Article Text

PDF
SP0076 Proteasome as A Therapeutic Target in Osteoarthritis?
  1. A. Ahmed
  1. Karolinska Institutet, Stockholm, Sweden

Abstract

Osteoarthritis (OA) is a common chronic joint disorder affecting approximately 10% of the population today. Pain is the predominant symptom in patients with OA followed by changes in articular cartilage, subchondral bone, synovial membrane and adjacent supporting connective tissues. The mechanisms of pain in OA remain obscure and the current treatments are mainly symptomatic to reduce the pain and joint replacement surgery at the end stage of disease. Thus, the mediators and mechanisms that monitor pain and inflammation in OA are of great interest in search for new treatment modalities in OA.

The ubiquitin proteasome system (UPS) is one of the recently highlighted systems participating in the mechanisms of pain and inflammation through its effects on pro-nociceptive and pro-inflammatory mediators. UPS is a non-lysosomal proteolytic system of selective degradation of intracellular proteins. It plays an essential role in the activation of transcription factor-κB (NF-κB) through proteolytic degradation of inhibitory protein IκB. NF-κB in turn activates pro-nociceptive and pro-inflammatory mediators such as cytokines and neuropeptides involved in pain and inflammation. Furthermore, UPS-mediated protein degradation promotes osteoclast maturation, which induces cartilage and bone destruction in inflammatory joint disorders such as rheumatoid arthritis and OA.

Recently, we have demonstrated that the inhibition of the UPS by synthetic small molecule, MG132, reduced severity of arthritis and reversed joint pain behavior in animal model of OA. In addition, MG132 therapy reversed the up-regulated expression of pro-nociceptive sensory neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) in knee joint as well as in the dorsal root ganglion, a site of neuropeptide synthesis. Increased levels of SP are reported in the capsule of hip joints and soft tissues in patients with painful OA. MG132 therapy attenuated cartilage and bone destruction and resulted in decreased matrix metalloproteinase -3 (MMP-3) expression in OA knee joint. MMPs, especially MMP-3, exacerbate pathogenesis of OA through proteoglycans degradation. MMP-3 synthesis is regulated by the NF-κB, the activation of which is under the control of UPS.

A robust effect with reversal of pain behavior, attenuated cartilage destruction and decreased SP, CGRP and MMP-3 expression suggest that UPS is one of the intracellular pathways critical for the development of both pain and joint destruction in animal model of OA. Proteasome system may represent a promising system/mechanism for treatment modality in OA. Thus, novel safe proteasome inhibitors with limited adverse effects would be beneficial to attenuate the development of arthritis and hence reduce the pain.

Disclosure of Interest None declared

DOI 10.1136/annrheumdis-2014-eular.6331

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.