ERα-Targeting PROTAC as a Chemical Knockdown Tool to Investigate the Estrogen Receptor Function in Rat Menopausal Arthritis

Li Duan; Xiao Xu; Limei Xu; Caining Wen; Kan Ouyang; Zigang Li; Yujie Liang

doi:10.3389/fphar.2021.764154

Frontiers in Pharmacology (Nov 2021)

ERα-Targeting PROTAC as a Chemical Knockdown Tool to Investigate the Estrogen Receptor Function in Rat Menopausal Arthritis

Li Duan,
Xiao Xu,
Limei Xu,
Caining Wen,
Kan Ouyang,
Zigang Li,
Yujie Liang

Affiliations

Li Duan: Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
Xiao Xu: Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
Limei Xu: Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
Caining Wen: Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
Kan Ouyang: Department of Orthopedics, Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People’s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
Zigang Li: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
Yujie Liang: Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, China

DOI: https://doi.org/10.3389/fphar.2021.764154
Journal volume & issue: Vol. 12

Abstract

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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.

Published in Frontiers in Pharmacology

ISSN: 1663-9812 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://journal.frontiersin.org/journals/pharmacology

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