Does Shiftwork Sleep Disorder Exacerbate OA Outcomes

About This Grant

PROJECT SUMMARY Chronic sleep disruption has recently been implicated in osteoarthritis (OA) pathology. Sleep is chronically disrupted for the millions of American workers with schedules outside of normal 9am- 5pm hours (shift workers) which are up to 49% more likely to develop OA relative to daytime counterparts. These data indicate sleep plays an important role in OA onset and likely progression; however little is known about how sleep relates to OA and there are few animal studies examine how disrupted sleep relates to OA onset and progression. This proposal intends to address that knowledge gap by leveraging a unique expertise in animal phenotyping of both sleep and post-traumatic OA (PTOA) with novel noninvasive sensor approaches to investigate the first connections between shift work schedules that disrupt sleep and PTOA pain, disability, and tissue damage in both sexes. The overarching objective of our research program is to quantify causal links between sleep and PTOA pain, tissue damage, and disability in preclinical models using the following aims. Aim1 will investigate whether shift work sleep schedules exacerbate PTOA pain, disability, and tissue damage in a surgical mouse model of knee PTOA. we hypothesize that mice experiencing shift work schedules disrupting sleep will have worse PTOA outcomes in pain, disability, and tissue damage compared to mice with normal sleep schedules. Results of this aim will provide the first rich datasets evaluating sleep impacts on PTOA, opening new avenues of inquiry for subsequent investigations of mechanistic sleep impacts in PTOA, other OA, and the clinic. Aim 2 will Determine whether sleep-disrupting shift work schedules attenuate PTOA pain relief from the promising analgesic and potential disease modifying drug, Celecoxib. We hypothesize that Celecoxib analgesia will be reduced in animals with disrupted sleep compared to those with normal sleep. Results of this aim will generate knowledge of cyclooxygenase-2 roles in the sleep-PTOA axis, providing the first evidence that sleep disruption may alter efficacy of Celecoxib with implications for other forms of OA and drugs with similar mechanistic pathways. Overall, This work will determine whether shiftwork schedules exacerbate preclinical PTOA outcomes and response Celecoxib. This information will help clinicians identify higher-risk patients and recommend more effective PTOA pain management regimes, furthering the goals of NIAMS by increasing our understanding of understudied risk factors that contribute to OA onset, pathogenesis, and variability in health outcomes.