Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway
Abstract Objective Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated...
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2024-11-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-024-03417-3 |
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| author | Jeonghyeon Moon Keun-Hyung Cho JooYeon Jhun JeongWon Choi Hyun-Sik Na Jeong Su Lee Seung Yoon Lee Jun-Ki Min Anan Shetty Sung-Hwan Park Seok Jung Kim Mi-La Cho |
| author_facet | Jeonghyeon Moon Keun-Hyung Cho JooYeon Jhun JeongWon Choi Hyun-Sik Na Jeong Su Lee Seung Yoon Lee Jun-Ki Min Anan Shetty Sung-Hwan Park Seok Jung Kim Mi-La Cho |
| author_sort | Jeonghyeon Moon |
| collection | DOAJ |
| description | Abstract Objective Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB. Methods OA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells. Results Less cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17). Conclusion Our results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells. |
| format | Article |
| id | doaj-art-918bd055aef54a63a6b69ed875df85ba |
| institution | Kabale University |
| issn | 1478-6362 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
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| series | Arthritis Research & Therapy |
| spelling | doaj-art-918bd055aef54a63a6b69ed875df85ba2024-11-17T12:39:49ZengBMCArthritis Research & Therapy1478-63622024-11-0126111110.1186/s13075-024-03417-3Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathwayJeonghyeon Moon0Keun-Hyung Cho1JooYeon Jhun2JeongWon Choi3Hyun-Sik Na4Jeong Su Lee5Seung Yoon Lee6Jun-Ki Min7Anan Shetty8Sung-Hwan Park9Seok Jung Kim10Mi-La Cho11Departments of Immunobiology and Neurology, Yale School of MedicineLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaDepartment of Internal Medicine, and the Clinical Medicine Research Institute of Bucheon St. Mary’s Hospital, The Catholic University of KoreaInstitute of Medical Sciences, Canterbury Christ Church UniversityDepartment of Internal Medicine, Division of Rheumatology, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of KoreaDepartment of Orthopaedic Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of KoreaLab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of KoreaAbstract Objective Osteoarthritis (OA) is a degenerative joint disease caused by the breakdown of joint cartilage and adjacent bone. Joint injury, being overweight, differences in leg length, high levels of joint stress, abnormal joint or limb development, and inherited factors have been implicated in the etiology of OA. In addition to physical damage to the joint, a role for inflammatory processes has been identified as well. Small heterodimer partner-interacting leucine zipper protein (SMILE) regulates transcription and many cellular functions. Among the proteins activated by SMILE is the peroxisome proliferator-activated receptor (PPAR) γ, which mediates the activities of CD4 + T helper cells, including Th1, Th2, and Th17, as well as Treg cells. PPAR-γ binds to STAT3 to inhibit its transcription, thereby suppressing the expression of the NF-κB pathway, and in turn, the expression of the inflammatory cytokines interferon (IFN), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which are sub-signals of STAT3 and NF-κB. Methods OA was induced in control C57BL/6 mice and in C57BL/6-derived SMILE-overexpressing transgenic (SMILE Tg) mice. The protein expression levels in the joint and spleen tissues were analyzed by immunohistochemistry and immunofluorescence images. In addition, flow cytometry was performed for detecting changes of the changes of immune cells. Results Less cartilage damage and significantly reduced levels of OA biomarkers (MMP13, TIMP3 and MCP-1) were observed in SMILE Tg mice. Immunohistochemistry performed to identify the signaling pathway involved in the link between SMILE expression and OA revealed decreased levels of IL-1β, IL-6, TNF-α, and phosphorylated AMPK in synovial tissues as well as a significant decrease in phosphorylated STAT3 in both cartilage and synovium. Changes in systemic immune cells were investigated via flow cytometry to analyze splenocytes isolated from control and SMILE Tg mice. SMILE Tg mice had elevated proportions of CD4 + IL-4 + cells (Th2) and CD4 + CD25 + Foxp3 + cells (Treg) and a notable decrease in CD4 + IL-17 + cells (Th17). Conclusion Our results show that overexpressed SMILE attenuates the symptoms of OA, by increasing AMPK signaling and decreasing STAT3, thus reducing the levels of inflammatory immune cells.https://doi.org/10.1186/s13075-024-03417-3Osteoarthritis (OA)Small heterodimer partner-interacting leucine zipper protein (SMILE)Cyclic AMP-response element binding protein Zhangfei (CREBZF)Signal transducer and activator of transcription 3 (STAT3)Helper T cell (th cell) |
| spellingShingle | Jeonghyeon Moon Keun-Hyung Cho JooYeon Jhun JeongWon Choi Hyun-Sik Na Jeong Su Lee Seung Yoon Lee Jun-Ki Min Anan Shetty Sung-Hwan Park Seok Jung Kim Mi-La Cho Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway Arthritis Research & Therapy Osteoarthritis (OA) Small heterodimer partner-interacting leucine zipper protein (SMILE) Cyclic AMP-response element binding protein Zhangfei (CREBZF) Signal transducer and activator of transcription 3 (STAT3) Helper T cell (th cell) |
| title | Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway |
| title_full | Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway |
| title_fullStr | Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway |
| title_full_unstemmed | Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway |
| title_short | Small heterodimer partner-interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the AMPK/STAT3 signaling pathway |
| title_sort | small heterodimer partner interacting leucine zipper protein suppresses pain and cartilage destruction in an osteoarthritis model by modulating the ampk stat3 signaling pathway |
| topic | Osteoarthritis (OA) Small heterodimer partner-interacting leucine zipper protein (SMILE) Cyclic AMP-response element binding protein Zhangfei (CREBZF) Signal transducer and activator of transcription 3 (STAT3) Helper T cell (th cell) |
| url | https://doi.org/10.1186/s13075-024-03417-3 |
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