Cited by 47Telomeres, Telomerase, and SenescenceOsteoarthritis Treatment and MechanismsGenetics, Aging, and Longevity in Model Organisms

In Vitro Characterization of Doxorubicin-Mediated Stress-Induced Premature Senescence in Human Chondrocytes

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Kirsch, Valeria, Ramge, Jan-Moritz, Schoppa, Astrid, Ignatius, Anita, Riegger, Jana·2022·Cells

Abstract

Accumulation of senescent chondrocytes is thought to drive inflammatory processes and subsequent cartilage degeneration in age-related as well as posttraumatic osteoarthritis (OA). However, the underlying mechanisms of senescence and consequences on cartilage homeostasis are not completely understood so far. Therefore, suitable in vitro models are needed to study chondrocyte senescence. In this study, we established and evaluated a doxorubicin (Doxo)-based model of stress-induced premature senescence (SIPS) in human articular chondrocytes (hAC). Cellular senescence was determined by the investigation of various senescence associated (SA) hallmarks including β-galactosidase activity, expression of p16, p21, and SA secretory phenotype (SASP) markers (IL-6, IL-8, MMP-13), the presence of urokinase-type plasminogen activator receptor (uPAR), and cell cycle arrest. After seven days, Doxo-treated hAC displayed a SIPS-like phenotype, characterized by excessive secretion of SASP factors, enhanced uPAR-positivity, decreased proliferation rate, and increased β-galactosidase activity. This phenotype was proven to be stable seven days after the removal of Doxo. Moreover, Doxo-treated hAC exhibited increased granularity and flattened or fibroblast-like morphology. Further analysis implies that Doxo-mediated SIPS was driven by oxidative stress as demonstrated by increased ROS levels and NO release. Overall, we provide novel insights into chondrocyte senescence and present a suitable in vitro model for further studies.

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Crossref · 10.3390/cells11071106

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  • In doxorubicin-treated cells, the expression of 4-HNE and GPX4 increases, while SIRT1 expression decreases.

    “In this model, cells treated with doxorubicin display characteristic features of senescence. For instance, the expression of 4-HNE and GPX4 increases, while SIRT1 expression decreases.”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [289]

    Results §3.3 reports no alteration in SIRT1 gene expression in doxorubicin-treated human chondrocytes and a positive trend in its protein expression, contrary to the claimed decrease. The paper supports the presence of senescence features, but the passages found do not report increased 4-HNE or GPX4 expression; the Discussion (§4) mentions GPX1, a different enzyme. Page numbers were not available in our copy. (LLM, conf=0.88)

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  • These senescent cells exhibit elevated levels of pro-inflammatory cytokines like IL-6, IL-17, and TNF-α, along with reduced levels of the anti-inflammatory cytokine IL-4, indicating the presence of inflammation.

    “Furthermore, these senescent cells exhibit elevated levels of pro-inflammatory cytokines like IL-6, IL-17, and TNF-α, along with reduced levels of the anti-inflammatory cytokine IL-4, indicating the presence of inflammation.289”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [289]

    The Results (§3.2) report increased IL-6 secretion in doxorubicin-treated human chondrocytes, and the Discussion (§4) identifies it as a pro-inflammatory senescence-associated factor. The paper does not report elevated IL-17 or TNF-α or reduced IL-4 in these cells; its measured cytokines were IL-6 and IL-8. (LLM, conf=0.90)

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Authors
Kirsch, V., Ramge, J.-M., Schoppa, A., Ignatius, A., & Riegger, J.
Affiliations
Universität Ulm (DE)
Corresponding author
Riegger, Jana
Venue
Cells
Publisher
MDPI AG
Published
2022-03-25
Volume
11
Issue
7
Pages
1106
ISSN
2073-4409 (ISSN-L)
OpenAlex
W4220709306
Cited by
47
References
63
Citations by year
2026: 13 · 2025: 15 · 2024: 11 · 2023: 7 · 2022: 1
FWCI
5.26
Type
journal article
Language
en
Open access
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • German Research Foundation (DFG) (Project-ID 251293561)
  • University of Ulm (Baustein Program)
  • European Social Fund and by the Ministry of Science, Research and Arts Baden-Württemberg (Margarete von Wrangell Habilitation Program)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
stress-induced premature senescence, chondrocyte senescence, doxorubicin, articular chondrocytes, osteoarthritis, senescence-associated secretory phenotype, urokinase-type plasminogen activator receptor, oxidative stress, reactive oxygen species, nitric oxide, cartilage degeneration
MeSH terms
beta-Galactosidase, Doxorubicin, Humans, Osteoarthritis, Cellular Senescence, Chondrocytes

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