Pathophysiology of osteoarthritis: canonical NF-kappa B/IKK beta-dependent and kinase-independent effects of IKK alpha in cartilage degradation and chondrocyte differentiation

Osteoarthritis (OA), a whole-joint disease driven by abnormal biomechanics and attendant cell-derived and tissue-derived factors, is a rheumatic disease with the highest prevalence, representing a severe health burden with a tremendous economic impact. Members of the nuclear factor kappa B (NF-kappa B) family orchestrate mechanical, inflammatory and oxidative stress-activated processes, thus representing a potential therapeutic target in OA disease. The two pivotal kinases, I kappa B kinase (IKK) alpha and IKK beta, activate NF-kappa B dimers that might translocate to the nucleus and regulate the expression of specific target genes involved in extracellular matrix remodelling and terminal differentiation of chondrocytes. IKK alpha, required for the activation of the so-called non-canonical pathway, has a number of NF-kappa B-independent and kinase-independent functions in vivo and in vitro, including controlling chondrocyte hypertrophic differentiation and collagenase activity. In this short review, we will discuss the role of NF-kappa B signalling in OA pathology, with emphasis on the functional effects of IKK alpha that are independent of its kinase activity and NF-kappa B activation.