Signalling networks in focus
The NF-κB signalling pathway in osteoarthritis

https://doi.org/10.1016/j.biocel.2013.08.018Get rights and content

Highlights

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    Osteoarthritis (OA) is a degenerative disease affecting all compartments of the joint.

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    NF-κB signalling pathway is a major catabolic pathway in OA joints.

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    NF-κB triggers the expression of various genes which are implicated in cartilage destruction, synovial membrane inflammation and increased subchondral bone resorption.

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    Targeting of the NF-κB signalling cascade is a promising therapeutic strategy for OA treatment.

Abstract

Nuclear factor-kappaB (NF-κB) proteins constitute a family of transcription factors that are stimulated by pro-inflammatory cytokines, chemokines, stress-related factors and extracellular matrix (ECM) degradation products. Upon stimulation, the activated NF-κB molecules trigger the expression of an array of genes which induce destruction of the articular joint, leading to osteoarthritis (OA) onset and progression. Therefore, targeted strategies that interfere with NF-κB signalling could offer novel potential therapeutic options for OA treatment. In this review, we discuss the involvement of NF-κB in OA pathogenesis and how pharmacological inhibition of the NF-κB signalling pathway affects OA incidence and evolution.

Introduction

Osteoarthritis (OA) is a common arthritic disease which gradually leads to cellular changes, structural defects and dysfunction of all the joint compartments, i.e. cartilage, bone and synovium (Scanzello and Goldring, 2012). Specifically, this “whole joint disorder” is characterised by the articular cartilage breakdown, subchondral bone sclerosis, osteophyte formation, inflammation of the synovial membrane and vascularisation of the articular cartilage (Jansen et al., 2012, Hou et al., 2013). Causes and origins of OA have not been fully elucidated. Nevertheless, major risk factors, such as genetic background, abnormal loading and ageing, have been associated with the pathogenesis of the disease via activation of many different molecular pathways which contribute to the initiation and progression of articular injury (Krasnokutsky et al., 2008). Therefore, unravelling the role of signalling pathways engaged in OA development is fundamental for the treatment of this joint malady. Here we will focus on one of these cascades and particularly we will overview the contribution of the NF-κB signalling pathway to OA pathobiology and summarise therapeutic approaches to target this pathway.

Section snippets

The NF-κB signalling pathway

The NF-κB molecules are a family of ubiquitously expressed transcription factors involved in immunity, stress responses, inflammatory diseases, cell proliferation and cell death (Oeckinghaus and Ghosh, 2009). The mammalian NF-κB subfamily comprises five proteins: RelA or p65, RelB, c-Rel, NF-κB1 or p50 (or p105 as precursor inactive form of p50) and NF-κB2 or p52 (or p100 as a precursor inactive form of p52). The common feature of all the above transcription factors is a shared N-terminal

The NF-κB pathway in articular cartilage

The articular cartilage is an avascular tissue consisting of a hydrated extracellular matrix (ECM) of collagens, proteoglycans and other proteins that embed a small number of chondrocytes. Normal chondrocytes do not divide and regulate the balance between catabolism and anabolism in cartilage (Goldring et al., 2011). Nevertheless, after stimulation the articular cells are activated and disrupt joint cartilage homeostasis leading to OA development.

The articular chondrocytes express on their

Therapeutic implications

The decisive role of NF-κB in OA onset and development provides evidence that intervention with this signalling pathway might have beneficial therapeutic effects. Thus, a spectrum of pharmacological agents have been developed so far, aiming at inhibiting distinct stages of the canonical or alternative NF-κB activation pathway. The non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are some of these pharmacologically active compounds that hinder the activation of NF-κB cascades (

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