Catabolic cytokines disrupt the circadian clock and the expression of clock-controlled genes in cartilage via an NFкB-dependent pathway

Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

Signaling by the transcription factor nuclear factor kappa B (NF-kappaB) involves its release from inhibitor kappa B (IkappaB) in the cytosol, followed by translocation into the nucleus. NF-kappaB regulation of IkappaBalpha transcription represents a delayed negative feedback loop that drives oscillations in NF-kappaB translocation. Single-cell time-lapse imaging and computational modeling of NF-kappaB (RelA) localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased IkappaBalpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of RelA phosphorylation and dephosphorylation. The functional consequences of NF-kappaB signaling may thus depend on number, period, and amplitude of oscillations.

Although older age is the greatest risk factor for osteoarthritis (OA), OA is not an inevitable consequence of growing old. Radiographic changes of OA, particularly osteophytes, are common in the aged population, but symptoms of joint pain may be independent of radiographic severity in many older adults. Ageing changes in the musculoskeletal system increase the propensity to OA but the joints affected and the severity of disease are most closely related to other OA risk factors such as joint injury, obesity, genetics and anatomical factors that affect joint mechanics. The ageing changes in joint tissues that contribute to the development of OA include cell senescence that results in development of the senescent secretory phenotype and ageing changes in the matrix including formation of advanced glycation end-products that affect the mechanical properties of joint tissues. An improved mechanistic understanding of joint ageing will likely reveal new therapeutic targets to slow or halt disease progression. The ability to slow progression of OA in older adults will have enormous public health implications given the ageing of our population and the increase in other OA risk factors such as obesity. Copyright 2009 Elsevier Ltd. All rights reserved.