NF-kappa B Signaling: Multiple Angles to Target OA

作者：Marcu Kenneth B^*; Otero Miguel; Olivotto Eleonora; Borzi Rosa Maria; Goldring Mary B

来源：Current Drug Targets, 2010, 11(5): 599-613.

• Cartilage
• chondrocytes
• homeostasis
• hypertrophy
• inflammation
• osteoarthritis
• NF-kappa B and IKKs

In the context of OA disease, NF-kappa B transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-kappa B regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-kappa B also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a "loss of maturational arrest" that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-kappa B signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-kappa B activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-kappa B activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-kappa B kinases IKK alpha or IKK beta or specific activating canonical NF-kappa B subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-kappa B inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects.

• 出版日期2010-5