"Go upstream, young man": lessons learned from the p38 saga

Abstract

Despite the success of biological therapies in rheumatoid arthritis (RA), orally active small-molecule drugs are desirable. Signal transduction inhibitors have been the focus of intense efforts, with some recent notable successes and failures. p38alpha is a signalling molecule that regulates proinflammatory cytokines, which makes it a logical target for RA. Unfortunately, selective p38alpha inhibitors have limited efficacy. An attempt is made here to put these studies into perspective and offer possible explanations for the failure of p38alpha blockers. Alternative strategies, such as targeting kinases higher in the signalling cascade or using less selective compounds, might be more successful as suggested by the efficacy seen with Syk and JAK inhibitors.

Figure 1

A simplified mitogen-activated protein kinase (MAPK) pathway: complex parallel and crossover signalling cascades link the three main MAPK families, extracellular-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38, which are activated by cytokines, stress and growth factors. The top level shows the MAP3Ks, the second tier shows the upstream MAPK kinases (MKKs) and the third tier comprises the MAPKs (ERK, JNK, p38) that regulate various genes through phosphorylation of transcription factors (eg, c-Jun, ATF2) and other kinases (MAPKAPK2/MK2). The primary, but overlapping, responses include cell growth and differentiation (ERK), matrix regulation (JNK) and inflammatory cytokine production (p38). Reprinted by permission from MacMillan Publishers Ltd: Nat Clin Pract Rheumatol 2007;3:651–60, copyright©2007. http://www.nature.com/clinicalpractice/index

Figure 2

Kinetic analysis of synovial signalling and gene expression in animal models of arthritis. (Top) Disease severity scores in K/BxN and collagen-induced arthritis (CIA) models. Passive K/BxN arthritis was induced by injecting mice with arthritogenic serum from K/BxN mice (n = 4/time point) on day 0. For CIA, mice were immunised on day 0 and day 20 (n = 6/time point). Arthritis was quantified using a clinical scoring system with maximum score of 16. (Middle) Kinetics of p38 activation in arthritic mice; (Bottom) interleukin 6 (IL6) gene expression in arthritic synovium. *p<0.05. Joints from mice were collected at the indicated time points and assayed for phospho-p38 (P-p38) by western blot analysis and for IL6 by quantitative PCR. Note that the time course for IL6 expression, p38 activation and clinical evidence of arthritis do not always correlate. The interpretation of animal model data requires careful consideration of the differences with rheumatoid arthritis. Data modified from Fukushima et al.