title: RANK-RANKL-OPG in hemophilic arthropathy: from clinical and imaging diagnosis to histopathology.
abstract: OBJECTIVE
  Hemarthrosis triggers hemophilic arthropathy, involving the target joints. The histopathogenesis of blood-induced joint damage remains unclear. The triad of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG; RANK-RANKL-OPG) controls bone turnover. Our aim was to evaluate RANK-RANKL-OPG expression in the synovium of hemophilic patients with severe arthropathy.
  
  
  METHODS
  Synovial biopsies were obtained from 18 patients with hemophilic arthropathy and 16 with osteoarthritis (OA) who were undergoing total knee replacement and synovectomy. The severity of hemophilic arthropathy was evaluated according to ultrasonography score, the World Federation of Hemophilia (WFH) orthopedic joint scale, and the radiographic Pettersson score. RANK-RANKL-OPG expression was examined by immunohistochemistry and Western blotting. Serum levels of soluble RANKL (sRANKL) and OPG from an extended group of 67 patients with hemophilic arthropathy and 30 healthy controls were measured by ELISA.
  
  
  RESULTS
  The mean ultrasonography, WFH orthopedic joint scale, and Pettersson scores in patients with hemophilic arthropathy indicated severe arthropathy. A decreased expression of OPG was found in hemophilic arthropathy synovium compared with patients with OA. RANK and RANKL immunopositivity was strong in the lining and sublining layers in hemophilic arthropathy synovial tissue. Western blotting confirmed the immunohistological findings. Serum levels of sRANKL and OPG in patients with hemophilia were lower than in healthy controls.
  
  
  CONCLUSIONS
  In hemophilic arthropathy, the synovium highly expressed RANK and RANKL, whereas OPG immunopositivity decreased, suggesting an osteoclastic activation. Low tissue expression of OPG paralleled the serum levels of this protein and the severity of hemophilic arthropathy assessed by ultrasonography, Pettersson, and WFH orthopedic joint scale scores.
authors: Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy. ibba@unifi.it
authors: Daniela
authors: D
authors: Melchiorre
authors: Anna Franca
authors: AF
authors: Milia
authors: Silvia
authors: S
authors: Linari
authors: Eloisa
authors: E
authors: Romano
authors: Gemma
authors: G
authors: Benelli
authors: Mirko
authors: M
authors: Manetti
authors: Serena
authors: S
authors: Guiducci
authors: Claudia
authors: C
authors: Ceccarelli
authors: Massimo
authors: M
authors: Innocenti
authors: Christian
authors: C
authors: Carulli
authors: Roberto
authors: R
authors: Civinini
authors: Massimo
authors: M
authors: Morfini
authors: Marco
authors: M
authors: Matucci-Cerinic
authors: Lidia
authors: L
authors: Ibba-Manneschi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005260:Female; D006395:Hemarthrosis / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B