Author: Au, Man Ting
Title: Endothelin receptor subtypes in cartilage homeostasis and disease
Advisors: Wen, Chunyi (BME)
Huang, Chien-ling (HTI)
Degree: Ph.D.
Year: 2020
Subject: Endothelins
Knee -- Diseases
Hong Kong Polytechnic University -- Dissertations
Department: Department of Biomedical Engineering
Pages: 192 pages
Language: English
Abstract: Knee osteoarthritis (OA) is a prevalent debilitating joint disease that is also the leading cause of pain and disability in elderly. As a multifactorial disease, it has been conceived as a result of the interplay between local and systemic risk factors such as injury, obesity and hypertension. Endothelial dysfunction and associated pathogenic factors such as endothelin-1 (ET-1) and its receptors have been implicated in the pathogenesis of OA. ET-1, the most potent vasoconstrictor, has been reported to induce endothelial senescence; yet the role of ET-1 in chondrocyte senescence remains unclear. We aimed to determine the role of ET-1 and its receptors in reactive oxygen species (ROS) accumulation and cellular senescence in osteoarthritis development as well as the feasibility of employing endothelin receptor blockers for OA treatment. In this study, we demonstrated a positive correlation between plasma ET-1 and severity of OA in a DMM-induced PTOA model. OA-like cartilage phenotype was also observed in transgenic mice overexpressing ET-1 in endothelial cells. Articular chondrocytes go along the senescence pathway after terminal differentiation. DMM-induced ET-1 led to activation of inflammatory pathway, upregulation of oxidative stress and matrix-degrading enzyme as well as joint tissue senescence. All these markers were observed on the superficial layer of articular cartilage, where hypertrophic chondrocytes were abundant.
We also identified the role of ETAR and ETBR in OA development. ETBR was activated in OA cartilage in a PTOA model. ET-1 transduces via both ET receptors to activate nuclear translocation of NF-kB p65, which further leads to production of matrix-degrading enzyme, MMP13. We also showed that ET-1 leads to chondrocyte senescence via ETBR, but not ETAR, through increasing ROS and p16INK4a. Upregulation of MMP13 and senescence marker at articular chondrocytes result in cartilage degradation. Previous study has shown selective ETAR blockade attenuated radiographic OA. However, our data showed that blocking ETBR, but not ETAR, could attenuate OA progression through lowering ROS and chondrocyte senescence. Although selective blockade of ETAR did not show beneficial effect on DMM-induced cartilage damage, it lowered NF-kB p65 nuclear translocation and MMP13 production. Therefore, we suggest that PTOA is more likely to be driven by loss of replicative function of chondrocytes than production of SASPs. Moreover, our data demonstrated the impracticality of blocking both endothelin receptors. Macitentan, a dual endothelin receptor blocker, drove chondrocytes to hypertrophy instead of attenuating surgery-induced cartilage damage. Macitentan caused a paradoxical increase of plasma ET-1, leading to reduction of DKK-1. This possibly resulted in activation of Wnt/Ī²-catenin signalling pathway, causing production of MMP13 and cartilage degradation eventually. In short, endothelial dysfunction has been reported in subchondral bone and synovium of OA pathologies. This study, for the first time, implicates ET-1, an endotheliumĀ­derived vasoconstrictor, to link endothelial dysfunction with cartilage homeostasis and disease. We decipher the intracellular and extracellular signalling of ET-1, as a deterministic factor for chondrocyte senescence (through ETBR) and hypertrophy (via DKK1) in the development of murine post-traumatic OA. Our findings consolidate ET-1 as a potential therapeutic target for OA. Most importantly, we point in the direction of future research to ET-1 neutralization or depletion, rather simply blockading its receptors and intra-cellular signalling pathways, for rescue of OA.
Rights: All rights reserved
Access: open access

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