NF-κB Signaling: Multiple Angles to Target OA

Abstract

In the context of OA disease, NF-κB 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-κB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-κB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including β-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-κB 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-κB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-κB 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-κB kinases IKKα or IKKβ or specific activating canonical NF-κB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-κB 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.

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

“…Aging is associated with inflammation through acquisition of a senescence‐associated secretory phenotype (SASP) with IL‐6 and IL‐1 being the most prominent cytokines (Coppe, Desprez, Krtolica & Campisi, 2010). Furthermore, mechanical overloading induces translocation of NF‐κB into the nucleus, stimulation of NF‐κB signaling pathway, and IL‐6 transcription activation in chondrocytes (Marcu, Otero, Olivotto, Borzi & Goldring, 2010; Olivotto, Otero, Marcu & Goldring, 2015). Therefore, biochemical and biomechanical crosstalk among different tissue compartments likely plays an important role in the onset and progression of OA by initiation and maintenance of a persistent low‐grade pro‐inflammatory environment in the joint (Little & Hunter, 2013).…”

Caesalpinia sappan extract inhibits IL1β-mediated overexpression of matrix metalloproteinases in human chondrocytes

“…*indicates significant differences with respect to cells treated with IL1b only (P \ 0.05). # indicates significant differences with respect to untreated controls (P \ 0.05) factors, including NF-kB (Vincenti and Brinckerhoff 2002;Marcu et al 2010). To further explore the mechanism underlying suppression of MMP transcription by CSE, human T/C-28a2 chondrocytes were co-transfected with a MMP-13 reporter construct and p65/p50 expression vectors in the presence or absence of CSE.…”

Laserterapia Em Afecções Locomotoras: Revisão Sistemática De Estudos Experimentais

“…Entretanto, de acordo com Marcu et al 50 , uma vez ativado, controla a expressão de várias citocinas reguladoras da inflamação como, por exemplo, as IL-6, 8 e 10, o fator estimulante de colônias de granulócitos e macrófagos e a proteína quimiotativa para monócitos que, por sua vez, desencadeiam a degradação enzimática da matriz pelas MMPs-1, 3 e 13, e agrecanases. Portanto, o estudo desses autores sugere que a redução da sinalização ao NF-kB revela eficácia da laserterapia.…”