Role of Norepinephrine in IL-1β-Induced Chondrocyte Dedifferentiation under Physioxia.

Saskia Speichert,Natalie Molotkov,Andrea Meurer,Karima El Bagdadi,Frank Zaucke,Zsuzsa Jenei-Lanzl

doi:10.3390/ijms20051212

Abstract

As part of the pathogenesis of osteoarthritis (OA), chondrocytes lose their phenotype and become hypertrophic, or dedifferentiate, mainly driven by interleukin-1β (IL-1β). The contribution of other factors to the dedifferentiation process is not completely understood. Recent studies suggested a dose-dependent role for the sympathetic neurotransmitter norepinephrine (NE) in OA chondrocyte metabolism. Therefore, the aim of this study was to analyze the contribution of NE (10−8 M, 10−6 M) to human articular OA chondrocyte dedifferentiation in the absence or presence of IL-1β (0.5 ng/mL). Here, we demonstrate that OA chondrocytes express α2A-, α2C- and β2-adrenoceptors (AR) and show the characteristic shift towards a fibroblast-like shape at day 7 in physioxic monolayer culture. NE alone did not affect morphology but, in combination with IL-1β, markedly accelerated this shift. Moderate glycosaminoglycan (GAG) staining was observed in untreated and NE-treated cells, while IL-1β strongly decreased GAG deposition. IL-1β alone or in combination with NE decreased SOX9, type II collagen, COMP, and aggrecan, and induced MMP13 and ADAMTS4 gene expression, indicating an accelerated dedifferentiation. NE alone did not influence gene expression and did not modulate IL-1β-mediated effects. In conclusion, these results indicate that low-grade inflammation exerts a dominant effect on chondrocyte dedifferentiation and should be targeted early in OA therapy.

Highlights

Osteoarthritis (OA) is one of the most common painful and disabling chronic degenerative joint diseases worldwide [1,2]
Morphological changes and alterations in the expression of extracellular matrix (ECM)-related genes in OA chondrocytes after seven days in monolayer culture were investigated
Gene expression levels of COL1A1 and COL2A1 increased, while COL10A1, matrix metallopeptidase 13 (MMP13), and ADAM metallopeptidase with thrombospondin type 1 motif 4 (ADAMTS4) expression decreased during dedifferentiation, compared to chondrocytes at day 0 (COL1A1, p < 0.001; COL2A1, p = 0.007; COL10A1, p = 0.007; MMP13, p = 0.008; ADAMTS4, p = 0.014)

Summary

Introduction

Osteoarthritis (OA) is one of the most common painful and disabling chronic degenerative joint diseases worldwide [1,2]. Sympathetic nerve fibers are characterized by high tyrosine hydroxylase (TH) expression and activity [17]. Due to the affinity of the distinct ARs, NE in low concentrations (≤10−7 M) primarily acts via αARs, while βARs are preferentially activated at high NE concentrations (≥10−7 M) [20,21]. These studies were performed under 20% O2 concentration, representing a hyperoxic and unphysiological condition for articular chondrocytes, because O2 concentrations in cartilage tissue lie between 1–3% (physioxia) [22]. An upregulation of SOX9 and COL2A1 under physioxic conditions led to a prolonged stabilization of the chondrocytic phenotype [23]

Objectives

Results

Conclusion