Elsevier

Biomedicine & Pharmacotherapy

Volume 106, October 2018, Pages 1713-1719
Biomedicine & Pharmacotherapy

Activation of the bile acid receptor GPBAR1 (TGR5) ameliorates interleukin-1β (IL-1β)- induced chondrocytes senescence

https://doi.org/10.1016/j.biopha.2018.06.154Get rights and content

Highlights

  • TGR5 is expressed in chondrocytes and upregulated in chondrocytes from OA patients.

  • INT-777 reduces IL-1β- induced SA-β-Gal activity and cell cycle arrest in G1 phase.

  • INT-777 mitigates p53 acetylation, expression of p21 and PAI-1, mediated by sirt1.

  • The inhibitory effects of INT-777 in IL-1β- induced senescence is mediated by TGR5.

Abstract

Osteoarthritis is the most common chronic condition of the joint disease. Chondrocyte is the sole cell type in joint tissues. Senescence of chondrocytes is known to contribute to the causation of osteoarthritis. Local inflammatory cytokines- caused chondrocytes senescence is proposed to be one of the molecular mechanisms of osteoarthritis. In this study, we show that the bile acid receptor GPBAR1 (TGR5), a G protein couples bile acid receptor, plays important roles in protecting chondrocytes from interleukin 1β (IL-1β)- caused senescence. TGR5 is fairly expressed in cultured chondrocytes. Its expression is reduced in isolated chondrocytes from osteoarthritis patients, and IL-1β treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic agonist, INT-777, dramatically reduces senescence associated β galactosidase activity by IL-1β. Mechanistically, the action of INT-777 ameliorates IL-1β- induced chondrocytes entry of G0/G1 arrest phase and exit of S and G2/M phases. INT-777 inhibits IL-1β- induced expression of p21, PAI-1, and K382 acetylation of p53 as well as reduction of Sirt1. The knockdown of TRG5 abolished the protective role of INT-777 on these molecules. Collectively, our data indicates that activation of TGR5 is necessary for protection of IL-1β- induced chondrocytes senescence.

Introduction

Osteoarthritis is a very common chronic joint disease. Osteoarthritis often occurs in middle age to elderly people and is estimated to affect more than 100 million people globally [1]. Cellular senescence is a state during which normal cells cease to divide and to stay at the stable arrest status. Accumulation of senescent cells in various tissues could impair the normal function and is implicated in the development of many age-related diseases. Osteoarthritis is featured by progressive tissue remodeling and loss of joint function, and age is the most important risk factor of its development [2]. Chondrocyte is the major cell type of articular cartilage in joint tissue. It is responsible for the production of extracellular matrix (ECM) and for maintaining cartilage structure and function. Senescence of chondrocytes possesses various senescence markers, such as increased senescence-associated beta-galactosidase ((S)-Ab-Gal) activity, telomere attrition, and accumulation of p16ink4a protein [3,4]. It has been recognized that chondrocytes senescence plays an important pathological role in the causation of osteoarthritis [4]. Therefore, a complete understanding of the biology of chondrocyte and blockage of its senescence are essential for the treatment of Osteoarthritis.

TGR5 receptor was first identified G-coupled protein receptor specific for bile acids [5]. Since then, a variety of studies have found that TGR5 is widely expressed in different tissues and to activate various intracellular signaling pathways upon interaction with bile acids [6]. More recently, TGR5 is found to be the receptor for multiple selective synthetic agonists such as 6α-ethyl-23(S)-methyl-cholic acid (6-EMCA, INT-777) and a series of 4-benzofuranyloxynicotinamde derivatives to regulate energy homeostasis, bile acid homeostasis, glucose metabolism, cancer and liver regeneration, TGR5 has emerged as a potential target for the treatment of metabolic disorders [7]. Previous studies have shown that activation of TGR5 in immune cells mediates potent pro-inflammatory response, suggesting that activation of TGR5 could have therapeutic potentials in inflammatory and metabolic diseases [8,9]. Under the condition of aging and osteoarthritis, we reason that activation of TGR5 would have a beneficial role to highly inflamed aging chondrocytes. In this study, we investigated actions of TGR5 in the context of cytokine- induced senescence of chondrocytes.

Section snippets

Cell culture and treatment experiments

Experimental procedures were approved by the institutional ethics committee at The Second Affiliated Hospital of Harbin Medical University. Experiments involving human subjects were designed in accordance with the World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. Specimens of human OA articular cartilage were obtained from tibial plateaus of patients undergoing total knee replacement surgery (n = 5; 2 male and 3 female). All

TGR5 is fairly expressed in chondrocytes and downregulated in chondrocytes from osteoarthritis patients

To determine the TGR5 expression in chondrocytes, we examined expression levels of TGR5 in primary chondrocytes, chondrocyte cell line SW1353 cells and endoC-βH1 β cells. The endoC-βH1 β cells are known to express TGR5 and used as the reference. Compared to β cells, both transcript mRNA and protein of TGR5 are fairly expressed in SW1353 and primary chondrocytes (Fig. 1A and B).

Next, we determined to check the relative expression level of TGR5 in chondrocytes from healthy normal subjects and

Discussion

Chondrocytes are characterized for their secretion of two predominant extracellular matrix (ECM) components, type II collagen and aggrecan. These cells are responsible for producing and maintaining the balance of ECM and receiving nutrients and external signals from the synovial. The senescence of chondrocytes has been implicated in the development of osteoarthritis [17,4]. One of direct evidence is the animal study by transplanting senescent chondrocytes suggest that the injection of small

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