Correlation Between Circadian Rhythm And Intervertebral Disc Degeneration And The Effect Of Chronotherapy

BackgroundLow back pain(LBP)is pain or discomfort below the rib margin of the back and above the hip creases,with or without pain in the lower extremities.According to statistics,about80% of individuals have experienced LBP in their lifetime,40% of individuals have been suffering from LBP for a long time,and the annual medical expenditure generated by LBP is comparable to coronary heart disease and diabetes,so LBP has become a public health problem of global concern.Disc degeneration is the most common causative factor of LBP.The latest research has found that the homeostasis maintenance of intervertebral disc tissue is closely related to circadian rhythm,and the disturbance of circadian rhythm will accelerate the occurrence of intervertebral disc degeneration.Therefore,circadian rhythm is of great significance in the prevention and treatment of intervertebral disc degeneration.However,current population-based studies mainly focus on the effect of circadian rhythm disturbances caused by the nature of work(e.g.,shift work)on disc degeneration,and there is a lack of systematic and comprehensive epidemiological studies on whether circadian rhythm is an independent risk factor for disc degeneration.Human circadian rhythms are composed of a series of complex phenotypes,and circadian rhythm types are one of the main means of quantifying individual circadian rhythms.Therefore,the correlation between circadian rhythm and disc degeneration can be comprehensively and deeply analyzed by circadian rhythm type.Secondly,in view of the characteristics of different physiological functions of intervertebral disc tissue,it is of great significance to explore the influence of circadian rhythm in the treatment of intervertebral disc degeneration.Chronotherapy based on circadian rhythm characteristics is the concept of optimizing treatment time to maximize treatment effect and minimize treatment side effects.However,such principle in the treatment of disc degeneration is not well studied.In view of the above problems,this study first grouped the clinical samples according to the Morningness-eveningness questionnaire(MEQ),analyzed and compared the parameters of intervertebral disc degeneration of different circadian rhythm types,determined the correlation between circadian rhythm type and intervertebral disc degeneration,and clarified that the night type is an independent risk factor for intervertebral disc degeneration.On this basis,we take pulsed electromagnetic field(PEMF)as the research model to analyze and compare the therapeutic effect of PEMF at different time periods of day and night,and find that the treatment effect during the day is significantly better than the treatment at night,and clarify that the circadian rhythm has an important influence in the treatment of intervertebral disc degeneration,which provides a new idea for discussing the treatment plan of clinical disc degeneration with circadian rhythm as the starting point.Objectives1.To clarify the correlation between clinical disc degeneration and circadian rhythm type through epidemiological studies,and identify whether circadian rhythm type was an independent risk factor for intervertebral disc degeneration.2.Using a mouse intervertebral disc degeneration research model and non-invasive physical stimulation PEMF as the research object,the role and mechanism of circadian rhythm in the treatment of rat intervertebral disc degeneration were determined.Methods1.Research on the correlation between the occurrence of IVDD and circadian rhythm: 238 patients with low back pain in the spinal surgery clinic of our hospital were collected.Inclusion Criteria:(1)age 18-35 years;(2)Symptoms are manifested as lumbosacral hip pain,with or without symptoms of lower limbs;(3)Clear lumbar spine MRI imaging data;Exclusion Criteria:(1)previous history of lumbar spine surgery;(2)Low back trauma and muscle strain;(3)Patients with lumbar fractures,isthmus fissures,spondylolisthesis,congenital spinal deformities and osteoporosis;(4)Patients with ankylosing spondylitis,rheumatoid arthritis,spinal tuberculosis,primary tumors of the spine or secondary tumors;(5)Serious primary diseases in other systems,such as: coronary heart disease,diabetes,epilepsy and tumors;(6)Special occupational groups: for example,sports athletes,drivers,heavy physical workers,etc.;(7)Familial genetic diseases.The basic information of patients was collected by questionnaire survey,and the Morningnesseveningness questionnaire(MEQ)was used to evaluate the type of circadian rhythm of patients.In addition,the occurrence of disc degeneration was evaluated:(1)functional score:ODI score and VAS score;(2)Structural score: Pfirmann score;Modic changes and SNS.The characteristics of patients with disc degeneration of three different rhythm types(morning,intermediate and evening type)were summarized.Multivariate logistic regression analysis were used to clarify the correlation between IVDD and circadian rhythm.A general linear regression model was constructed to determine the correlation between pain scores and circadian rhythm types.2.Study on the effect of applying PEMF at different times of day and night on IVDD in rats: construct an PEMF generation system and a model of IVDD in rats.Rats were randomly divided into 4 groups,blank control group,puncture group,puncture +DPEMF group,puncture + NPEMF group.DPEMF(daytime treatment)time period was07:00-11:00,the NPEMF(nighttime treatment)period was 19:00-23:00,and PEMF was applied the day after puncture.The treatment was carried out for 8 weeks,and the effect of PEMF was evaluated by X-ray,MRI,IVD tissue morphology,decomposition and expression of anabolic molecules.The potential targets and related mechanisms of PEMF were preliminarily explored through circadian clock gene analysis and transcriptomic analysis.Results1.Correlation between the occurrence of intervertebral disc degeneration and circadian rhythm: According to the MEQ score,in this sample,48 cases(20.2%)were night type,and 57 cases(23.9%)were morning type.133 cases(55.9%)were intermediate type.There was no statistically significant difference in the proportion of individual characteristics except sitting time and work type in these groups.The morning type had a Pfirmann score of 10.32(± 2.03)and the intermediate Pfirmann score was 10.95(± 2.61).The night type Pfirmann score was 12.77(± 3.3),with night type scores significantly higher than intermediate and early morning(P<0.001).In addition,the number of positive Modic change in night type was significantly higher than that of morning type and intermediate type(P=0.014).There was no statistically significant association between circadian rhythm types and SNS.In multivariate analysis,the occurrence of disc degeneration was significantly associated with night work,shift work,and circadian rhythm type.Based on the above results,multivariate logistic regression analysis was used to correct for potential confounders,and the results showed that the night type was an independent risk factor.The risk of the night type is 2.81 times than the morning type(P=0.026).There were significant differences in ODI score and VAS score between different types.However,after the general linear regression model was constructed to correct for potential confounding factors such as smoking history,sitting time,work nature,and disc degeneration,there were no significant differences in the results(ODI score: morning type as the reference group,intermediate P=0.589,night type P=0.301;VAS score: morning type as the reference group,intermediate type P=0.092,night type P=0.277).The findings suggest that no association was found between circadian rhythm type and pain scores.2.Therapeutic effect of circadian rhythm modulated PEMF on rat IVDD: This part of the study systematically evaluates circadian rhythm-mediated PEMF treatment effect on the needle-induced degeneration of rat tail disc.Our results suggest that daytime pulsed electromagnetic field therapy(DPEMF)is more effective than nighttime pulsed electromagnetic field therapy(NPEMF)at alleviating IVDD.In addition,rats treated with DPEMF maintained better disc stability and histological morphology after 8 weeks relative to NPEMF.In addition,the mediating role of circadian rhythms in PEMF therapy was investigated in nucleus pulposus cell models.We applied serum shock to induce different levels of clock gene expression in nucleus pulposus cells,thereby mimicking circadian rhythms in vitro.PEMF of ZT8(higher levels of clock gene expression)is associated with higher expression of extracellular matrix(ECM)components compared to ZT20(lower level clock gene expression).Further transcriptome analysis suggests that circadian rhythmrelated genes in IVD tissues may be a potential factor influencing PEMF treatment differences during the day and night,and that the PI3K-Akt signaling pathway may be a key signaling pathway leading to treatment differences.Taken together,these data suggest that circadian rhythms play an important role in regulating the beneficial effects of PEMF on IVDD.Conclusion1.Different circadian rhythm types were associated with the occurrence of intervertebral disc degeneration in the LBP aged 18-35 years.The incidence of intervertebral disc degeneration,the Pfirmann score of lumbar discs and the number of Modic change intervertebral spaces in the night type group were significantly higher than those of the morning type and the intermediate type.Risk factor analysis showed that people with night type had a higher risk of disc degeneration than morning type,suggesting that night type people had an increased risk of disc degeneration.2.In rats,daytime PEMF treatment was more effective than nighttime PEMF treatment in alleviating disc degeneration,suggesting that circadian rhythm is a key factor affecting treatment effectiveness.Circadian rhythm-related genes in intervertebral disc tissue are potential factors influencing PEMF treatment differences during the day and at night,and the PI3K-Akt signaling pathway is a key signaling pathway leading to treatment differences.which provides a new idea for exploring the treatment options for clinical disc degeneration with circadian rhythm as the starting point.However,rodents(rats)and humans exhibit opposite sleep-wake cycles and circadian rhythm activity,so the role of circadian rhythm in the prevention and treatment of intervertebral disc degeneration in human medical applications needs to be further clarified.