GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis
Estrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRα, ERRβ, and ERRγ, regulating diverse isoform-specific functions. We have reported the importance of ERRγ in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRγ...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/13/12/429 |
| _version_ | 1797546489713524736 |
|---|---|
| author | Yunhui Min Dahye Kim Godagama Gamaarachchige Dinesh Suminda Xiangyu Zhao Mangeun Kim Yaping Zhao Young-Ok Son |
| author_facet | Yunhui Min Dahye Kim Godagama Gamaarachchige Dinesh Suminda Xiangyu Zhao Mangeun Kim Yaping Zhao Young-Ok Son |
| author_sort | Yunhui Min |
| collection | DOAJ |
| description | Estrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRα, ERRβ, and ERRγ, regulating diverse isoform-specific functions. We have reported the importance of ERRγ in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRγ against OA associated with inflammatory mechanisms remain limited. Herein, we examined the therapeutic potential of a small-molecule ERRγ inverse agonist, GSK5182 (4-hydroxytamoxifen analog), in OA, to assess the relationship between ERRγ expression and pro-inflammatory cytokines in mouse articular chondrocyte cultures. ERRγ expression increased following chondrocyte exposure to various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Pro-inflammatory cytokines dose-dependently increased ERRγ protein levels. In mouse articular chondrocytes, adenovirus-mediated ERRγ overexpression upregulated matrix metalloproteinase (MMP)-3 and MMP-13, which participate in cartilage destruction during OA. Adenovirus-mediated ERRγ overexpression in mouse knee joints or ERRγ transgenic mice resulted in OA. In mouse joint tissues, genetic ablation of <i>Esrrg</i> obscured experimental OA. These results indicate that ERRγ is involved in OA pathogenesis. In mouse articular chondrocytes, GSK5182 inhibited pro-inflammatory cytokine-induced catabolic factors. Consistent with the in vitro results, GSK5182 significantly reduced cartilage degeneration in ERRγ-overexpressing mice administered intra-articular Ad-<i>Esrrg</i>. Overall, the ERRγ inverse agonist GSK5182 represents a promising therapeutic small molecule for OA. |
| first_indexed | 2024-03-10T14:30:04Z |
| format | Article |
| id | doaj.art-d91cef96f9b04a1098649c167d4a576a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T14:30:04Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-d91cef96f9b04a1098649c167d4a576a2023-11-20T22:41:42ZengMDPI AGPharmaceuticals1424-82472020-11-01131242910.3390/ph13120429GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for OsteoarthritisYunhui Min0Dahye Kim1Godagama Gamaarachchige Dinesh Suminda2Xiangyu Zhao3Mangeun Kim4Yaping Zhao5Young-Ok Son6Interdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju City 63243, KoreaDepartment of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju City 63243, KoreaInterdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju City 63243, KoreaInterdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju City 63243, KoreaDepartment of Animal Biotechnology, Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju City 63243, KoreaSchool of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, ChinaInterdisciplinary Graduate Program in Advanced Convergence Technology and Science, Jeju National University, Jeju City 63243, KoreaEstrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRα, ERRβ, and ERRγ, regulating diverse isoform-specific functions. We have reported the importance of ERRγ in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRγ against OA associated with inflammatory mechanisms remain limited. Herein, we examined the therapeutic potential of a small-molecule ERRγ inverse agonist, GSK5182 (4-hydroxytamoxifen analog), in OA, to assess the relationship between ERRγ expression and pro-inflammatory cytokines in mouse articular chondrocyte cultures. ERRγ expression increased following chondrocyte exposure to various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Pro-inflammatory cytokines dose-dependently increased ERRγ protein levels. In mouse articular chondrocytes, adenovirus-mediated ERRγ overexpression upregulated matrix metalloproteinase (MMP)-3 and MMP-13, which participate in cartilage destruction during OA. Adenovirus-mediated ERRγ overexpression in mouse knee joints or ERRγ transgenic mice resulted in OA. In mouse joint tissues, genetic ablation of <i>Esrrg</i> obscured experimental OA. These results indicate that ERRγ is involved in OA pathogenesis. In mouse articular chondrocytes, GSK5182 inhibited pro-inflammatory cytokine-induced catabolic factors. Consistent with the in vitro results, GSK5182 significantly reduced cartilage degeneration in ERRγ-overexpressing mice administered intra-articular Ad-<i>Esrrg</i>. Overall, the ERRγ inverse agonist GSK5182 represents a promising therapeutic small molecule for OA.https://www.mdpi.com/1424-8247/13/12/429GSK5182ERRγcartilage degenerationosteoarthritis |
| spellingShingle | Yunhui Min Dahye Kim Godagama Gamaarachchige Dinesh Suminda Xiangyu Zhao Mangeun Kim Yaping Zhao Young-Ok Son GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis Pharmaceuticals GSK5182 ERRγ cartilage degeneration osteoarthritis |
| title | GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis |
| title_full | GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis |
| title_fullStr | GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis |
| title_full_unstemmed | GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis |
| title_short | GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis |
| title_sort | gsk5182 4 hydroxytamoxifen analog a new potential therapeutic drug for osteoarthritis |
| topic | GSK5182 ERRγ cartilage degeneration osteoarthritis |
| url | https://www.mdpi.com/1424-8247/13/12/429 |
| work_keys_str_mv | AT yunhuimin gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis AT dahyekim gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis AT godagamagamaarachchigedineshsuminda gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis AT xiangyuzhao gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis AT mangeunkim gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis AT yapingzhao gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis AT youngokson gsk51824hydroxytamoxifenanaloganewpotentialtherapeuticdrugforosteoarthritis |