| First Author | Min Y | Year | 2020 |
| Journal | Pharmaceuticals (Basel) | Volume | 13 |
| Issue | 12 | PubMed ID | 33261216 |
| Mgi Jnum | J:336545 | Mgi Id | MGI:6728284 |
| Doi | 10.3390/ph13120429 | Citation | Min Y, et al. (2020) GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis. Pharmaceuticals (Basel) 13(12) |
| abstractText | Estrogen-related receptors (ERRs) are the first identified orphan nuclear receptors. The ERR family consists of ERRalpha, ERRbeta, and ERRgamma, regulating diverse isoform-specific functions. We have reported the importance of ERRgamma in osteoarthritis (OA) pathogenesis. However, therapeutic approaches with ERRgamma against OA associated with inflammatory mechanisms remain limited. Herein, we examined the therapeutic potential of a small-molecule ERRgamma inverse agonist, GSK5182 (4-hydroxytamoxifen analog), in OA, to assess the relationship between ERRgamma expression and pro-inflammatory cytokines in mouse articular chondrocyte cultures. ERRgamma expression increased following chondrocyte exposure to various pro-inflammatory cytokines, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Pro-inflammatory cytokines dose-dependently increased ERRgamma protein levels. In mouse articular chondrocytes, adenovirus-mediated ERRgamma overexpression upregulated matrix metalloproteinase (MMP)-3 and MMP-13, which participate in cartilage destruction during OA. Adenovirus-mediated ERRgamma overexpression in mouse knee joints or ERRgamma transgenic mice resulted in OA. In mouse joint tissues, genetic ablation of Esrrg obscured experimental OA. These results indicate that ERRgamma 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 ERRgamma-overexpressing mice administered intra-articular Ad-Esrrg. Overall, the ERRgamma inverse agonist GSK5182 represents a promising therapeutic small molecule for OA. |
