The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence

Copp, M.E.; Flanders, M.C.; Gagliardi, Riccardo; Gilbertie, Jessica M.; Sessions, Garrett A.; Chubinskaya, Susan; Loeser, Richard F.; Schnabel, Lauren V.; Diekman, Brian O.

doi:10.1016/j.joca.2020.11.004

Cited by 26 publications

(38 citation statements)

References 53 publications

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“…In further support of the hypothesis that MT-derived ROS triggers MT transfer from MSCs, chondrocytes increased expression of inflammation-and senescence-associated genes in hyperoxic culture; Increased TIMP1 expression, a regulator of metalloproteinases and ECM turnover, is indicative of an inflammatory phenotype in chondrocytes (42). We also found that CDKn2a, a marker of chondrocyte senescence (43) was increased in hyperoxia. These findings are in agreement with studies that reveal excess MTderived ROS upregulate release of inflammatory cytokines including IL-1ß, cartilage ECMdegrading enzymes matrix metalloproteinase 1 and 3, and senescence associated βgalactosidase in part through activation of the NF-kB signaling pathway in chondrocytes (44)(45)(46)(47).…”

Section: Discussionsupporting

confidence: 79%

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Fahey

Bennett

Thomas

et al. 2022

Preprint

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Avascular soft tissues of the skeletal system, including articular cartilage, have limited healing capacity, in part due to their low metabolic activity. No drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Therefore, mesenchymal stromal cell (MSC)-based regenerative therapies are increasingly common in the treatment of OA, but questions regarding their clinical efficacy and mechanisms of action remain unanswered. Our group recently reported that mitochondrial dysfunction is one of the earliest responses of cartilage to injury, resulting in chondrocyte death, extracellular matrix degeneration, and ultimately OA. MSCs have been found to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. Here, we demonstrate that MSCs transfer mitochondria to stressed chondrocytes in cell culture and in injured cartilage tissue. Conditions known induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and hyperoxia, increased transfer. Stressed chondrocytes increased expression of genes related to inflammation and senescence, further supporting the link between mitochondrial dysfunction and transfer. MSC-chondrocyte mitochondrial transfer was blocked by non-specific and specific (connexin-43) gap-junction inhibition. When MSCs were exposed to mechanically injured cartilage they localized to areas of matrix damage and extended cellular processes deep into microcracks, delivering mitochondria to chondrocytes. This work provides insights into the chemical, environmental, and mechanical conditions that can elicit MSC-chondrocyte mitochondrial transfer in vitro and in situ, and our findings suggest a new potential role for MSC-based therapeutics after cartilage injury.Significance StatementRecent evidence suggests that although articular cartilage is avascular and relatively metabolically quiescent, acute injury induces chondrocyte mitochondrial dysfunction, driving cartilage degradation and OA. We present the first evidence that MSCs donate mitochondria to articular chondrocytes undergoing mitochondrial dysfunction in vitro and in situ. These findings support a new role for MSCs in the context of cartilage injury and OA, and intercellular mitochondrial transfer may represent a new biological approach to augment mitochondrial capacity in injured chondrocytes. This work establishes multiple experimental models to study MSC mitochondrial donation for the treatment of OA and related degenerative diseases of avascular orthopedic tissues.

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Section: Discussionsupporting

confidence: 79%

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Fahey

Bennett

Thomas

et al. 2022

Preprint

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“…Remarkably, 10 Gy irradiation was required for young chondrocytes to reach the levels of DNA damage found in aged and OA chondrocytes. This high level of baseline damage is likely to have phenotypic consequences, as we have shown that 10 Gy irradiation is sufficient to induce senescence in human chondrocytes when coupled with growth factor activation (Copp et al, 2021 ). Markers of senescence increase with age in both human and murine chondrocytes (Diekman et al, 2018 ), and the presence of senescent cells in the joint has been implicated in OA pathophysiology (Jeon et al, 2017 ).…”

Section: Discussionmentioning

confidence: 94%

Comet assay for quantification of the increased DNA damage burden in primary human chondrocytes with aging and osteoarthritis

et al. 2022

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It is known that chondrocytes from joints with osteoarthritis (OA) exhibit high levels of DNA damage, but the degree to which chondrocytes accumulate DNA damage during “normal aging” has not been established. The goal of this study was to quantify the DNA damage present in chondrocytes obtained from cadaveric donors of a wide age range, and to compare the extent of this damage to OA chondrocytes. The alkaline comet assay was used to measure the DNA damage in normal cartilage from the ankle (talus) and the knee (femur) of cadaveric donors, as well as in OA chondrocytes obtained at the time of total knee replacement. Chondrocytes from younger donors (<45 years) had less DNA damage than older donors (>70 years) as assessed by the percentage of DNA in the comet “tail”. In donors between 50 and 60 years old, there was increased DNA damage in chondrocytes from OA cartilage as compared to cadaveric. Talar chondrocytes from 23 donors between the ages of 34 and 78 revealed a linear increase in DNA damage with age (R2 = 0.865, p < 0.0001). A “two‐tailed” comet assay was used to demonstrate that most of the accumulated damage is in the form of strand breaks as opposed to alkali‐labile base damage. Chondrocytes from young donors required 10 Gy irradiation to recapitulate the DNA damage present in chondrocytes from older donors. Given the potential for DNA damage to contribute to chondrocyte dysfunction and senescence, this study supports the investigation of mechanisms by which hypo‐replicative cell types accumulate high levels of damage.

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“…In a recent study, it was found that the combination of mitogenic stimulation and DNA damage induced chondrocyte senescence and increase the production of senescence marker: SA-β-Gal, p16, and γH2AX, etc. [21].…”

Section: Key Stimuli For Cellular Senescence and Oamentioning

confidence: 99%

Senescent skeletal cells cross-talk with synovial cells plays a key role in the pathogenesis of osteoarthritis

Liu

Huan

et al. 2022

Arthritis Res Ther

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Osteoarthritis (OA) has been recognized as an age-related degenerative disease commonly seen in the elderly that affects the whole “organ” including cartilage, subchondral bone, synovium, and muscles. An increasing number of studies have suggested that the accumulation of senescent cells triggering by various stresses in the local joint contributes to the pathogenesis of age-related diseases including OA. In this review, we mainly focus on the role of the senescent skeletal cells (chondrocytes, osteoblasts, osteoclasts, osteocyte, and muscle cells) in initiating the development and progression of OA alone or through cross-talk with the macrophages/synovial cells. Accordingly, we summarize the current OA-targeted therapies based on the abovementioned theory, e.g., by eliminating senescent skeletal cells and/or inhibiting the senescence-associated secretory phenotype (SASP) that drives senescence. Furthermore, the existing animal models for the study of OA from the perspective of senescence are highlighted to fill the gap between basic research and clinical applications. Overall, in this review, we systematically assess the current understanding of cellular senescence in OA, which in turn might shed light on the stratified OA treatments.

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The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence

Cited by 26 publications

References 53 publications

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Comet assay for quantification of the increased DNA damage burden in primary human chondrocytes with aging and osteoarthritis

Senescent skeletal cells cross-talk with synovial cells plays a key role in the pathogenesis of osteoarthritis

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