Abstract
Proteolytic targeting chimeras (PROTACs) is a rapid and reversible chemical knockout method. Compared with traditional gene-editing tools, it can avoid potential genetic compensation, misunderstandings caused by spontaneous mutations, or gene knockouts that lead to embryonic death. To study the role of estrogen receptor alpha (ERα) in the occurrence and progression of menopausal arthritis, we report a chemical knockout strategy in which stable peptide-based (PROTACs) against ERα to inhibit their function. This chemical knockdown strategy can effectively and quickly inhibit ERα protein in vivo and in vitro. In the rat menopausal arthritis model, this study showed that inhibiting estrogen function by degrading ERα can significantly interfere with cartilage matrix metabolism and cause menopausal arthritis by up-regulating matrix metalloproteinase (MMP-13). The results of this study indicate that ERα is a crucial estrogen receptor for maintaining cartilage metabolism. Inhibition of ERα function by PROTACs can promote the progression of osteoarthritis.
Highlights
Menopausal arthritis is one of the most frequently encountered types of arthritic diseases (Wluka et al, 2000; Watt, 2018)
The most significant finding of this study is that we confirmed that ERα is one of the major estrogen receptors (ERs) in joint cartilage matrix metabolism in vivo
There are many ways to study the role of ERs in OA pathogenesis
Summary
Menopausal arthritis is one of the most frequently encountered types of arthritic diseases (Wluka et al, 2000; Watt, 2018). Most used knockout methods, such as transcription activator-like effector nucleases (TALEN), CreLoxP, clustered regularly interspaced short palindromic repeats/ CRISPR-associated proteins 9 (CRISPR/Cas9), etc., can knock out at the gene level, and RNA interference can act on the transcription level (Elbashir et al, 2001; Chan, 2013; Doudna and Charpentier, 2014; Sengupta et al, 2017; Wang and Sun, 2019) These methods usually need to construct animal gene knockout models, especially non-human primate models, which are complicated, time-consuming, and irreversible loss of function caused by gene knockout. The results of this study will provide evidence for the role of ERα in menopausal arthritis progression
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