Review
Small-molecule inhibitors of NF-κB for the treatment of inflammatory joint disease

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Abstract

Recent advances in our understanding of the role of cytokine networks in inflammatory processes have led to the development of novel biological agents for the treatment of chronic inflammatory diseases. At the present time, significant efforts are focused on characterizing the complex signal transduction cascades that are activated by these cytokines and, in turn, regulate their expression. The transcription factor NF-κB is a pivotal regulator of the inducible expression of key proinflammatory mediators, and activated NF-κB has been observed in several debilitating inflammatory disorders, including rheumatoid arthritis and osteoarthritis. In light of its central role in inflammation, the identification of inhibitors of NF-κB should provide novel therapeutics for the treatment of chronic joint disease.

Introduction

The two most common diseases affecting human articulating joints are rheumatoid arthritis (RA) and osteoarthritis (OA). The debilitating joint destruction associated with RA has long been attributed to ongoing chronic inflammation of the synovial lining. The infiltration of this tissue with immunocompetent cells and the proliferation of synovial fibroblasts leads to the formation of pannus tissue, which invades and degrades the articular cartilage and subchondral bone. In comparison, the major pathological feature of OA is the gradual destruction and loss of the articular cartilage, which has been linked to a combination of mechanical and biochemical factors. Synovial inflammation in OA is thought to be a secondary process driven by the degradation of articular cartilage and the release of potentially immunogenic molecules during this process [1].

Despite the obvious differences in their pathologies, both diseases share a number of molecular targets that have been considered key control points for therapeutic intervention. These include the pleiotropic proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor α (TNF-α); extracellular matrix degrading enzymes such as the matrix metalloproteinases (MMPs); prostaglandins and nitric oxide. Evidence for the pivotal roles of TNF-α and IL-1β in the pathogenesis of RA has been demonstrated both in preclinical [2] and, more importantly, clinical studies using biological agents such as etanercept (Enbrel®; Immunex Corporation, Seattle, WA, USA) and infliximab (Remicade®; Centocor Inc., Malvern, PA, USA) to block their activity 3., 4.. There is also compelling evidence implicating these molecules in the progressive destruction of the articular cartilage in OA 5., 6•.. The use of biological agents for the treatment of OA appears unlikely, given that the nature of the disease is not life threatening, coupled with the prohibitive cost of biological therapies. It is also becoming increasingly clear that inhibition of a single cytokine may be insufficient to arrest the disease process 3., 7.. An alternative approach would be to develop orally active small-molecule inhibitors of the signal transduction pathways that drive the production and activity of these cytokines. The activation of nuclear factor-κB (NF-κB) is known to be pivotal for the regulated synthesis and activity of inflammatory cytokines, including TNF-α and IL-1β, and also for several other mediators involved in the pathogenesis of OA and RA, including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and MMP-1. In this review, we will discuss the NF-κB activation pathway, its role in inflammation and the potential for therapeutic modulation in chronic joint diseases.

NF-κB was first described in 1986 as a DNA-binding protein bound to a decameric consensus motif in the immunoglobulin κ light-chain gene enhancer [8]. Since then, NF-κB proteins have been identified in the cytoplasm of every cell type examined. The NF-κB family comprises proteins belonging to the Rel family of transcription factors, which includes five distinct gene products in mammals: RelA (p65), RelB, c-Rel, p50/p105 (NF-κB1), and p52/p100 (NF-κB2) 9., 10., 11., 12.. Although the individual family members have the ability to form a variety of homodimers and heterodimers, RelA/p50 complexes are predominately observed in activated cells and are thus considered the classical NF-κB dimer. All NF-κB/Rel proteins possess a conserved amino-terminal Rel homology domain (RHD), which is required for dimer formation, interaction with inhibitor κB (IκB) proteins, nuclear translocation and sequence-specific DNA binding. In addition, unlike p50 and p52, which are processed from precursor proteins, RelA, c-Rel and RelB possess C-terminal transactivation domains and are therefore capable of directly inducing the transcription of target genes 9., 10., 11., 12.. Knockout studies of individual NF-κB proteins have clearly demonstrated specific biological functions for the various family members, thus providing additional insight into the complex nature of the Rel family of transcription factors 13., 14•..

The activity of NF-κB is regulated through its association with an IκB protein. This class of inhibitory proteins includes IκBα, IκBβ, IκBγ, IκBε, p100, p102, Bcl-3 and the recently described inducible-IκBζ 9., 10., 11., 15•.. Each IκB protein possesses a conserved ankyrin-like repeat domain, which mediates the protein–protein interaction with NF-κB. In addition, IκBα, IκBβ and IκBε contain N-terminal regulatory domains that are required for their signal-induced degradation. To date, IκBα is the best-characterized member of this family.

Section snippets

Regulation of NF-κB activation by IκB and the IκB kinases

In most unstimulated cells, NF-κB is found in an inactive state complexed to an IκB protein 9., 10., 11.. Binding of IκB to NF-κB effectively masks the nuclear localization sequence present in the RHD, resulting in the cytoplasmic sequestration of the NF-κB dimers. However, upon cell activation by stimuli such as cytokines (including TNF-α and IL-1β), endotoxin (lipopolysaccharide, LPS), reactive oxygen intermediates, viral proteins and physical stress, IκB undergoes phosphorylation on two

NF-κB activation and joint inflammation

Constitutive activation of NF-κB has been reported in a number of inflammatory disorders, including asthma [37], inflammatory bowel disease [38] and RA 39., 40.. Immunohistochemical staining for active NF-κB has been demonstrated in the synovium of RA patients 39., 40. and is associated with cells of the intimal lining and vascular endothelium [40]. Activated NF-κB has also been observed in the synovium of OA patients, albeit to a lesser extent. Furthermore, constitutive activation of NF-κB has

Potential points of therapeutic intervention

In light of its important role as a central mediator of inflammation, selective inhibitors of NF-κB should prove to be efficacious anti-inflammatory agents. Interestingly, anti-inflammatory drugs such as glucocorticoids, and high-dose aspirin and sulfasalazine have been reported to decrease NF-κB activation through various mechanisms [48]. As such, some of the anti-inflammatory action of these compounds may be mediated through the inhibition of NF-κB activation. In addition, other small

Conclusions

NF-κB is a master coordinator of inflammatory processes and its role in inflammatory diseases is well established. It is widely believed that the identification of safe, selective inhibitors of NF-κB activation will result in powerful new agents for the treatment of chronic inflammatory disorders. Recent advances in our understanding of the complex molecular mechanisms regulating this signal transduction pathway have yielded numerous potential targets for therapeutic intervention. As compounds

Acknowledgements

The authors acknowledge Elizabeth Capper and Sanjay Kumar for critical reading of the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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