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

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.

Adrenoceptor Expression during Intervertebral Disc Degeneration

“…We found a very similar AR expression profile in isolated and expanded IVD cells as in IVD tissue homogenates indicating that cell culture conditions over more than 2 weeks do not substantially influence the AR expression. A similar phenomenon was observed in human articular chondrocytes after 7 days in monolayer culture [40]. However, α1band β2-AR expression was slightly upregulated under culture conditions.…”

“…However, α1band β2-AR expression was slightly upregulated under culture conditions. The reason for this observation might be that monolayer culture conditions lead to dedifferentiation processes, which in turn could result in AR regulation [40]. Indeed, also degeneration results in dedifferentiation, therefore, we believe that our monolayer culture conditions used in the present study and as performed by others [41] optimally mimic the phenotype and behavior of IVD cells in vivo.…”

Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation

“…In contrast, Han et al could only confirm the expression of α1A-, α1Band α1D-AR in rat BMSCs while α2and β-AR were not detected [25]. One possible reason for this discrepancy might be that the AR gene expression profile differs between species [26] or that gene expression of resident BMSCs changes in the long-lasting pathophysiological microenvironment of OA damaged joint tissues [27]. This might also explain why the expression of α2Cand β2-AR was higher in trauma BMSCs compared to OA BMSCs.…”

Osteoarthritis and Cartilage Regeneration: Focus on Pathophysiology and Molecular Mechanisms

“…Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis [11]. Speichert and colleagues analyzed the contribution of the sympathetic neurotransmitter norepinephrine (NE) to human articular OA chondrocyte dedifferentiation under physioxic conditions [12]. NE alone did not affect morphology but, in combination with IL-1ß, markedly accelerated this shift.…”