposure, Mutation research, 736, 48
- 10.1371/journal.pgen.1009302 · DOI
- 10.1371/journal.pgen.1006385 · DOI · Paper page
- 10.1002/em.22215 · DOI
- 10.1146/annurev-genom-111320-090436 · DOI
- Maslov AY , Vijg J . Somatic mutation burden in relation to aging and functional life span: implications for cellular reprogramming and rejuvenation. Curr Opin Genet Dev. 2023;83:102132. · DOI
- 2024, Analyzing somatic mutations by single-cell whole-genome sequencing, Nature protocols, 19, 487, 10.1038/s41596-023-00914-8 · DOI · Paper page
- 10.1002/jcp.21965 · DOI
- 2018, Expression of p16(INK)(4a) is a biomarker of chondrocyte aging but does not cause osteoarthritis, Aging Cell, 17, e12771, 10.1111/acel.12771 · DOI · Paper page
- 10.1101/sqb.2009.74.027 · DOI
- 10.1016/S0027-5107(98)00066-9 · DOI · Paper page
- Kavli B , Slupphaug G , Krokan HE. Genomic Uracil in Biology, Immunity and Cancer. In: Dizdaroglu M, Lloyd RS, Dizdaroglu M, Lloyd RS, editors. DNA Damage, DNA Repair and Disease: Volume 1: The Royal Society of Chemistry; 2020. p. 0. · DOI
- 10.1101/cshperspect.a012708 · DOI · Paper page
- 10.1093/nar/gkad611 · DOI
- 10.1016/j.molcel.2012.04.009 · DOI
- 10.1038/ng.2702 · DOI
- 10.1074/jbc.M107696200 · DOI · Paper page
- 10.1093/nar/gkaa150 · DOI
- 10.1007/3-540-31390-7_10 · DOI
- 10.1038/ng.3441 · DOI
- 10.1186/s12864-023-09584-y · DOI
- 10.1186/s12864-018-5330-5 · DOI
- 10.1016/j.canlet.2005.07.039 · DOI
- 2013, Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation, Pharmacology & therapeutics, 138, 103, 10.1016/j.pharmthera.2012.12.007 · DOI · Paper page
- 2000, Conversion of epoxyeicosatrienoic acids (EETs) to chain-shortened epoxy fatty acids by human skin fibroblasts, Journal of Lipid Research, 41, 66, 10.1016/S0022-2275(20)32075-7 · DOI
- 10.1194/jlr.P085118 · DOI
- 2016, Epoxyeicosatrienoic acids (EETs) form adducts with DNA in vitro, Prostaglandins Other Lipid Mediat, 123, 63, 10.1016/j.prostaglandins.2016.04.006 · DOI
- 2014, Potential health effects associated with dermal exposure to occupational chemicals, Environ Health Insights, 8, 51
- Duan M , Speer RM , Ulibarri J , Liu KJ , Mao P . Transcription-coupled nucleotide excision repair: New insights revealed by genomic approaches. DNA Repair (Amst). 2021;103:103126. · DOI
- Spivak G , Ganesan AK . The complex choreography of transcription-coupled repair. DNA Repair (Amst). 2014;19. · DOI · Paper page
- 2002, Repair of deaminated bases in DNA, Free radical biology & medicine, 33, 886, 10.1016/S0891-5849(02)00902-4 · DOI
- 10.1126/science.1135400 · DOI
- 10.1093/nar/gkl1159 · DOI
- 1969, Reaction of nitrous acid with alkylaminopurines, Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 174, 403, 10.1016/0005-2787(69)90268-8 · DOI
- 10.1016/j.freeradbiomed.2007.01.035 · DOI
- Ansari MY , Ahmad N , Haqqi TM . Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols. Biomed Pharmacother. 2020;129:110452. · DOI
- 10.1016/j.saa.2005.10.013 · DOI
- 1997, Genetic control of microsatellite stability, Mutation Research/DNA Repair, 383, 61, 10.1016/S0921-8777(96)00046-8 · DOI
- 1998, Yeast ARMs (DNA at-risk motifs) can reveal sources of genome instability, Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 400, 45, 10.1016/S0027-5107(98)00047-5 · DOI
- 10.1021/bi952178h · DOI
- 10.1146/annurev-genet-112414-054722 · DOI
- 10.1128/MCB.17.5.2859 · DOI
- 10.1038/cr.2007.111 · DOI · Paper page
- 2025, Genetic Regulation of DNA Double-Strand Breaks and Repair Pathways, Front Biosci (Schol Ed, 17, 46225, 10.31083/FBS46225 · DOI
- 10.1002/art.27528 · DOI
- 10.1038/s41586-021-03477-4 · DOI · Paper page
- 10.1016/j.cell.2020.06.024 · DOI · Paper page
- 10.1038/s41573-025-01212-6 · DOI
- 10.1038/s41584-020-00533-7 · DOI · Paper page
- 10.1089/ten.tea.2019.0214 · DOI
- 10.1016/S1063-4584(97)80029-5 · DOI
- 10.48550/arXiv.1303.3997 · DOI
- 10.1101/gr.129684.111 · DOI
- 2018, Strelka2: fast and accurate calling of germline and somatic variants, Nature methods, 15, 591, 10.1038/s41592-018-0051-x · DOI
- 10.1101/gr.221028.117 · DOI
- 10.1093/bioinformatics/bts378 · DOI
- 10.1203/01.PDR.0000022341.72856.72 · DOI
- 10.1093/nar/gku181 · DOI
- 2018, MutationalPatterns: comprehensive genome-wide analysis of mutational processes, Genome Medicine, 10, 33, 10.1186/s13073-018-0539-0 · DOI · Paper page
- Wickham H. Data analysis. ggplot2: elegant graphics for data analysis: Springer; 2016. p. 189–201. · DOI
- Hoppe J. Adobe Illustrator CC: a complete course and compendium of features. 1st edition ed. San Rafael, CA: Rocky Nook, Inc.; 2020.
Metadata
- Authors
- Sauty, S. M., Shine, J., Bostan, H., Li, J.-L., Mieczkowski, P. A., Loeser, R. F., Diekman, B. O., & Gordenin, D. A.
- Affiliations
- National Institute of Environmental Health Sciences (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Diekman, Brian O
- Gordenin, Dmitry A
- ORCID
- Venue
- PLoS Genetics
- Publisher
- openRxiv
- Published
- 2026-02-15
- Volume
- 22
- Issue
- 5
- Pages
- e1012156-e1012156
- ISSN
- 1553-7390 (ISSN-L)
- PMC
- PMC12918860
- OpenAlex
- W7161770165
- Cited by
- 0
- References
- 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS Genetics (publishedVersion, public-domain)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, public-domain)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, public-domain)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UNC Libraries
- Funders
- US National Institutes of Health Intramural Research Program (Z1AES103266)
- National Institutes of Health (R01AG081734, RO1AG044034)
- Topics
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- articular chondrocytes, dermal fibroblasts, somatic mutations, genomic instability, osteoarthritis, DNA damage, UV-induced mutations, 5-methylcytosine, indels, structural variants, common fragile sites, mutational signatures, DNA repair, mesenchymal cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
