Systematic analysis of the cerebrospinal fluid proteome of fibromyalgia patients.

Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling. SIGNIFICANCE: Fibromyalgia is present in as much as 2% of the population, causing pain, stiffness, and tenderness of the muscles. Upon accurate diagnostic, nonpharmacological and pharmacological therapies can be used to alleviate pain and manage other symptoms. However, lack of objective, universal applicable diagnostic criteria as well as vague and diffused symptoms, have made diagnosis difficult. In this context, our findings can shed light on potential value of CSF proteome for objectively diagnosing FM.

[1]  P. Caboni,et al.  Metabolomics Analysis and Modeling Suggest a Lysophosphocholines-PAF Receptor Interaction in Fibromyalgia , 2014, PloS one.

[2]  Roland Staud,et al.  Heart rate variability as a biomarker of fibromyalgia syndrome. , 2008, Future rheumatology.

[3]  Robert Burke,et al.  ProteoWizard: open source software for rapid proteomics tools development , 2008, Bioinform..

[4]  W. Qidwai,et al.  Fibromyalgia syndrome: an overview of pathophysiology, diagnosis and management. , 2012, Oman medical journal.

[5]  William Stafford Noble,et al.  qvality: non-parametric estimation of q-values and posterior error probabilities , 2009, Bioinform..

[6]  C. Gottfries,et al.  Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. , 1997, Scandinavian journal of rheumatology.

[7]  J. Mountz,et al.  Abnormal functional activity of the central nervous system in fibromyalgia syndrome. , 1998, The American journal of the medical sciences.

[8]  M. E. Hernández,et al.  Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index , 2010, BMC Research Notes.

[9]  B. Fantino,et al.  Rheumatoid Arthritis and Fibromyalgia: A Frequent Unrelated Association Complicating Disease Management , 2009, The Journal of Rheumatology.

[10]  Gorjan Alagic,et al.  #p , 2019, Quantum information & computation.

[11]  L. Crofford Neuroendocrine abnormalities in fibromyalgia and related disorders. , 1998, The American journal of the medical sciences.

[12]  P. Alam ‘G’ , 2021, Composites Engineering: An A–Z Guide.

[13]  P. Tsai,et al.  Fibromyalgia Is Associated With Coronary Heart Disease: A Population-Based Cohort Study , 2014, Regional Anesthesia & Pain Medicine.

[14]  P. Talmud,et al.  Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets* , 2013, The Journal of Biological Chemistry.

[15]  L. Devi,et al.  ProSAAS Processing in Mouse Brain and Pituitary* , 2001, The Journal of Biological Chemistry.

[16]  Tae Ik Kim,et al.  Arterial Stiffness in Female Patients With Fibromyalgia and Its Relationship to Chronic Emotional and Physical Stress , 2011, Korean circulation journal.

[17]  K. Mannerkorpi,et al.  Comparison of the Levels of Pro-Inflammatory Cytokines Released in the Vastus Lateralis Muscle of Patients with Fibromyalgia and Healthy Controls during Contractions of the Quadriceps Muscle – A Microdialysis Study , 2015, PloS one.

[18]  Chris Sander,et al.  Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome , 2016, Cell.

[19]  Kyungmo Park,et al.  Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. , 2010, Arthritis and rheumatism.

[20]  A. Larsson,et al.  Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma , 2017, Journal of pain research.

[21]  M. Waye,et al.  Developmental regulation and cellular distribution of human cytosolic malate dehydrogenase (MDH1) , 2005, Journal of cellular biochemistry.

[22]  F. Wolfe,et al.  Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize ra patients with fibromyalgia. , 2004, The Journal of rheumatology.

[23]  Kim-Anh Lê Cao,et al.  mixOmics: An R package for ‘omics feature selection and multiple data integration , 2017, bioRxiv.

[24]  H. Yoon,et al.  Galectin-3 Exerts Cytokine-Like Regulatory Actions through the JAK–STAT Pathway , 2010, The Journal of Immunology.

[25]  J E Michalek,et al.  Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. , 1994, Arthritis and rheumatism.

[26]  H. Lardy,et al.  Sources of intramitochondrial malate , 1989, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  L. Crofford,et al.  Chronic widespread pain and fibromyalgia: what we know, and what we need to know. , 2003, Best practice & research. Clinical rheumatology.

[28]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[29]  G. Trovato,et al.  Pain assessment in fibromyalgia and rheumatoid arthritis: influence of physical activity and illness perception. , 2010, Clinica Terapeutica.

[30]  J. Lan,et al.  Increased Risk of Coronary Heart Disease in Patients with Primary Fibromyalgia and Those with Concomitant Comorbidity—A Taiwanese Population-Based Cohort Study , 2015, PloS one.

[31]  William Stafford Noble,et al.  Semi-supervised learning for peptide identification from shotgun proteomics datasets , 2007, Nature Methods.

[32]  B. Gerdle,et al.  Systemic alterations in plasma proteins from women with chronic widespread pain compared to healthy controls: a proteomic study , 2017, Journal of pain research.

[33]  Terry M. Therneau,et al.  Faster cyclic loess: normalizing RNA arrays via linear models , 2004, Bioinform..

[34]  B. Gerdle,et al.  Specific proteins of the trapezius muscle correlate with pain intensity and sensitivity – an explorative multivariate proteomic study of the trapezius muscle in women with chronic widespread pain , 2016, Journal of pain research.

[35]  F. Berven,et al.  In-depth Characterization of the Cerebrospinal Fluid (CSF) Proteome Displayed Through the CSF Proteome Resource (CSF-PR)* , 2014, Molecular & Cellular Proteomics.

[36]  J. Berg,et al.  Gluconeogenesis and Glycolysis Are Reciprocally Regulated , 2002 .

[37]  F. Sacks,et al.  The risk of cardiovascular events with increased apolipoprotein CIII: A systematic review and meta-analysis. , 2015, Journal of clinical lipidology.

[38]  R. Gay,et al.  Galectin 3 and its binding protein in rheumatoid arthritis. , 2003, Arthritis and rheumatism.

[39]  R. Vassilopoulou-sellin Endocrine effects of cytokines. , 1994, Oncology.

[40]  C. Barbato,et al.  Circulating microRNA Profiles as Liquid Biopsies for the Characterization and Diagnosis of Fibromyalgia Syndrome , 2017, Molecular Neurobiology.

[41]  Pain management in fibromyalgia. , 2016, Pain management.

[42]  I. Russell,et al.  Biology and therapy of fibromyalgia. Evidence-based biomarkers for fibromyalgia syndrome , 2008, Arthritis research & therapy.

[43]  G. Norata,et al.  Apolipoprotein C-III: From Pathophysiology to Pharmacology. , 2015, Trends in pharmacological sciences.

[44]  Suzanne Craft,et al.  Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation , 2012, Journal of Neuroinflammation.

[45]  B. Gerdle,et al.  Clear differences in cerebrospinal fluid proteome between women with chronic widespread pain and healthy women – a multivariate explorative cross-sectional study , 2017, Journal of pain research.

[46]  H. Burdett Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia , 2016, Annals of clinical biochemistry.

[47]  M. Åsberg,et al.  A New Depression Scale Designed to be Sensitive to Change , 1979, British Journal of Psychiatry.

[48]  D. Clauw,et al.  Biomarkers in fibromyalgia , 2009, Current pain and headache reports.

[49]  F. Togo,et al.  Cytokines across the Night in Chronic Fatigue Syndrome with and without Fibromyalgia , 2010, Clinical and Vaccine Immunology.

[50]  A. Zwinderman,et al.  Apolipoprotein C-III Levels and Incident Coronary Artery Disease Risk: The EPIC-Norfolk Prospective Population Study , 2017, Arteriosclerosis, thrombosis, and vascular biology.

[51]  G. Giovannoni Cerebrospinal fluid analysis. , 2014, Handbook of clinical neurology.

[52]  Thomas Brinker,et al.  A new look at cerebrospinal fluid circulation , 2014, Fluids and Barriers of the CNS.

[53]  O. Čulić,et al.  Serum activities of adenosine deaminase, dipeptidyl peptidase IV and prolyl endopeptidase in patients with fibromyalgia: diagnostic implications , 2016, Clinical Rheumatology.

[54]  Richard D. Smith,et al.  Establishing the Proteome of Normal Human Cerebrospinal Fluid , 2010, PloS one.

[55]  J. García,et al.  Altered release of chemokines by phagocytes from fibromyalgia patients: a pilot study , 2016, Innate immunity.

[56]  I. Todd,et al.  Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short‐term cultured blood mononuclear cells , 2003, Clinical and experimental immunology.

[57]  R A Musrati,et al.  Malate dehydrogenase: distribution, function and properties. , 1998, General physiology and biophysics.

[58]  William Stafford Noble,et al.  Efficient marginalization to compute protein posterior probabilities from shotgun mass spectrometry data. , 2010, Journal of proteome research.

[59]  P. Alam ‘N’ , 2021, Composites Engineering: An A–Z Guide.

[60]  M. Yunus,et al.  Primary fibromyalgia syndrome and myofascial pain syndrome: clinical features and muscle pathology. , 1988, Archives of physical medicine and rehabilitation.

[61]  P. Alam,et al.  R , 1823, The Herodotus Encyclopedia.

[62]  T. Wakefield,et al.  The role of galectin-3 and galectin-3-binding protein in venous thrombosis. , 2015, Blood.

[63]  N. Seidah,et al.  Inhibitory Specificity and Potency of proSAAS-derived Peptides toward Proprotein Convertase 1* , 2001, The Journal of Biological Chemistry.

[64]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[65]  B. Gerdle,et al.  Signs of ongoing inflammation in female patients with chronic widespread pain , 2017, Medicine.

[66]  J. Ablin,et al.  Association Between Fibromyalgia and Coronary Heart Disease and Coronary Catheterization , 2009, Clinical cardiology.

[67]  Yvonne C. Lee Effect and Treatment of Chronic Pain in Inflammatory Arthritis , 2012, Current Rheumatology Reports.

[68]  L. Fricker,et al.  ProSAAS-Derived Peptides Are Differentially Processed and Sorted in Mouse Brain and AtT-20 Cells , 2014, PloS one.

[69]  P. Alam ‘L’ , 2021, Composites Engineering: An A–Z Guide.

[70]  M. Luo,et al.  The emerging role of apolipoprotein C-III: beyond effects on triglyceride metabolism , 2016, Lipids in Health and Disease.

[71]  L. Bradley,et al.  Central nervous system mechanisms of pain in fibromyalgia and other musculoskeletal disorders: behavioral and psychologic treatment approaches. , 2002, Current opinion in rheumatology.

[72]  Serge H. Roy,et al.  Lack of association between fibromyalgia syndrome and abnormalities in muscle energy metabolism. , 1994, Arthritis and rheumatism.

[73]  G. Vega,et al.  Apolipoproteins in human cerebrospinal fluid. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[74]  F. Salaffi,et al.  The evaluation of the fibromyalgia patients. , 2011, Reumatismo.

[75]  F. Kapczinski,et al.  Evaluation of cytokines, oxidative stress markers and brain-derived neurotrophic factor in patients with fibromyalgia - A controlled cross-sectional study. , 2016, Cytokine.

[76]  A. Silman,et al.  Psychological stress and fibromyalgia: a review of the evidence suggesting a neuroendocrine link , 2004, Arthritis research & therapy.

[77]  E. Briones-Vozmediano,et al.  Patients' and professionals' views on managing fibromyalgia. , 2013, Pain research & management.

[78]  N. Seidah,et al.  Disruption of Proprotein Convertase 1/3 (PC1/3) Expression in Mice Causes Innate Immune Defects and Uncontrolled Cytokine Secretion* , 2012, The Journal of Biological Chemistry.

[79]  I. Russell,et al.  Treatment of fibromyalgia syndrome with Super Malic: a randomized, double blind, placebo controlled, crossover pilot study. , 1995, The Journal of rheumatology.

[80]  J. Lampa,et al.  Evidence of central inflammation in fibromyalgia — Increased cerebrospinal fluid interleukin-8 levels , 2012, Journal of Neuroimmunology.

[81]  Pavel A. Pevzner,et al.  Universal database search tool for proteomics , 2014, Nature Communications.

[82]  Thomas de Quincey [C] , 2000, The Works of Thomas De Quincey, Vol. 1: Writings, 1799–1820.

[83]  K. Reinert,et al.  OpenMS: a flexible open-source software platform for mass spectrometry data analysis , 2016, Nature Methods.

[84]  I. Lindberg,et al.  A novel function for proSAAS as an amyloid anti‐aggregant in Alzheimer's disease , 2014, Journal of neurochemistry.

[85]  F. Young Biochemistry , 1955, The Indian Medical Gazette.

[86]  E. Bosmans,et al.  The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble gp130, the common signal transducer protein of various neurotrophic cytokines , 1999, Psychoneuroendocrinology.

[87]  R. Day,et al.  Coexpression of Proprotein Convertase SPC3 and the Neuroendocrine Precursor ProSAAS1. , 2001, Endocrinology.

[88]  B. Gerdle,et al.  Protein alterations in women with chronic widespread pain – An explorative proteomic study of the trapezius muscle , 2015, Scientific Reports.

[89]  José A. Dianes,et al.  2016 update of the PRIDE database and its related tools , 2015, Nucleic Acids Res..

[90]  Georg Schett,et al.  Cytokines in the pathogenesis of rheumatoid arthritis , 2007, Nature Reviews Immunology.

[91]  Filippo Castoldi,et al.  Fibromyalgia Syndrome: Etiology, Pathogenesis, Diagnosis, and Treatment , 2012, Pain research and treatment.

[92]  C. Sokollik,et al.  From Diarrhea to Obesity in Prohormone Convertase 1/3 Deficiency: Age-dependent Clinical, Pathologic, and Enteroendocrine Characteristics , 2013, Journal of clinical gastroenterology.

[93]  R. Geenen,et al.  Deviations in the endocrine system and brain of patients with fibromyalgia: cause or consequence of pain and associated features? , 2010, Annals of the New York Academy of Sciences.

[94]  P. Oktayoğlu,et al.  Central nervous system abnormalities in fibromyalgia and chronic fatigue syndrome: new concepts in treatment. , 2008, Current pharmaceutical design.

[95]  C. Sokollik,et al.  Congenital proprotein convertase 1/3 deficiency causes malabsorptive diarrhea and other endocrinopathies in a pediatric cohort. , 2013, Gastroenterology.

[96]  J. Holst,et al.  Prohormone Convertase 1/3 Is Essential for Processing of the Glucose-dependent Insulinotropic Polypeptide Precursor* , 2006, Journal of Biological Chemistry.

[97]  Tsuyoshi Murata,et al.  {m , 1934, ACML.

[98]  Daniel J Clauw,et al.  Improving the recognition and diagnosis of fibromyalgia. , 2011, Mayo Clinic proceedings.

[99]  P. Igaz,et al.  CYTOKINES IN DISEASES OF THE ENDOCRINE SYSTEM , 2000, Cell biology international.

[100]  P. Henningsen,et al.  Classification and Clinical Diagnosis of Fibromyalgia Syndrome: Recommendations of Recent Evidence-Based Interdisciplinary Guidelines , 2013, Evidence-based complementary and alternative medicine : eCAM.

[101]  Andreas Quandt,et al.  An automated pipeline for high-throughput label-free quantitative proteomics. , 2013, Journal of proteome research.

[102]  L. Arnold,et al.  The science of fibromyalgia. , 2011, Mayo Clinic proceedings.

[103]  J. Pintar,et al.  The propeptide precursor proSAAS is involved in fetal neuropeptide processing and body weight regulation , 2010, Journal of neurochemistry.

[104]  M. First,et al.  Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research version (SCID-I RV) , 2002 .