Amino acid racemization reveals differential protein turnover in osteoarthritic articular and meniscal cartilages

INTRODUCTION: Certain amino acids within proteins have been reported to change from the L form to the D form over time. This process is known as racemization and is most likely to occur in long-lived low-turnover tissues such as normal cartilage. We hypothesized that diseased tissue, as found in an osteoarthritic (OA) joint, would have increased turnover reflected by a decrease in the racemized amino acid content. METHODS: Using high-performance liquid chromatography methods, we quantified the L and D forms of amino acids reported to racemize in vivo on a biological timescale: alanine, aspartate (Asp), asparagine (Asn), glutamate, glutamine, isoleucine, leucine (Leu), and serine (Ser). Furthermore, using a metabolically inactive control material (tooth dentin) and a control material with normal metabolism (normal articular cartilage), we developed an age adjustment in order to make inferences about the state of protein turnover in cartilage and meniscus. RESULTS: In the metabolically inactive control material (n = 25, ages 13 to 80 years) and the normal metabolizing control material (n = 19, ages 17 to 83 years), only Asp + Asn (Asx), Ser, and Leu showed a significant change (increase) in racemization with age (P < 0.01). The age-adjusted proportions of racemized to total amino acid (D/D+L expressed as a percentage of the control material) for Asx, Ser, and Leu when compared with the normal articular cartilage control were 97%, 74%, and 73% in OA meniscal cartilage and 97%, 70%, and 78% in OA articular cartilage. We also observed lower amino acid content in OA articular and meniscal cartilages compared with normal articular cartilage as well as a loss of total amino acids with age in the OA meniscal but not the OA articular cartilage. CONCLUSIONS: These data demonstrate comparable anabolic responses for non-lesioned OA articular cartilage and OA meniscal cartilage but an excess of catabolism over anabolism for the meniscal cartilage

Imaging Biomarker Validation and Qualification Report: 6th OARSI Workshop on Imaging in Osteoarthritis Combined with 3rd OA Biomarkers Workshop.

Summary The sixth Osteoarthritis Research Society International (OARSI) Workshop on Imaging in Osteoarthritis combined with the third osteoarthritis (OA) Biomarkers Workshop is the first to bring together the imaging and molecular biomarker communities to focus on clinical validation and qualification of OA biomarkers. The workshop was held in Hilton Head, SC, USA, from June 12–14, 2012; 138 attendees participated, including representatives from academia, pharmaceutical and magnetic resonance imaging (MRI) industries, Food and Drug Administration (FDA), and National Institutes of Health (NIH). Presentations and discussions raised awareness, consolidated knowledge, and identified strategies to overcome challenges for the development and application of imaging and biochemical biomarkers in OA research studies and clinical trials. Conclusion The OA research communities need to work alongside regulatory agencies across the world, to qualify and validate new chemical and imaging biomarkers for future research and clinical trials

Higher dietary diversity scores and protein-rich food consumption were associated with lower risk of all-cause mortality in the oldest old

Background & aims: Dietary diversity is widely advocated in national and international recommendations although whether the beneficial effects on survival or longevity still apply in the final phase of the lifespan remains understudied. We aimed to prospectively examine the association of dietary diversity, food items with all-cause mortality among the oldest old (80+) and determine whether dietary diversity recommendations were appropriate for this population. Methods: The study included 28,790 participants aged 80+ (9957 octogenarians, 9925 nonagenarians, and 8908 centenarians). A baseline dietary diversity score (DDS) was constructed based on nine food items of a food frequency questionnaire. Cox models with penalized splines evaluated non-linear associations of DDS as continuous variable with mortality to identify cut-offs of DDS. Results: We documented 23,503 deaths during 96,739 person-years of follow-up. Each one unit increase in DDS was associated with a 9% lower risk of mortality (adjusted hazard ratio (HR): 0.91; 95% confidential interval (CI): 0.90–0.92). Compared to participants whose DDS less than 2 scores, those with a DDS of 2, 3, 4, 5, and higher than 6 scores had a lower mortality risk, the HRs were 0.86 (0.82–0.89), 0.78 (0.75–0.81), 0.69 (0.66–0.72), 0.65 (0.62–0.68), and 0.56 (0.53–0.58) respectively, and a significant trend emerged (p \u3c 0.001). Protein-rich food items were associated with prominent beneficial effects on mortality including meat (HR and 95% CI for high vs low frequency: 0.70 (0.68–0.72)), fish and sea food (HR, 0.74 (0.72–0.77)), egg (HR, 0.75 (0.73–0.77)), and bean (HR, 0.80 (0.78–0.82)). Conclusions: Even after the age of 80, the DDS tool may offer a simple and straightforward mean of identifying and screening individuals at high risk for mortality. Recommendation of dietary diversity, especially consumption of protein-rich food, may be advocated to reduce mortality risk and promote longevity in the oldest old

Long-term exposure to PM\u3csub\u3e2.5\u3c/sub\u3e and incidence of disability in activities of daily living among oldest old

Currently the Chinese government has adopted World Health Organization interim target-1 values as the national ambient air quality standards values. However, the population-based evidence was insufficient, especially for the oldest old (aged 80+). We evaluated the association of fine particulate matters (PM2.5) exposure and incidence of disability in activities of daily living (ADL) in 15 453 oldest old in 886 counties/cities in China from 2002 to 2014 using Cox model with penalized splines and competing risk models to evaluate the linear or non-linear association. After adjusting for potential confounders, a J-shaped association existed between PM2.5 exposure with a threshold concentration of 33 μg/m3, and incident disability in ADL. Above this threshold, the risk magnitude significantly increased with increase of PM2.5 concentrations; compared to 33 μg/m3, the hazard ratio ranged from 1.03 (1.00–1.06) at 40 μg/m3 to 2.25 (1.54–3.29) at 110 μg/m3. The risk magnitude was not significantly changed below this threshold. Each 10 μg/m3 increase in PM2.5 exposure corresponded to a 7.7% increase in the risk of disability in ADL (hazard ratio 1.077, 95% CI 1.051–1.104). Men, smokers, and participants with cognitive impairment might be more vulnerable to PM2.5 exposure. The study provided limited population-based evidence for the oldest old and detected a threshold of 33 μg/m3, and supported that reduction to current World Health Organization interim target-1value (35 μg/m3) and Chinese national ambient air quality standards (35 μg/m3) or lower may be associated with lower risk of disability in ADL

Inverse association of general joint hypermobility with hand and knee osteoarthritis and serum cartilage oligomeric matrix protein levels

Extensive joint hypermobility, lower serum cartilage oligomeric matrix protein (COMP), and early-onset osteoarthritis (OA) are phenotypes of inherited pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). However, few studies have evaluated the association between articular hypermobility and primary OA. Therefore, we evaluated this association and tested the hypothesis that COMP level is associated with hypermobility in OA and non-OA individuals

Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations

BACKGROUND: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs. OBJECTIVE: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease. METHODS: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients. RESULTS: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity. CONCLUSION: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials

Revisiting the Association of Blood Pressure with Mortality in Oldest Old People in China: Community Based, Longitudinal Prospective Study

Objective To examine the associations of blood pressure with all cause mortality and cause specific mortality at three years among oldest old people in China. Design Community based, longitudinal prospective study. Setting 2011 and 2014 waves of the Chinese Longitudinal Healthy Longevity Survey, conducted in 22 Chinese provinces. Participants 4658 oldest old individuals (mean age 92.1 years). Main outcome measures All cause mortality and cause specific mortality assessed at three year follow-up. Results 1997 deaths were recorded at three year follow-up. U shaped associations of mortality with systolic blood pressure, mean arterial pressure, and pulse pressure were identified; values of 143.5 mm Hg, 101 mm Hg, and 66 mm Hg conferred the minimum mortality risk, respectively. After adjustment for covariates, the U shaped association remained only for systolic blood pressure (minimum mortality risk at 129 mm Hg). Compared with a systolic blood pressure value of 129 mm Hg, risk of all cause mortality decreased for values lower than 107 mm Hg (from 1.47 (95% confidence interval 1.01 to 2.17) to 1.08 (1.01 to 1.17)), and increased for values greater than 154 mm Hg (from 1.08 (1.01 to 1.17) to 1.27 (1.02 to 1.58)). In the cause specific analysis, compared with a middle range of systolic blood pressure (107-154 mm Hg), higher values (\u3e154 mm Hg) were associated with a higher risk of cardiovascular mortality (adjusted hazard ratio 1.51 (95% confidence interval 1.12 to 2.02)); lower values (Hg) were associated with a higher risk of non-cardiovascular mortality (1.58 (1.26 to 1.98)). The U shaped associations remained in sensitivity and subgroup analyses. Conclusions This study indicates a U shaped association between systolic blood pressure and all cause mortality at three years among oldest old people in China. This association could be explained by the finding that higher systolic blood pressure predicted a higher risk of death from cardiovascular disease, and that lower systolic blood pressure predicted a higher risk of death from non-cardiovascular causes. These results emphasise the importance of revisiting blood pressure management or establishing specific guidelines for management among oldest old individuals

Low-density lipoprotein cholesterol was inversely associated with 3-year all-cause mortality among Chinese oldest old: Data from the Chinese Longitudinal Healthy Longevity Survey

Objective: Low-density lipoprotein cholesterol (LDL-C) is a risk factor for survival in middle-aged individuals, but conflicting evidence exists on the relationship between LDL-C and all-cause mortality among the elderly. The goal of this study was to assess the relationship between LDL-C and all-cause mortality among Chinese oldest old (aged 80 and older) in a prospective cohort study. Methods: LDL-C concentration was measured at baseline and all-cause mortality was calculated over a 3-year period. Multiple statistical models were used to adjust for demographic and biological covariates. Results: During three years of follow-up, 447 of 935 participants died, and the overall all-cause mortality was 49.8%. Each 1 mmol/L increase of LDL-C concentration corresponded to a 19% decrease in 3-year all-cause mortality (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.71–0.92). The crude HR for abnormally higher LDL-C concentration (≥3.37 mmol/L) was 0.65 (0.41–1.03); and the adjusted HR was statistically significant around 0.60 (0.37–0.95) when adjusted for different sets of confounding factors. Results of sensitivity analysis also showed a significant association between higher LDL-C and lower mortality risk. Conclusions: Among the Chinese oldest old, higher LDL-C level was associated with lower risk of all-cause mortality. Our findings suggested the necessity of re-evaluating the optimal level of LDL-C among the oldest old

Cartilage biomarkers in the osteoarthropathy of alkaptonuria reveal low turnover and accelerated ageing

Objective. Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis. Typically, this occurs in joint cartilages, leading to an early onset, rapidly progressing osteoarthropathy. The aim of this study was to examine tissue turnover in cartilage affected by ochronosis and its role in disease initiation and progression. Methods. With informed patient consent, hip and knee cartilages were obtained at surgery for arthropathy due to AKU (n = 6; 2 knees/4 hips) and OA (n = 12; 5 knees/7 hips); healthy non-arthritic (non-OA n = 6; 1 knee/5 hips) cartilages were obtained as waste from trauma surgery. We measured cartilage concentrations (normalized to dry weight) of racemized aspartate, GAG, COMP and deamidated COMP (D-COMP). Unpaired AKU, OA and non-OA samples were compared by non-parametric Mann–Whitney U test. Results. Despite more extractable total protein being obtained from AKU cartilage than from OA or non-OA cartilage, there was significantly less extractable GAG, COMP and D-COMP in AKU samples compared with OA and non-OA comparators. Racemized Asx (aspartate and asparagine) was significantly enriched in AKU cartilage compared with in OA cartilage. Conclusions. These novel data represent the first examination of cartilage matrix components in a sample of patients with AKU, representing almost 10% of the known UK alkaptonuric population. Compared with OA and non-OA, AKU cartilage demonstrates a very low turnover state and has low levels of extractable matrix proteins

Subchondral Bone Trabecular Integrity Predicts and Changes Concurrently with Radiographic and MRI Determined Knee Osteoarthritis Progression

OBJECTIVE: To evaluate subchondral bone trabecular integrity (BTI) on radiographs as a predictor of knee osteoarthritis (OA) progression. METHODS: Longitudinal (baseline, 12-month, and 24-month) knee radiographs were available for 60 female subjects with knee OA. OA progression was defined by 12- and 24-month changes in radiographic medial compartment minimal joint space width (JSW) and medial joint space area (JSA), and by medial tibial and femoral cartilage volume on magnetic resonance imaging. BTI of the medial tibial plateau was analyzed by fractal signature analysis using commercially available software. Receiver operating characteristic (ROC) curves for BTI were used to predict a 5% change in OA progression parameters. RESULTS: Individual terms (linear and quadratic) of baseline BTI of vertical trabeculae predicted knee OA progression based on 12- and 24-month changes in JSA (P < 0.01 for 24 months), 24-month change in tibial (P < 0.05), but not femoral, cartilage volume, and 24-month change in JSW (P = 0.05). ROC curves using both terms of baseline BTI predicted a 5% change in the following OA progression parameters over 24 months with high accuracy, as reflected by the area under the curve measures: JSW 81%, JSA 85%, tibial cartilage volume 75%, and femoral cartilage volume 85%. Change in BTI was also significantly associated (P < 0.05) with concurrent change in JSA over 12 and 24 months and with change in tibial cartilage volume over 24 months. CONCLUSION: BTI predicts structural OA progression as determined by radiographic and MRI outcomes. BTI may therefore be worthy of study as an outcome measure for OA studies and clinical trials. Copyright 2013 by the American College of Rheumatology