Distinct serum and cerebrospinal fluid metabolic signatures associate with pain and fatigue in knee osteoarthritis

Pain is the primary reason patients with knee osteoarthritis (OA) seek surgical intervention when pharmacological treatments lose efficacy. The pain arises from complex mechanisms involving peripheral and central sensitization and inflammatory processes. Emerging research links altered metabolites and lipids, such as lysophosphatidylcholine 16:0 and polyunsaturated fatty acids, to OA pathophysiology and pain modulation. Metabolomic studies in serum and synovial fluid have revealed potential biomarkers and novel therapeutic targets related to pain severity. This study aims to identify metabolic signatures in serum and cerebrospinal fluid (CSF) from knee OA patients, explore systemic and central metabolic interactions, and examine associations with symptom severity. The study included 36 knee OA patients, 38 healthy controls (HC) for serum analysis, and a separate non-healthy CSF control group of 39 individuals with non-inflammatory neurological symptoms (NINS). Samples were subjected to two targeted metabolomics methods using liquid chromatography high resolution mass spectrometry. Participants completed detailed questionnaires assessing pain intensity, fatigue, sleep disturbances, depression, anxiety, and functional disability. HC exhibited higher levels of 11 amino acids (including branched-chain amino acids, histidine, and tryptophan), five bile acids, and four lipids in serum. Conversely, OA patients showed elevated uracil concentrations. Notably, bile acids, glycocholic acid, and glycochenodeoxycholic acid were positively correlated with pain and symptom severity, despite being reduced in OA patients. Lower levels of alanine, isoleucine, and short-chain acylcarnitines (CARs 3:0, 4:0, and 5:0) were associated with higher fatigue ratings. Nucleotides and their derivatives correlated with knee pain intensity, pressure pain sensitivity, and fatigue. In CSF, OA patients generally had increased metabolite levels compared to NINS controls, such as 3-hydroxyphenylacetic acid, histamine, indole, and glutarylcarnitine. Histamine and 3-hydroxyphenylacetic acid were also significantly associated with pain intensity, sleep disturbance, and pressure pain sensitivity. Furthermore, numerous CSF metabolites showed moderate to high correlations with serum levels. This study reveals serum and CSF metabolic changes in knee OA patients linked to symptoms like pain and fatigue. It highlights complex systemic and central metabolism interactions and identifies potential biomarkers for personalized OA treatment, advancing clinical understanding.