Identification Of Metabolites Causally Associated With Osteoarthritis And Its Association With Knee Osteoarthritis

BackgroundOsteoarthritis(OA)is an age-related low-grade inflammatory disease of the synovial j oint and is one of the most costly and disabling forms of arthritis,of which Knee Osteoarthritis(KOA)is the most common type.Several studies have shown that OA is a metabolic disorder,with metabolic dysregulation mainly occurring in joint tissues such as articular cartilage,subchondral bone,and synovium of OA patients.The metabolic capacity of chondrocytes,synoviocytes,and osteocytes is affected,or synovial macrophages interact with the immune system,thus contributing to the development of the disease.The symptoms and signs of KOA mainly include pain,stiffness,restricted joint movement,and muscle weakness.However,reports suggest that the severity of imaging symptoms and structural damage is usually inconsistent.At present,the diagnosis of OA mainly depends on clinical symptoms and radiological methods.In early OA,this inconsistency may reflect the insensitivity of radiology,while magnetic resonance imaging(MRI)may reveal disease manifestations in high-risk populations of KOA.MRI can identify joint tissues and may become a tool for whole-organ imaging of j oints.MRI total knee score has been developed for auxiliary diagnosis.OA patients are often accompanied by osteoporosis(OP).The main characteristics of OP are low bone mineral density(BMD)and decreased bone strength,which is associated with an increased risk of low-trauma fractures.Although evidence has been found through MR for a causal relationship between BMD and the risk of hip osteoarthritis(HipOA)and KOA,there are still inconsistent research results.However,research on the relationship between metabolites in KOA patients and BMD is still lacking.In recent years,with the deepening of metabolomics research,OA has been increasingly recognized as a metabolic disease of j oint tissues,and various metabolically related molecular biology factors are involved in the onset and progression of the disease.However,previous metabolomics analyses of OA were based on simple cross-sectional studies.So far,there are still no studies to explore the causal effects of multiple different metabolites on OA and its subtypes.This leads to the fact that the metabolites that are associated with OA cannot be used as the biological tar very accurately.Objectives1.Explore the causal effects of human serum metabolites on OA and its subtypes,and identify metabolites with causal effects.2.Analyze the correlation between glycine,arginine and sphingomyelin in serum metabolites and joint symptoms and joint structural changes in KOA patients.3.Explore the causal effect of glycine on BMD in different sites,and analyze the correlation between glycine and BMD in different sites of KOA patients.Method1.Performed Mendelian randomization(MR)analysis by using the serum metabolite genome-wide association study data(mGWAS)and the GW AS data of OA and its subtypes to identify the Metabolites and their isoforms with causal effects.Sensitivity analysis is performed to confirm the results after adjusting for confounding factors,such as body mass index(BMI).2.Evaluated joint symptoms of 205 symptomatic knee osteoarthritis(KOA)patients included in the Anhui Osteoarthritis(AHOA)cohort using the Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC)and Lequesne index.It also assesses the knee joint structures of these patients,including bone marrow lesion(BML),cartilage volume,cartilage defect,synovitis area,infrapatellar fat pad(IPFP)volume,and signal changes using MRI images.The study then analyzes the correlation between glycine,arginine,sphingomyelin d18:1/16:0,and knee joint symptoms and structural changes using metabolomics data.3.Performed MR analysis to investigate the causal relationship between glycine and BMD in different body parts.It also analyzes the correlation between glycine and BMD in different body parts in KOA patients using the BMD data measured in the AHOA cohort.Results1.In Any Site Osteoarthritis(AllOA),we identified 24 metabolites that are causally related to it(5 amino acids,4 acylcarnitines,11 glycerophospholipids and 4 sphingolipids),where the causal effects of glycine,tyrosine,and SM C16:0 on AllOA were validated by multiple MR methods.Among the KOA,we identified 15 metabolites with which they were causally related(3 amino acids,4 acyl carnitines,4 glycerophospholipids,and 4 sphingolipids),of which the causal effect of glycine KOA was validated by multiple MR methods.In TKR,10 metabolites(3 amino acids,4 glycerophospholipids,and 3 sphingolipids)were identified as causally related.In Early-onset OA(Early_Al1OA),we identified 4 metabolites(2 amino acids,1 acylcarnitine and 1 glycerophospholipid)that were causally associated with the disease.The causal effect of glycine on Early_AllOA was verified by multiple MR Methods.2.The study found that serum levels of glycine were positively correlated with several clinical symptoms,including stiffness symptoms,post-activity stiffness,bone marrow lesions(BMLs),and synovial effusion.The study also found that serum levels of arginine were negatively correlated with cartilage defects in the medial femorotibial joint and positively correlated with cartilage volume in the lateral femorotibial j oint.However,no significant correlation was found between SM d18:1/16:0 and any clinical symptoms in KOA patients.3.It was found that glycine had a negative causal effect on femoral neck BMD.However,the study did not find any significant clinical correlation between glycine and BMD in any joint location in OA patients.Conclusion1.We found that glycine,tyrosine,and sphingomyelin had causal effects on OA.Glycine was positively correlated with the risks of AllOA,KOA and Early_AllOA,and there was a possible causal effect with the risk of TKR,suggesting that glycine may be related to the clinical manifestations and prognosis of OA.Sphingomyelin was negatively correlated with the risk of AllOA and KOA,suggesting the protective effect of sphingomyelin on OA disease.2.Glycine may be involved in the occurrence of KOA disease,and may affect the progression and prognosis of KOA.Arginine has a certain protective effect on KOA disease.Glycine and arginine were found to help prevent and manage KOA.However,further studies are needed to determine the biochemical and molecular mechanisms of these amino acids in OA.3.Glycine levels are risk factors for low femoral neck BMD and osteoporotic fractures.High glycine levels may be a biomarker of increased fracture risk.Further studies are required to examine if glycine is a risk factor of low BMD in KOA patients.