Impacts of Eccentric Resistance Exercise on DNA Methylation of Candidate Genes for Inflammatory Cytokines in Skeletal Muscle and Leukocytes of Healthy Males.

Physical inactivity and a poor diet increase systemic inflammation, while chronic inflammation can be reduced through exercise and nutritional interventions. The mechanisms underlying the impacts of lifestyle interventions on inflammation remain to be fully explained; however, epigenetic modifications may be critical. The purpose of our study was to investigate the impacts of eccentric resistance exercise and fatty acid supplementation on DNA methylation and mRNA expression of TNF and IL6 in skeletal muscle and leukocytes. Eight non-resistance exercise-trained males completed three bouts of isokinetic eccentric contractions of the knee extensors. The first bout occurred at baseline, the second occurred following a three-week supplementation of either omega-3 polyunsaturated fatty acid or extra virgin olive oil and the final bout occurred after eight-weeks of eccentric resistance training and supplementation. Acute exercise decreased skeletal muscle TNF DNA methylation by 5% (p = 0.031), whereas IL6 DNA methylation increased by 3% (p = 0.01). Leukocyte DNA methylation was unchanged following exercise (p > 0.05); however, three hours post-exercise the TNF DNA methylation decreased by 2% (p = 0.004). In skeletal muscle, increased TNF and IL6 mRNA expression levels were identified immediately post-exercise (p < 0.027); however, the leukocyte mRNA expression was unchanged. Associations between DNA methylation and markers of exercise performance, inflammation and muscle damage were identified (p < 0.05). Acute eccentric resistance exercise is sufficient to induce tissue-specific DNA methylation modifications to TNF and IL6; however, neither eccentric training nor supplementation was sufficient to further modify the DNA methylation.

Short-term pain trajectories in patients with knee osteoarthritis.

AIM: It is unknown if pain in knee osteoarthritis (KOA) follows distinct patterns over the short term. Therefore, the aim of this study was to identify whether persons with a previous history of KOA pain fluctuations have distinct trajectories of pain over 90 days and to examine associations between baseline characteristics and pain trajectories. METHOD: People with a previous history of KOA were selected from a web-based longitudinal study. Baseline variables were sex, age, being obese/overweight, years of KOA, knee injury, knee buckling, satisfactory Lubben Social Support Score, pain and stress scales, Intermittent Constant Osteoarthritis Pain Score (ICOAP), medication use, and physical activity. Participants completed a Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain subscale (KOOS-p, rated 0 = extreme to 100 = no knee problems) at 10-day intervals for 90 days. Short-term KOOS-p trajectories were identified using latent growth mixture modeling and the baseline risk factors for these pain trajectories were examined. RESULTS: Participants (n = 313) had a mean age of 62.2 (SD ± 8.1) years and and a body mass index of 29.8 (SD ± 6.6) kg/m2 . The three-class latent growth mixture modeling quadratic model with best fit indices was chosen (based on lowest sample-size-adjusted Bayesian Information Criterion, high probability of belonging, interpretability). Three distinct pain trajectory clusters (over 90 days) were identified: low-moderate pain at baseline with large improvement (n = 11), minimal change in pain over 90 days (n = 248), and moderate-high pain with worsening (n = 46). Higher ICOAP (intermittent scale), perceived stress, negative affect score, and knee buckling at baseline were associated with a worse knee pain trajectory (P < 0.05). CONCLUSIONS: Persons with KOA showed unique short-term pain trajectories over 90 days, with distinct characteristics at baseline associated with each trajectory.

Is being barefoot, wearing shoes and physical activity associated with knee osteoarthritis pain flares? Data from a usually barefoot Sri Lankan cohort.

AIM: To identify the association between hours of being barefoot/wearing footwear, physical activity (PA) and knee osteoarthritis pain flares (KOAF). METHODS: Persons with a diagnosis of knee osteoarthritis, who reported previous KOAF, were followed up in a 3 months long telephone-based case-crossover study. Exposures to risk factors were assessed every 10 days and whenever the participants experienced a KOAF. Conditional logistic regression examined associations of KOAF with following: hours of being barefoot/using footwear and PA performed (P < .05). RESULTS: There were 260 persons recruited, of whom 183 continued longitudinal follow up. Of them, 120 persons had at least one valid KOAF and control period. Participants were female (90%) with mean (SD) age and body mass index of 59.9 (7.0) years, 28.0 (5.0) kg/m2 respectively. Participants were barefoot for a mean duration of 12.7 hours (SD 4.6) and used footwear for 5.1 (SD 4.7) hours daily; 99% wore heel heights <2.5 cm. Duration of being barefoot, 1 and 2 days before, demonstrated reduced multivariate odds of KOAF (odds ratio [OR] = 0.85; 95% CI 0.80-0.90). Moderate PA performed 1, 2 days prior was associated with a significantly increased risk of KOAF (multivariate OR 4.29; 2.52-7.30 and OR 3.36; 2.01-5.61). Similarly, hours of using footwear 1 and 2 days before flare demonstrated increased odds of KOAF (OR 1.15; 1.07-1.23 and 1.10; 1.03-1.18). CONCLUSIONS: Increased duration of being barefoot 1 to 2 days before is associated with reduced risk of KOAF. Performing moderate PA 1 to 2 days before was associated with an increased risk of KOAF.

Impact of aerobic exercise and fatty acid supplementation on global and gene-specific DNA methylation.

Lifestyle interventions, including exercise and dietary supplementation, can modify DNA methylation and exert health benefits; however, the underlying mechanisms are poorly understood. Here we investigated the impact of acute aerobic exercise and the supplementation of omega-3 polyunsaturated fatty acids (n-3 PUFA) and extra virgin olive oil (EVOO) on global and gene-specific (PPARGC1A, IL6 and TNF) DNA methylation, and DNMT mRNA expression in leukocytes of disease-free individuals. Eight trained male cyclists completed an exercise test before and after a four-week supplementation of n-3 PUFA and EVOO in a double-blind, randomised, repeated measures design. Exercise triggered global hypomethylation (Pre 79.2%; Post 78.7%; p = 0.008), alongside, hypomethylation (Pre 6.9%; Post 6.3%; p < 0.001) and increased mRNA expression of PPARGC1A (p < 0.001). Associations between PPARGC1A methylation and exercise performance were also detected. An interaction between supplement and trial was detected for a single CpG of IL6 indicating increased DNA methylation following n-3 PUFA and decreased methylation following EVOO (p = 0.038). Global and gene-specific DNA methylation associated with markers of inflammation and oxidative stress. The supplementation of EVOO reduced DNMT1 mRNA expression compared to n-3 PUFA supplementation (p = 0.048), whereas, DNMT3a (p = 0.018) and DNMT3b (p = 0.046) mRNA expression were decreased following exercise. In conclusion, we demonstrate that acute exercise and dietary supplementation of n-3 PUFAs and EVOO induce DNA methylation changes in leukocytes, potentially via the modulation of DNMT mRNA expression. Future studies are required to further elucidate the impact of lifestyle interventions on DNA methylation.

Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics.

INTRODUCTION: Osteoarthritis (OA) is a leading cause of pain and disability among adults with a current prevalence of around 15% and a predicted prevalence of 35% in 2030 for symptomatic OA. It is increasingly recognized as a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity. Current therapeutic regimens for OA are only partially effective and often have significant associated toxicities. There are no disease-modifying drugs approved by the regulatory bodies. Areas covered: We reviewed the opportunities within key OA pathogenetic mechanism: cartilage catabolism/anabolism, pathological remodeling of subchondral bone and synovial inflammation to identify targeted disease-modifying osteoarthritis drugs, based on compounds currently in Phase II and III stages of clinical development in which x-ray and/or MRI was used as the structural outcome with/without symptomatic outcomes according to regulatory requirements. Expert opinion: Given the heterogeneity of the OA disease process and complex overlapping among these phenotypes, a 'one size fits all' approach used in most clinical trials would unlikely be practical and equally effective in all patients, as well as in all anatomical OA sites. On the other hand, it is a challenge to develop a targeted drug with high activity, specificity, potency, and bioavailability in the absence of toxicity for long-term use in this chronic disease of predominantly older adults. Further research and insight into evaluation methods for drug-targeted identification of early OA and specific characterization of phenotypes, improvement of methodological designs, and development/refinement of sensitive imaging and biomarkers will help pave the way to the successful discovery of disease-modifying drugs and the optimal administration strategies in clinical practice.

Does knee malalignment predict the efficacy of realignment therapy for patients with knee osteoarthritis?

BACKGROUND: Realignment therapies, including knee braces, foot orthoses and shoes are prescribed to patients with medial knee osteoarthritis (OA) with the goal of unloading the medial tibiofemoral (TF) compartment. It is uncertain whether realignment therapies have different effects in those with knee malalignment. We studied whether the efficacy of realignment therapy for pain and function in persons with medial TF OA is predicted by the severity of the baseline knee malalignment. METHODS: The baseline characteristics of 48 participants with moderate to severe medial knee OA were collected. Participants' pain and function were measured using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale before and after 12 weeks of realignment therapy using a valgus unloader knee brace plus bilateral neutral foot orthoses and motion control shoes. Anatomical axis (AA) was measured on weight-bearing knee radiographs by a blinded reader and knee malalignment was categorized as either varus malaligned (moderate or severe) or neutral according to the AA angle. We assessed for differences in response to treatment according to alignment category. General linear statistical models were generated to determine which of the measured alignment variables and covariates predicted change in the pain outcome. RESULTS: Anatomical axis knee alignment was not a significant predictor of pain or function change with active treatment. Baseline WOMAC scores were the best predictor of change in WOMAC (P < 0.01 and P = 0.06 for pain and function, respectively). CONCLUSIONS: Baseline knee alignment did not predict the efficacy of 12 weeks realignment therapy in participants with medial tibiofemoral OA. [Correction added on 27 August 2015, after first online publication: 'did predict' has been corrected to 'did not predict' in the conclusions of the abstract section.].

Effect of low-level laser therapy (904 nm) and static stretching in patients with knee osteoarthritis: a protocol of randomised controlled trial.

BACKGROUND: Osteoarthritis (OA) is a highly prevalent and disabling disease. It is estimated that by 2030 the prevalence of symptomatic OA could reach 30 % of the population above 60 years. This randomised controlled trial will investigate the effect of low-level laser therapy (LLLT) and static stretching exercises, as monotherapy and in combination, on pain, quality of life, function, mobility, knee range of motion (KROM) and hamstring shortening in participants with knee OA. METHODS: This study will involve 145 people aged 50-75 years with symptomatic-radiographic knee OA. It will consist of two types of treatments: Low-level laser therapy (LLLT) and stretching exercises. The patients will be randomly allocated to five groups LLLTACTIVE+Stretch, LLLTPLACEBO+Stretch, Stretch, LLLT and Control (n = 29 each). Treatment frequency will be three sessions/week for all active groups. LLLT will involve the use of a Gallium-Arsenide laser (904 nm, 40 milliwatts, 3 J/point, 27 J/knee) over 24 sessions for the monotherapy group and 9 sessions for the LLLT+Stretch groups. Stretching will consist of seven exercises completed over 24 sessions. The control group will receive a booklet. Participants will be treated for 2 months (Stretch, LLLT and Control groups) or 3 months (LLLT + Stretch groups). Participants and the outcome assessor will be blind to treatment allocation throughout the study. The primary outcome is pain measured by Visual Analogue Scale. Secondary outcomes include quality of life assessed by Western Ontario and McMaster Universities Arthritis Index, function by Lequesne Algofunctional Index, mobility by Timed Up and Go Test, KROM by goniometry of knee flexion and hamstring shortening by popliteal angle. The statistical method will follow the principles of per-protocol analysis. DISCUSSION: Although exercise therapy is considered an effective treatment in patients with knee osteoarthritis, the knowledge of which exercise modalities would be the most appropriate for this population is lacking. LLLT has been used as resource to increase the effects of physical therapy. However, the specific dose and treatment frequency need to be better defined. The findings from this randomised controlled trial will provide evidence of the efficacy or otherwise, of LLLT and stretching exercises in the management of knee OA symptoms. TRIAL REGISTRATION: NCT01738737  at ClinicalTrials.gov.

Emerging drugs for the treatment of knee osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is the most prevailing form of joint disease, with symptoms affecting 10 - 12% of the adult population with a projection of a 50% increase in prevalence in the next two decades. The disease characteristics are defined by articular cartilage damage, low-grade synovial inflammation and hypertrophic bone changes, leading to pain and functional deterioration. To date, available pain treatments are limited in their efficacy and have associated toxicities. No structural disease modification agents have been approved by regulatory agencies for this indication. AREAS COVERED: We reviewed drugs in Phase II - III for OA pain and joint structure modification. Different aspects of structure modification are divided into targets of inflammatory pathway, cartilage catabolism and anabolism, and subchondral bone remodeling. EXPERT OPINION: Further insight into the pathophysiology of the disease will allow for development of novel target classes focusing on the link between symptomatology and structural changes. Given the complexity of OA, one single therapy is unlikely to be universally and uniformly effective. Promising therapies are under development, but there are obstacles in the translation of treatment from preclinical models and trial designs need to be cognizant of the complex reasons for previous trial failures.

High frequency of meniscal hypertrophy in persons with advanced varus knee osteoarthritis.

To examine the morphological changes of the medial meniscus in advanced knee osteoarthritis (OA) we examined 167 knee joints of 106 patients who subsequently underwent total knee joint arthroplasty from January to May, 2007. All 106 patients were females and their ages ranged from 57 to 83 years (mean 68.7 +/- 5.6 years). For patients with complete loss of medial joint space by weight-bearing radiography, the meniscal position was assessed by measuring meniscal subluxation and meniscal height. Meniscal morphology was assessed using a modified WORMS MRI-based method. Description of the prevalence of different meniscal morphologies and their respective positions are presented. The predominant type (32.2, 64.1 and 83.8% in anterior horn, mid-body and posterior horn, respectively) of meniscal morphology abnormality was a hypertrophied displaced tear. Medial meniscus height was found to be higher than lateral meniscus height. In persons with an hypertrophied meniscus the height of the medial meniscus was 8.06 +/- 1.15, 10.03 +/- 1.79, and 8.61 +/- 1.57 mm at anterior horn, mid-body and posterior horn, respectively, compared to those in other categories whose height was 6.04 +/- 0.92, 5.08 +/- 1.68 and 6.43 +/- 1.26 mm. A large proportion of persons with end stage varus knee OA have a paradoxically hypertrophied medial meniscus. This new finding of hypertrophied menisci highlights that not all menisci in persons with end stage OA are macerated or destroyed.