| BackgroundOsteoarthritis(OA)is one of the most common joint diseases in the world.It affects the physical and mental health of about 10%of the world’s middle-aged and elderly population and brings a heavy economic burden to the society.At present,the specific pathogenesis of osteoarthritis is still unclear,and there is a lack of effective methods for early diagnosis of the disease,which makes it difficult for many osteoarthritis patients to receive timely diagnosis and treatment in the early stage of the disease.Therefore,we urgently need to find some specific biomarkers that can help clinicians diagnose osteoarthritis early,so as to intervene early and prevent further damage to joint structure and function.In recent years,metabolomics,as an emerging and rapidly developing field,has become one of the reliable tools for analyzing the metabolic mechanisms of diseases.In a previous metabolomics study,our team found that plasma amino acid ratios and phosphatidylcholine ratios were associated with the risk of knee osteoarthritis.In order to further explore the targeted biomarkers related to osteoarthritis from different perspectives,we decided to use the most prominent cartilage loss and pain symptoms in the progression of osteoarthritis as the research direction,and study the relationship between the development and severity of these two clinical symptoms.Biomarkers provide new ideas for studying the occurrence and development of osteoarthritis.Chapter 1 Metabolomic characteristics of knee cartilage volume loss in middle-aged and elderly peopleObjective:To reveal the characteristics of knee cartilage loss in middle-aged and elderly people and novel biomarkers for diagnosing cartilage loss.Methods:This study began in 2002 with participants randomly selected from electoral rolls in southern Tasmania,equal numbers of men and women,aged 50 to 80 years.Cartilage volumes of the medial,lateral,and patellofemoral compartments of the knee joint were measured by magnetic resonance imaging(MRI)at baseline,2.5,5,and 10-year follow-up.MRI data at baseline and at the fourth round of follow-up were selected Cartilage volume measurements were performed and the annual percent change in mean cartilage volume was calculated from the change in cartilage volume over 10 years.Fasting plasma samples collected at the 2.5-year follow-up were subjected to targeted metabolomic analysis of metabolite concentrations using TMIC Prime Metabolomics Technology,from which pair-wise metabolite concentration ratios of enzymatic reactions in vivo were calculated and then analyzed by linear regression.Relationship to changes in knee compartment cartilage volume,adjusted for age,sex,and BMI.The significance level in metabolite data analysis was defined as α=3.0*10-6 to control for statistical errors caused by multiple testing.Results:A total of 344 subjects(176 females,51.16%)were included in this study.The mean age at baseline was 62.83±6.13 years,and the mean BMI was 27.48±4.41 kg/m2.The mean follow-up time of the fourth round of follow-up was 10.84±0.66 years,and the mean annual reduction rates of cartilage volume in the medial,lateral,and patellofemoral joint compartments of the subjects were 1.34±0.72%,1.06±0.58%,and 0.98±0.98±0.98%,respectively.0.46%.Metabolomic analysis showed the ratio of hexadecenoylcarnitine(C16:1)/tetradecylcarnitine(C14)and the ratio of hexadecenoylcarnitine/dodecylcarnitine(C12)Correlation with the average annual reduction rate of patellofemoral cartilage volume,β values were 0.12±0.02%,p values were 8.80*10-07 and 2.66*10-06,respectively.Conclusions:The plasma concentration ratios of C16:1/C14 and C16:1/C12 are associated with long-term cartilage volume loss in the patellofemoral joint,suggesting their use as a measure of Potential for novel biomarkers of cartilage loss in osteoarthritis.Chapter 2 Metabolomic characterization of multi-site musculoskeletal pain in osteoarthritis populationObjective:To investigate the metabolic profile of multisite musculoskeletal pain(MSMP)in osteoarthritis populations and to uncover novel biomarkers for MSMP diagnosis.Methods:Participants in this study were all patients undergoing joint replacement surgery from the Newfoundland Osteoarthritis Study Cohort.Demographic and relevant clinical information were obtained in the form of self-reports,musculoskeletal pain was assessed using a self-administered pain questionnaire,pain sites were circled on the manikin,and the total number of pain sites and pain severity were counted.Fasting plasma samples were subjected to targeted metabolomic analysis of metabolite concentrations using the Biocrates AbsolutelDQ p180 kit.Plasma cytokine concentrations including tumor necrosis factor-a,interleukin-6,interleukin-1β,and macrophage migration inhibitory factor were measured by enzyme-linked immunosorbent assay.Finally,measurements of blood cholesterol profiles were retrieved and collected from the subjects’ medical records.Data analysis was performed using statistical analysis methods such as logistic regression.The significance level in metabolite data analysis was defined as α=3.0*10-4 to control the statistical error caused by multiple testing.Results:A total of 205 people were included in this study,of whom 83(67.47%female,mean age 63.86±7.30)had≥7 pain sites,and 122(51.64%female,mean age 66.40±8.20)had ≤1 pain site),suggesting that women and young adults are more likely to develop MSMP(P<0.02).Multi-site musculoskeletal pain was associated with higher risk of urinary incontinence,poorer functional status,longer periods of pain,and higher levels of LDL and non-HDL cholesterol(all P<0.03).Of the 186 metabolites measured,2 lysophosphatidylcholines,1 26-carbon compound without a double bond(LysoPC 26:0),were found to have natural log-transformed concentrations of lysoPC 26:0 in the multi-site musculoskeletal Mean-1.65±0.47 logμM in the pain group and-1.91 ±0.46 logμM in the non-multisite musculoskeletal pain group,1 compound with 28 carbons and 1 double bond(LysoPC 28:1),lysoPC 28:1 The natural log transformed concentrations in the multisite musculoskeletal pain group and the non-multisite musculoskeletal pain group were-1.21±0.33 logμM and-1.39±0.32 logμM,respectively,and after Bonferroni correction,these two metabolites were found to be associated with MSMP Occurrence was correlated(p-values 0.0001 and 0.00007,respectively).Conclusions:LysoPC 26:0 and 28:1 are positively correlated with the occurrence of MSMP,suggesting that these two metabolites have the potential to diagnose multi-site musculoskeletal pain in patients with osteoarthritis. |
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