Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

Zhang, Xinxin; He, Shi-Hao; Liang, Xu; Li, Wei; Li, Tian-Fang; Li, Daifeng

doi:10.3389/fphar.2021.728100

Cited by 42 publications

(36 citation statements)

References 186 publications

(267 reference statements)

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“…Current modeling methods for OA include intra articular injection, spontaneous animal models, and surgical modeling. 7 , 8 The most commonly employed modeling method is the intra‐articular injection of papain due to its shorter induction effect and higher success rates than those of other drugs 9 ; it can reduce the chance of infection and death in animals. It is a mature and reliable modeling method with a high success rate and a large number of precedents reported in previous modeling studies.…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates the Progression of Osteoarthritis in Rats by Inhibiting Inflammation and Related Oxidative Stress on the Surface of Knee Cartilage

Liu

Yang

et al. 2022

Orthopaedic Surgery

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Objective To investigate the correlation between melatonin and osteoarthritis (OA) in rats. To explore the relevant mechanisms in the occurrence and development of osteoarthritis in rats, and to further understand the disease of osteoarthritis. Methods Forty healthy 6‐month‐old male SD rats were randomly divided into two groups: sham and drug intervention groups. Pre‐OA modeling, enzyme‐linked immunosorbent assay was employed to detect the levels of IL‐1β, IL‐6, COX‐2, and melatonin in the serum of the rats in each group. For OA modeling, we administered an injection of papain into the knee cavity of all rats. The levels of IL‐1β, IL‐6, and COX‐2 in the serum of rats in each group were detected 2 weeks after the modeling. Additionally, 2 weeks after the modeling, the rats in the drug intervention group were intraperitoneally injected with melatonin antagonists. The rats in the sham group were intraperitoneally injected with normal saline for 2 weeks. The levels of IL‐1β, IL‐6, and COX‐2 in the serum of each group were measured at the second, third, and fourth weeks after the drug intervention, and the levels of melatonin in the serum were measured at the second week after the drug intervention. Finally, the rats were euthanized by cervical dislocation, and pathological sections were collected from the knee joint to observe the pathological tissue changes under a microscope, and Mankin score was determined. The independent samples t‐test method was used for analysis. Results The imaging examination after the drug intervention showed that the modeling of knee osteoarthritis in rats was successful. In the pathological findings, HE staining showed a legible cartilage structure of each layer, with cartilage proliferation and partial cartilage tearing to the radial layer. The tide line was intact; toluidine blue staining revealed more obvious changes. The differences among the mean values of IL‐6, IL‐1β, and COX‐2 measured in each period were statistically significant (t = 5.50, p < 0.05). The measured mean values of IL‐6, IL‐1β, and COX‐2 revealed statistically significant differences among the groups (t = 2.01, p < 0.05). The intergroup comparison of the Mankin scores in each period showed statistically significant differences. Conclusion Melatonin may inhibit inflammation and associated oxidative stress on the surface of knee cartilage. It may be related to the repair and regeneration of articular surface cartilage during the development of OA in the rat knee joint.

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Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates the Progression of Osteoarthritis in Rats by Inhibiting Inflammation and Related Oxidative Stress on the Surface of Knee Cartilage

Liu

Yang

et al. 2022

Orthopaedic Surgery

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“…Overall, it has been suggested that matrix degradation products may amplify the synovial inflammation, which in turn promotes the production of MMPs. Consequently, matrix degeneration stimulates synovial inflammation and vice versa, creating a vicious cycle [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

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

Kirsch

Ramge

Schoppa

et al. 2022

Cells

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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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“…Senescent fibroblasts transplanted into mouse knee joints induced cartilage degradation and osteophyte development and reduced mobility, implying that senescent cells modify the synovial milieu and cause OA-like arthropathy [16]. Senescent joint cells share characteristics such as the erosion of telomeres, the enhanced expressions of p53 and the CDK inhibitors p21 and p16INK4a (p16), the enhanced formation of ROS owing to mitochondrial failure, and the enhanced expression of senescence-associated heterochromatin [17]. SASP is found in osteocytes, chondrocytes, and synovial fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis

Weng

Pikatan

Setiawan

et al. 2022

IJMS

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Osteoarthritis (OA) is most prevalent in older individuals and exerts a heavy social and economic burden. However, an effective and noninvasive approach to OA treatment is currently not available. Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of OA. Furthermore, senescent chondrocytes (SnCCs) can release various proinflammatory cytokines, proteolytic enzymes, and other substances known as the senescence-associated secretory phenotype (SASP), allowing them to connect with surrounding cells and induce senesce. Studies have shown that the pharmacological elimination of SnCCs slows the progression of OA and promotes regeneration. Growth differentiation factor 15 (GDF15), a member of the tumor growth factor (TGF) superfamily, has recently been identified as a possible aging biomarker and has been linked to a variety of clinical conditions, including coronary artery disease, diabetes, and multiple cancer types. Thus, we obtained data from a publicly available single-cell sequencing RNA database and observed that GDF15, a critical protein in cellular senescence, is highly expressed in early OA. In addition, GDF15 is implicated in the senescence and modulation of MAPK14 in OA. Tissue and synovial fluid samples obtained from OA patients showed overexpression of GDF15. Next, we treated C20A4 cell lines with interleukin (IL)-1β with or without shGDF15 then removed the conditioned medium, and cultured C20A4 and HUVEC cell lines with the aforementioned media. We observed that C20A4 cells treated with IL-1β exhibited increased GDF15 secretion and that chondrocytes cultured with media derived from IL-1β–treated C20A4 exhibited senescence. HUVEC cell migration and tube formation were enhanced after culturing with IL-1β-treated chondrocyte media; however, decreased HUVEC cell migration and tube formation were noted in HUVEC cells cultured with GDF15-loss media. We tested the potential of inhibiting GDF15 by using a GDF15 neutralizing antibody, GDF15-nAb. GDF15-nAb exerted a similar effect, resulting in the molecular silencing of GDF15 in vivo and in vitro. Our results reveal that GDF15 is a driver of SnCCs and can contribute to OA progression by inducing angiogenesis.

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Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis

Cited by 42 publications

References 186 publications

Melatonin Attenuates the Progression of Osteoarthritis in Rats by Inhibiting Inflammation and Related Oxidative Stress on the Surface of Knee Cartilage

Melatonin Attenuates the Progression of Osteoarthritis in Rats by Inhibiting Inflammation and Related Oxidative Stress on the Surface of Knee Cartilage

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

Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis

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