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Background: Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures. Methods: We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach. Results: PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065). Conclusions: Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks. [ABSTRACT FROM AUTHOR]

Objective The inflammatory response following an articular fracture is thought to play a role in the development of posttraumatic arthritis (PTA) but has not been well characterized. The objective of this study was to characterize the acute inflammatory response, both locally and systemically, in joint synovium, synovial fluid (SF), and serum following articular fracture of the ankle. We hypothesized that intraarticular fracture would alter the synovial environment and lead to increased local and systemic inflammation. Methods Synovial tissue biopsy specimens, SF samples, and serum samples were collected from patients with an acute articular ankle fracture (n = 6). Additional samples (normal, ankle osteoarthritis [OA], and knee OA [n = 6 per group]) were included for comparative analyses. Synovial tissue was assessed for synovitis and macrophage count. SF and serum were assessed for cytokines (interferon-γ [IFNγ], interleukin-1β [IL-1β], IL-6, IL-8, IL-10, IL-12p70, and tumor necrosis factor α) and chemokines (eotaxin, eotaxin 3, IFNγ-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], MCP-4, macrophage-derived chemokine, macrophage inflammatory protein 1β, and thymus and activation-regulated chemokine). Results Synovitis scores were significantly higher in ankle fracture tissue compared with normal ankle tissue ( P = 0.007), and there was a trend toward an increased abundance of CD68+ macrophages in ankle fracture synovium compared with normal knee synovium ( P = 0.06). The concentrations of all cytokines and chemokines were elevated in the SF of patients with ankle fracture compared with those in SF from OA patients with no history of trauma. Only the concentration of IL-6 was significantly increased in the serum of patients with ankle fracture compared with normal serum ( P = 0.027). Conclusion Articular fracture of the ankle increased acute local inflammation, as indicated by increased synovitis, increased macrophage infiltration into synovial tissue, and increased SF concentrations of biomarkers of inflammation. Characterizing the acute response to articular fracture provides insight into the healing process and may help to identify patients who may be at greater risk of PTA. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between NF-κB activity, cytokine levels, and pain sensitivities in a rodent model of osteoarthritis (OA). Methods OA was induced in transgenic NF-κB-luciferase reporter mice via intraarticular injection of monosodium iodoacetate (MIA). Using luminescence imaging we evaluated the temporal kinetics of NF-κB activity and its relationship to the development of pain sensitivities and serum cytokine levels in this model. Results MIA induced a transient increase in joint-related NF-κB activity at early time points (day 3 after injection) and an associated biphasic pain response (mechanical allodynia). NF-κB activity, serum interleukin-6 (IL-6), IL-1β, and IL-10 levels accounted for ∼75% of the variability in pain-related mechanical sensitivities in this model. Specifically, NF-κB activity was strongly correlated with mechanical allodynia and serum IL-6 levels in the inflammatory pain phase of this model (day 3), while serum IL-1β was strongly correlated with pain sensitivities in the chronic pain phase of the model (day 28). Conclusion Our findings suggest that NF-κB activity, IL-6, and IL-1β may play distinct roles in pain sensitivity development in this model of arthritis and may distinguish the acute pain phase from the chronic pain phase. This study establishes luminescence imaging of NF-κB activity as a novel imaging biomarker of pain sensitivities in this model of OA. [ABSTRACT FROM AUTHOR]

Objective To test the hypotheses that obesity due to a very high-fat diet induces knee osteoarthritis (OA), and that short-term wheel-running exercise protects against obesity-induced knee OA by reducing systemic inflammation and metabolic dysregulation. Methods Male C57BL/6J mice were fed either a control diet (13.5% kcal from fat) or a very high-fat diet (60% kcal from fat) from age 12 weeks to age 24 weeks. From 20 to 24 weeks of age, half of the mice were housed with running wheels. The severity of knee OA was determined by assessing histopathologic features, and serum cytokines were measured using a multiplex bead immunoassay and enzyme-linked immunosorbent assays. Body composition was quantified by dual-energy x-ray absorptiometry, and insulin resistance was assessed by glucose tolerance testing. Results Feeding mice with a very high-fat diet increased knee OA scores and levels of serum leptin, adiponectin, KC (mouse analog of interleukin-8 [IL-8]), monokine induced by interferon-γ (CXCL9), and IL-1 receptor antagonist to an extent in proportion to the gain in body fat (3-fold increase in percent body fat compared to controls). Wheel-running exercise reduced progression of OA in the medial femur of obese mice. In addition, exercise disrupted the clustering of cytokine expression and improved glucose tolerance, without reducing body fat or cytokine levels. Conclusion Obesity induced by a very high-fat diet in mice causes OA and systemic inflammation in proportion to body fat. Increased joint loading is not sufficient to explain the increased incidence of knee OA with obesity, as wheel running is protective rather than damaging. Exercise improves glucose tolerance and disrupts the coexpression of proinflammatory cytokines, suggesting that increased aerobic exercise may act independently of weight loss in promoting joint health. [ABSTRACT FROM AUTHOR]