Hip and Knee Osteoarthritis, Not Nonsteroidal Anti-Inflammatory Drugs, are Linked to Cardiac Disease.

BACKGROUND: In 2005, the Food and Drug Administration placed a black-box warning (the most stringent warning for drugs) on all nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) stating that these agents may cause heart attacks and/or strokes. No level I evidence demonstrates that nonselective NSAIDs increase cardiovascular risk. An alternative hypothesis is that hip and knee osteoarthritis (OA) indirectly causes cardiovascular disease (CVD) through decreased activity and NSAIDs are correlated with CVD as an arthritis treatment. METHODS: Systematic reviews were conducted to find observational studies evaluating the association of hip and/or knee OA, CVD, activity, walking, and step counts. The systematic review found studies correlating hip and/or knee OA and CVD morbidity incidence (n = 2); CVD morbidity prevalence (n = 6); odds ratios, relative risks, or hazard ratios of CVD morbidity (n = 11); relative risk, standardized mortality ratios, or hazard ratios of CVD mortality (n = 14); and all-cause mortality hazard ratios associated with NSAID use (n = 3). RESULTS: Hip OA (5 studies), knee OA (9 studies), and hip and knee OA (6 studies) are linked to an increased risk of CVD morbidity and mortality. Cardiac risk increases with validated disability scores, use of walking aids, walking difficulties, longer follow-up times, younger ages of OA onset, numbers of joints involved, and OA severities. No study linked NSAID use to cardiac disease. CONCLUSIONS: All studies with more than 10-year follow-up linked cardiac disease with hip and knee OA. No study linked nonselective NSAID use to CVD. The Food and Drug Administration should reconsider the black-box warnings on naproxen, ibuprofen, and celecoxib.

Sir2 and Fun30 regulate ribosomal DNA replication timing via Mcm helicase positioning and nucleosome occupancy.

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well-known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). We have previously reported that in the absence of SIR2, a derepressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the non-displaced MCMs. Furthermore, we found that both, activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.