♦ Pathogenesis and etiology of osteoarthritis
Applying genomics and metabolomics approaches to identify novel genetic and metabolic markers for osteoarthritis, which can be used to predict disease risk and help better understand the pathogenesis of osteoarthritis.
♦ Population genetic structure of Newfoundland & Labrador
Unraveling genetic structure of isolated populations such as the Newfoundland & Labrador population using genome-wide genotype data, and facilitating the efficiency of genetic mapping using this population.
♦ Metabolomics and genomics of complex traits
Applying genomics and metabolomics approaches to complex traits including diabetes, obesity, colorectal cancer, and ankylosing spondylitis.
♦ Effects of Arginine on Osteoarthritis - Clinical Trial
Testing the effects of oral arginine supplementation on cartilage changes in knee osteoarthritis patients.
♦ NL Population Is a Very Valuable Source for Genetics Studies
We conducted a study on the genetic structure of the NL population, which was published in the European Journal of Human Genetics. The results showed that NL population has low genetic diversity, hence the overabundance of certain diseases. The genetic structure of NL resembles that of the British population, and can be divided into three clusters that correspond to religious/ethnic origins: Protestant English, Roman Catholic Irish, and North American Indigenous persons. These results are consistent with NL history and the fact that NL is geographically isolated. This also means that our NFOAS will benefit not only the NL population, but also populations of European origin.
See full article here:
Genetic structure of the Newfoundland and Labrador population: founder effects modulate variability.
♦ Metabolites and OA Classification
Metabolites are substances produced by or involved in the metabolism process, and reflect our body’s responses to genetic and environmental influences.
We analyzed 186 metabolites in OA patients’ joint fluid (fluid in joint cavities) samples, and distinguished OA patients into two groups based on metabolite levels. Elevated acylcarnitine levels were detected in one group of the OA patients, and the group with lower acylcarnitine levels can be further divided into two subgroups based on glycerophospholipids, sphingolipids and amino acids levels.
This is the first study using metabolites to classify OA patients. As some of the metabolites are associated with the progress of OA, and some indicate different mechanisms of disease development among different subgroups, this new classification system will help unravel the pathogenesis and develop targeted therapies for OA.
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Classification of osteoarthritis phenotypes by metabolomics analysis.
Endotypes of primary osteoarthritis identified by plasma metabolomics analysis.
♦ Metabolic Markers for Predicting Advanced Knee OA
We measured 186 metabolite concentrations and 4018 metabolite ratios in plasma samples from knee OA patients and a healthy control group, and found that the arginine level was 31% lower in knee OA patients, but ratios of certain metabolites (branched chain amino acids (BCAAs) / histidine; lysophosphatidylcholines (lysoPCs) / phosphatidylcholines(PCs)) were significant higher. And the higher the LysoPCs to PCs ratio is, the more likely the patient will undergo total knee replacement (TKR). These metabolic markers have great potential for predicting end-stage knee OA.
Arginine is an amino acid that’s essential for normal growth and development, and also important in posttraumatic situations. The LysoPCs to PCs ratio change was also linked to Alzheimer’s disease, reduced fertility, and the severity of rheumatoid arthritis (RA) found in other studies. So these metabolic changes can not only be used to monitor disease progression in knee OA patients, assist clinicians in their decision-making for TKR, but also point to directions for OA pathological pathway studies.
♦ OA Genes
In our cells, certain DNA and protein molecules work together to control certain cell functions, and we call this signalling pathways, as one molecule activates another till the signal reaches the last molecule, and then the function is carried out.
We examined some important genes in TGF-β signalling pathway (TGF-β1, SMAD3, MMP13 and BMP2), and found that in OA-affected cartilage, the damaging effect from MMP13 was magnified, and when the SMAD3/TGF-β pathway was trying to fix the damage by being overactive, it might have caused the overproduction and accumulation of certain proteins such as collagen, leading to cartilage swelling and breakage, and finally the involvement of the whole joint and OA presentation.
See full articles here:
TGF-β signal transduction pathways and osteoarthritis.
Overexpression of MMP13 in human osteoarthritic cartilage is associated with the SMAD-independent TGF-β signalling pathway.
SMAD3 Is Upregulated in Human Osteoarthritic Cartilage Independent of the Promoter DNA Methylation.
♦ DNA Methylation in Hip and Knee OA
If we consider DNA sequences as the instruction manual about how to build our body, then DNA methylation is like an erasable marker that covers some of the text in the manual, turns them on or off at certain stages.
We conducted a genome (the complete set of genes) wide DNA methylation analysis with hip and knee cartilage, to detect the overall DNA methylation level between OA patients and healthy controls, and found that the methylation patterns of genes involved in embryonic organ and skeletal system development were different between the two groups. This result was in line with some previous research findings about abnormal skeletal structure increasing the risk of OA.
This study was one of the few reports on the genome wide DNA methylation status of OA-free and OA-affected human cartilage, and shed light on the pathophysiology of OA and pave the road for further research in the field.
See full article here:
Genome-wide DNA methylation study of hip and knee cartilage reveals embryonic organ and skeletal system morphogenesis as major pathways involved in osteoarthritis.
♦ OA and Type 2 Diabetes
Our metabolomics study on Type 2 diabetes and OA showed that OA patients with and without type 2 diabetes had very distinctive metabolic profiles. The concentration of two unsaturated phosphatidylcholines (PC ae C34:3 and PC ae C36:3) were lower in OA patients than in healthy controls, and even lower in OA patients with type 2 diabetes.
Phosphatidylcholines (PCs) are a class of lipids that are involved in lubrication between cartilage, fluid transport in the joint, and maintaining normal physiological functions of joint cartilage. These lipids also play important roles in the regulation of glucose metabolism in type 2 diabetes, and lower PC levels are linked to reduced insulin secretion and lower insulin sensitivity, which is the hallmark of type 2 diabetes.
We further measured advanced glycation end products (AGEs) concentration in OA patients with and without diabetes. AGEs are proteins or lipids bound by sugar molecules; they can be a factor in the development or worsening of many degenerative diseases. Results showed that methylglyoxal (MG) and hydroimidazolone (MG-H1) levels were significantly higher in joint fluid samples from OA patients with diabetes, MG-H1 concentration in joint fluid was negatively correlated with the PCs that had lower levels in OA patients with diabetes.
We also observed higher hexose levels, which represent more than 90% of glucose, in joint fluid than in plasma, and all OA patients with diabetes had higher hexose levels than those without. This led us to believe that antidiabetic drugs may have immediate effects on reducing glucose level and inhibiting the production of AGEs in the blood, but the effect in the joint and other tissues may be lagging.
It is not certain if AGE mediated joint tissue damage is responsible for the altered PCs metabolism in OA and diabetes patients, but our findings provided new insights into the potential mechanism, and suggested that the PC metabolic pathway could be a potential target for novel interventions for OA.
See full article here:
Hyperglycemia-related advanced glycation end-products is associated with the altered phosphatidylcholine metabolism in osteoarthritis patients with diabetes.
♦ Is Surgery the Best Option?
Total joint replacement (TJR) is by far the most effective therapy for end-stage OA. However, our study shows that 18% of the patients are experiencing poor outcomes four years post-surgery, regardless of age, gender and BMI. Further investiagetion shows that patients with poorer functional improvement had higher levels of certain amino acids - histidine, sarcosine, phenylalaine, and serine in plasma, which indicated their great potential in predicting TJR outcomes. More studies are underway, and hopefully our findings will help OA patients and physicians with their decision-making when contemplating TJR in the future, also help develop prevention and alternative treatments for OA.
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Metabolomics Signature for Non-Responders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients: The Newfoundland Osteoarthritis Study.
Differential correlation network analysis identified novel metabolomics signatures for non-responders to total joint replacement in primary osteoarthritis patients.
Association Between Epidemiological Factors and Nonresponders to Total Joint Replacement Surgery in Primary Osteoarthritis Patients.