Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis
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....
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI
2022
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| Online Access: | https://repository.ugm.ac.id/283417/1/Pei-Wei%20Weng_Role%20of%20GDF15_MAPK14%20Axis.pdf |
| _version_ | 1826050642342313984 |
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| author | Weng, Pei-Wei Pikatan, Narpati Wesa Setiawan, Syahru Agung Yadav, Vijesh Kumar Fong, Iat-Hang Hsu, Chia-Hung Yeh, Chi-Tai Lee, Wei-Hwa |
| author_facet | Weng, Pei-Wei Pikatan, Narpati Wesa Setiawan, Syahru Agung Yadav, Vijesh Kumar Fong, Iat-Hang Hsu, Chia-Hung Yeh, Chi-Tai Lee, Wei-Hwa |
| author_sort | Weng, Pei-Wei |
| collection | UGM |
| description | 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. |
| first_indexed | 2024-03-14T00:07:48Z |
| format | Article |
| id | oai:generic.eprints.org:283417 |
| institution | Universiti Gadjah Mada |
| language | English |
| last_indexed | 2024-03-14T00:07:48Z |
| publishDate | 2022 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oai:generic.eprints.org:2834172023-11-21T02:37:28Z https://repository.ugm.ac.id/283417/ Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis Weng, Pei-Wei Pikatan, Narpati Wesa Setiawan, Syahru Agung Yadav, Vijesh Kumar Fong, Iat-Hang Hsu, Chia-Hung Yeh, Chi-Tai Lee, Wei-Hwa Orthopaedics Physiotherapy 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. MDPI 2022-07 Article PeerReviewed application/pdf en https://repository.ugm.ac.id/283417/1/Pei-Wei%20Weng_Role%20of%20GDF15_MAPK14%20Axis.pdf Weng, Pei-Wei and Pikatan, Narpati Wesa and Setiawan, Syahru Agung and Yadav, Vijesh Kumar and Fong, Iat-Hang and Hsu, Chia-Hung and Yeh, Chi-Tai and Lee, Wei-Hwa (2022) Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis. International Journal of Molecular Sciences, 23 (13). pp. 1-18. ISSN 16616596 https://www.mdpi.com/1422-0067/23/13/7043 10.3390/ijms23137043 |
| spellingShingle | Orthopaedics Physiotherapy Weng, Pei-Wei Pikatan, Narpati Wesa Setiawan, Syahru Agung Yadav, Vijesh Kumar Fong, Iat-Hang Hsu, Chia-Hung Yeh, Chi-Tai Lee, Wei-Hwa Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis |
| title | Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis |
| title_full | Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis |
| title_fullStr | Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis |
| title_full_unstemmed | Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis |
| title_short | Role of GDF15/MAPK14 Axis in Chondrocyte Senescence as a Novel Senomorphic Agent in Osteoarthritis |
| title_sort | role of gdf15 mapk14 axis in chondrocyte senescence as a novel senomorphic agent in osteoarthritis |
| topic | Orthopaedics Physiotherapy |
| url | https://repository.ugm.ac.id/283417/1/Pei-Wei%20Weng_Role%20of%20GDF15_MAPK14%20Axis.pdf |
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