Novel role of estrogen receptor-α on regulating chondrocyte phenotype and response to mechanical loading

N Wang; X Zhang; B B Rothrauff; M R Fritch; A Chang; Y He; M Yeung; S Liu; K E Lipa; G Lei; P G Alexander; H Lin

doi:10.1016/j.joca.2021.11.002

Novel role of estrogen receptor-α on regulating chondrocyte phenotype and response to mechanical loading

Osteoarthritis Cartilage. 2022 Feb;30(2):302-314. doi: 10.1016/j.joca.2021.11.002. Epub 2021 Nov 9.

Authors

N Wang¹, X Zhang², B B Rothrauff³, M R Fritch⁴, A Chang⁵, Y He⁶, M Yeung⁷, S Liu⁸, K E Lipa⁹, G Lei¹⁰, P G Alexander¹¹, H Lin¹²

Affiliations

¹ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Xiangya Third Hospital, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
² Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Xiangya Third Hospital, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
³ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. Electronic address: [email protected].
⁴ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. Electronic address: [email protected].
⁵ Department of Bioinformatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. Electronic address: [email protected].
⁶ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China; Xiangya Third Hospital, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
⁷ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 15219, USA. Electronic address: [email protected].
⁸ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. Electronic address: [email protected].
⁹ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 15219, USA. Electronic address: [email protected].
¹⁰ Department of Orthopaedic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
¹¹ Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. Electronic address: [email protected].
¹² Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA; Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, 15219, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. Electronic address: [email protected].

PMID: 34767957
DOI: 10.1016/j.joca.2021.11.002

Abstract

Objective: In knee cartilage from patients with osteoarthritis (OA), both preserved cartilage and damaged cartilage are observed. In this study, we aim to compare preserved with damaged cartilage to identify the molecule(s) that may be responsible for the mechanical loading-induced differences within cartilage degradation.

Methods: Preserved and damaged cartilage were harvested from the same OA knee joint. RNA Sequencing was performed to examine the transcriptomic differences between preserved and damaged cartilage cells. Estrogen receptor-α (ERα) was identified, and its function of was tested through gene knockin and knockout. The role of ERα in mediating chondrocyte response to mechanical loading was examined via compression of chondrocyte-laded hydrogel in a strain-controlled manner. Findings from the studies on human samples were verified in animal models.

Results: Level of estrogen receptor α (ERα) was significantly reduced in damaged cartilage compared to preserved cartilage, which were observed in both human and mice samples. Knockdown of ESR1, the gene encoding ERα, resulted in an upregulation of senescence- and OA-relevant markers in chondrocytes. Conversely, knockin of ESR1 partially reversed the osteoarthritic and senescent phenotype of OA chondrocytes. Using a three-dimensional (3D) culture model, we demonstrated that mechanical overload significantly suppressed ERα level in chondrocytes with concomitant upregulation of osteoarthritic phenotype. When ESR1 expression was suppressed, mechanical loading enhanced hypertrophic and osteogenic transition.

Conclusion: Our study demonstrates a new estrogen-independent role of ERα in mediating chondrocyte phenotype and its response to mechanical loading, and suggests that enhancing ERα level may represent a new method to treat osteoarthritis.

Keywords: Chondrocytes; Estrogen receptor-α; Mechanical loading; Mechanotransduction; Osteoarthritis; Senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chondrocytes / physiology*
Estrogen Receptor alpha / physiology*
Humans
Male
Mice
Mice, Inbred C57BL
Osteoarthritis, Knee / pathology*
Phenotype
Weight-Bearing / physiology*

Substances

Estrogen Receptor alpha