GSK5182, 4-Hydroxytamoxifen Analog, a New Potential Therapeutic Drug for Osteoarthritis.

Yunhui Min,Yaping Zhao,Xiangyu Zhao,Godagama Gamaarachchige Dinesh Suminda,Young-Ok Son,Mangeun Kim,Dahye Kim

doi:10.3390/ph13120429

Yunhui Min, Yaping Zhao + Show 5 more

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https://doi.org/10.3390/ph13120429

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Abstract

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 Esrrg 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-Esrrg. Overall, the ERRγ inverse agonist GSK5182 represents a promising therapeutic small molecule for OA.

Highlights

Osteoarthritis (OA) is the most well-known arthritic disease
Reverse transcription-polymerase chain reaction (RT-PCR) analyses revealed that ERRγ was remarkably increased in IL-1β, IL-6, and tumor necrosis factor (TNF)-α-exposed chondrocytes (Figure 1A–C)
Our group has reported that ERRγ acts as a catabolic regulator of cartilage degeneration and OA pathogenesis [7]

Summary

Introduction

Osteoarthritis (OA) is the most well-known arthritic disease. OA primarily involves chronic inflammation of the articular cartilage [1,2,3] and shows pathological changes in the synovial membrane, meniscus, and infrapatellar fat pad with low-grade inflammation [4,5]. Environmental or genetic OA risk elements change biochemical mechanisms in articular chondrocytes, resulting in loss of the extracellular matrix (ECM). Catabolic elements of the pro-inflammatory cytokine interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α activate transcription of nuclear kappa B (NF-κB), and control the loss of the matrix in articular cartilage through upregulation of MMP-3, MMP-13, and ADAMTS5 [3,15,16]. These cytokines increase intracellular reactive oxygen species (ROS) concentration, thereby inducing chondrocyte apoptosis [17]. Even though pro-inflammatory cytokines are primary therapeutic targets for osteoarthritis, only a few clinical studies have been completed [15,17]

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