Signaling transduction: target in osteoarthritis

Abstract

Purpose of review: The pathophysiology of osteoarthritis is the result of an imbalance between anabolic and catabolic pathways. This imbalance is the result of the activation of joint cells by inflammatory mediators, matrix components, and mechanical stress. All these mediators act through specific receptors that transmit the signals to the nucleus to activate the transcription of matrix metalloproteinases and inflammatory genes. Targeting these signaling pathways in osteoarthritis is considered a novel approach to modulate this imbalance.

Recent findings: Although many signaling pathways are necessary for physiologic cell life, it is now well established that a few are more specifically induced in an inflammatory environment. In osteoarthritis, the nuclear factor-kappaB and mitogen-activated protein kinase pathways have been shown to play a predominant role in the expression of metalloproteinases and inflammatory genes and proteins. Also involved in the activation of osteoarthritic cells are other molecules interacting with one or several signaling pathways, such as nitric oxide, peroxisome proliferator-activated receptor-gamma ligands, or C/EBP transcriptional factors. Based on this knowledge, specific inhibitors for some of these signaling pathways have been designed and include p38 mitogen-activated protein kinase or nuclear factor-kappaB inhibitors. Experimental studies evaluating cartilage degradation in arthritis models are promising, although fewer have been done specifically in osteoarthritis models.

Summary: Targeting signaling pathways in osteoarthritis did not seem feasible a few years ago because of the complexity of the multiple intracellular pathways, mainly physiologic, defined by a high degree of redundancy and cross-talk. However, important advances in the knowledge of chondrocyte and synoviocyte signaling in osteoarthritis have been achieved in recent years and suggest that inhibitors of specific signaling pathways could shortly provide effective treatments for this disease.