Associations Between Melatonin And Cortisol And Symptoms,Joint Structures And Biomarkers In Knee Osteoarthritis

Background Osteoarthritis(OA)is a common joint disease,which is one of the main causes of disability.The pathogenesis of OA is still unclear.Age,obesity,and chronic inflammation are known risk factors for OA,and age-related decline in brain function,including the decline of the circadian rhythm system,may affect joint homeostasis.The secretion of melatonin(MLT)and cortisol(COR)has a certain circadian rhythm,which can reflect the changes of circadian rhythm.Basic research shows that MLT may have protective effects on OA,which may be related to the regulation of oxidative stress process,pro-inflammatory cytokine secretion,and mitochondrial dysfunction during OA cartilage degradation,but no relevant clinical studies have been found.Epidemiological studies have found that COR levels are positively correlated with pain changes in WOMAC scores in patients with OA,but some studies have shown that there is no association between COR and OA pain.Therefore,related researchs on the relationship between serum COR and OA have been still controversial.Objective To investigate the relationships between serum MLT and COR levels and knee joint symptoms,joint structures and serum biomarkers in patients with knee OA.Methods A total of 169 patients with knee OA were included.The general condition of the patients was investigated.Magnetic Resonance Imaging(MRI)was used to measure the knee joint of the patients.Cartilage volume(CV)was measured by Osirix software,and cartilage defects and bone marrow lesions(BMLs)were evaluated.The knee radiographs of the subjects were photographed,and the severity of the radiological structural changes of the knee joints was evaluated using the OARSI map.Serum levels of MLT,matrix metalloproteinase(MMP)-3,MMP-10,MMP-13,interleukin(IL)-6,IL-8,tumor necrosis factor-alpha(TNF-?),leptin,resistin and adiponectin were measured using enzyme-linked immunosorbent assay(ELISA).SPSS 21.0 software was used to analyze the association between serum levels of MLT and COR and knee OA symptoms,joint structures and biomarkers.Results1.Subjects were split based on the median level of MLT(0.91 ng/ml).Patients with higher and lower levels of MLT were similar in age,gender,body mass index(BMI),cartilage volume,cartilage defects,BMLs and levels of IL-8,leptin,adiponectin,MMP-10 and MMP-13.However,patients with higher level of MLT had higher levels of IL-6,TNF-?,resistin and lower level of MMP-3(P < 0.05).2.After adjustment for potential confounders(age,gender and body mass index),serum levels of MLT were significantly and negatively associated with MMP-3(OR = 0.55,95% CI = 0.37 ? 0.81,P = 0.03),and were significantly and positively associated with IL-6,TNF-? and leptin(OR = 2.05,95% CI = 1.27 ? 3.29,P = 0.003;OR = 2.25,95%CI = 1.40 ? 3.63,P = 0.001;OR = 1.59,95% CI = 1.05 ? 2.42,P = 0.028,respectively).Serum levels of MLT were not significantly associated with other biomarkers.3.We did not find significant associations between serum levels of melatonin and cartilage volume,cartilage defects and BMLs,before or after adjustment for potential confounders.4.Patients were divided into two groups according to the median serum COR concentration(81.71 ng/ml).Patients with higher and lower levels of COR were similar in gender,age,BMI,total CD score,total BMLs score,and infrapatellar fat pad(IPFP)signal intensity alteration.However,subjects in the high-level COR group had higher total knee CV,total joint space narrowing score,and medial joint space narrowing score than those in the low-level COR group(P < 0.05).5.COR and biomarkers: after adjustment for confounding factors,serum COR levels were not significanlt associated with MMP-3,MMP-10,MMP-13,IL-6,IL-8,TNF-?,leptin,resistin and adiponectin levels.6.Serum COR levels were positively correlated with total knee CV,medial tibial CV,and patellar CV in patients with knee OA(? = 0.42,95% CI = 0.03 ? 0.82,P = 0.037;?= 0.12,95% CI = 0.01 ? 0.24,P = 0.037;? = 2.23,95% CI = 0.09 ? 4.36,P = 0.041).After adjusting for confounding factors,serum COR was positively correlated with total knee CV and medial tibial CV(? = 0.34,95% CI = 0.01 ? 0.67,P = 0.047;? = 0.11,95% CI = 0.01 ? 0.21,P = 0.036),but the correlation with patellar CV disappeared(? =1.66,95% CI =-0.11 ? 3.43,P = 0.066).Serum COR levels were negatively correlated with total joint space narrowing score and lateral joint space narrowing score in patients with knee OA(OR = 0.44,95% CI = 0.22 ? 0.89,P = 0.023;OR = 0.40,95% CI = 0.17? 0.91,P = 0.029),and was positively correlated with IPFP signal intensity alteration(OR = 2.40,95% CI = 1.17 ? 4.98,P = 0.019).The above results still had statistical significance after adjustment for confounding factors.Conclusions1.Serum levels of MT was negatively associated with MMP-3 and positively associated with IL-6,TNF-? and leptin,but not with joint structural changes.These suggest that MT may play a role in knee OA which needs to be examined by further studies.2.Serum COR was positively correlated with total knee CV and medial tibial CV in knee OA patients,negatively correlated with total joint space narrowing score and lateral joint space narrowing score,and positively correlated with IPFP signal intensity alteration.The results of our study suggest that serum levels of COR may play a role in patients with knee OA.