Circadian Clock Disruption as a Novel Mechanism to Influence Osteoarthritis Risk in Aging Populations - PROJECT SUMMARY/ABSTRACT Half of US adults age 65 or older report doctor-diagnosed arthritis, with osteoarthritis being the most common type. While osteoarthritis is strongly associated with aging, the mechanisms through which the aging process influences osteoarthritis risk and progression are still being explored. Circadian rhythm disruptions could be a key component. Laboratory studies indicate that circadian rhythms are important factors for maintaining homeostasis of the joint tissues. And genetic and environmental disruption of the circadian clock can lead to osteoarthritis -like cartilage degeneration in rodent models. Circadian clock disruptions also increase risk of obesity, a key osteoarthritis risk factor. But little is known about the relationship between circadian clock disruption and osteoarthritis risk in human populations. Shift work, particularly night shift work, is an extreme, but common example of such a disruption in the real-world. To better understand the links between shift work, circadian clock disruption, and osteoarthritis, our goal is to evaluate the effect of duration of time in night shift work and age at night shift work on osteoarthritis risk (Aim 1) and examine the influence of chronotype on these associations (Aim 2). We will use the UK Biobank, a prospective cohort of half a million people in the United Kingdom with data on genotype, shift work, and other relevant factors for osteoarthritis risk such as age, sex, heavy manual labor, socioeconomic status, and body mass index. Frequency of night shift work is reported by all working UK Biobank participants. Through the National Health Service, the full cohort is linked to hospital data and half the cohort is linked to primary care data, providing reliable means to ascertain osteoarthritis diagnoses and joint arthroplasty. Our team has extensive experience with UK Biobank, with particular expertise examining occupational and genetic risk factors for musculoskeletal disease. Aim 1 will focus on a 100,000-person subset of UK Biobank that reported lifetime job histories, including history of shift work. Associations of years duration of night shift work and night shift work done at different ages will be estimated with osteoarthritis endpoints. For Aim 2, associations of shift work with osteoarthritis endpoints will be estimated in analyses stratified by chronotype, considering both self-reported chronotype and genetic chronotype. Evaluation of the effect of duration of night shift work, age at night shift work, and the modification of effects by chronotype will be a critical step forward in determining if these associations are indicative of the effects of circadian rhythm disruption on osteoarthritis and identifying populations that may be most vulnerable. Circadian clock disruption may be a novel risk factor for osteoarthritis that influences cartilage degeneration both through effects on obesity, and obesity-independent pathways. These disruptions could be a crucial piece of the relationship between aging and osteoarthritis. Importantly, as lifestyle changes and chronotherapy can reduce circadian clock disruptions, these findings can point to new potential ways to prevent osteoarthritis development and progression.
