title: Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.
abstract: To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies.
  
  
  
  Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF-R1) and NGAL were assayed and quantitated using mono-specific enzyme-linked immunosorbent assays for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t-test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver-operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression.
  
  
  
  Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF-R1 and MMP-9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex, and urinary severity was significantly positively associated with MMP-9, MMP-9/NGAL complex and VEGF-R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF-R1.
  
  
  
  Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Adelle
authors.initials: A
authors.lastname: Dagher
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Curatolo
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Monisha
authors.initials: M
authors.lastname: Sachdev
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alisa J
authors.initials: AJ
authors.lastname: Stephens
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Mullins
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: J Richard
authors.initials: JR
authors.lastname: Landis
authors.affiliation: Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Adrie
authors.initials: A
authors.lastname: van Bokhoven
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: El-Hayek
authors.affiliation: Department of Urology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Froehlich
authors.affiliation: Department of Urology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Briscoe
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Roopali
authors.initials: R
authors.lastname: Roy
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
authors.forename: Michel A
authors.initials: MA
authors.lastname: Pontari
authors.affiliation: Department of Surgery, Harvard Medical School, Boston, MA, USA.|Department of Anesthesia, Boston Children's Hospital, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.affiliation: Department of Urology, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lee
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Boston Children's Hospital, Boston, MA, USA.|Department of Surgery, Harvard Medical School, Boston, MA, USA.
authors.forename: Marsha A
authors.identifier: 0000-0003-3108-0704
authors.initials: MA
authors.lastname: Moses
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D035843:Biomedical Research; D059350:Chronic Pain; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D033183:Interdisciplinary Communication; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D017699:Pelvic Pain / Q000503:physiopathology* / Q000523:psychology*; D012107:Research Design; D013577:Syndrome; D014481:United States; D014551:Urinary Tract / Q000473:pathology*; D014570:Urologic Diseases / Q000378:metabolism* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Lipocalin 2 (also known as NGAL); Multidisciplinary Approach to the Study of Chronic Pelvic Pain; matrix metalloproteinase; neutrophil gelatinase associated lipocalin; vascular endothelial growth factor; vascular endothelial growth factor receptor 1