title: Deficiency of fibroblast activation protein alpha ameliorates cartilage destruction in inflammatory destructive arthritis.
abstract: BACKGROUND
  Inflammatory destructive arthritis, like rheumatoid arthritis (RA), is characterized by invasion of synovial fibroblasts (SF) into the articular cartilage and erosion of the underlying bone, leading to progressive joint destruction. Because fibroblast activation protein alpha (FAP) has been associated with cell migration and cell invasiveness, we studied the function of FAP in joint destruction in RA.
  
  
  METHODS
  Expression of FAP in synovial tissues and fibroblasts from patients with osteoarthritis (OA) and RA as well as from wild-type and arthritic mice was evaluated by immunohistochemistry, fluorescence microscopy and polymerase chain reaction (PCR). Fibroblast adhesion and migration capacity was assessed using cartilage attachment assays and wound-healing assays, respectively. For in vivo studies, FAP-deficient mice were crossed into the human tumor necrosis factor transgenic mice (hTNFtg), which develop a chronic inflammatory arthritis. Beside clinical assessment, inflammation, cartilage damage, and bone erosion were evaluated by histomorphometric analyses.
  
  
  RESULTS
  RA synovial tissues demonstrated high expression of FAP whereas in OA samples only marginal expression was detectable. Consistently, a higher expression was detected in arthritis SF compared to non-arthritis OA SF in vitro. FAP-deficiency in hTNFtg mice led to less cartilage degradation despite unaltered inflammation and bone erosion. Accordingly, FAP(-/-) hTNFtg SF demonstrated a lower cartilage adhesion capacity compared to hTNFtg SF in vitro.
  
  
  CONCLUSIONS
  These data point to a so far unknown role of FAP in the attachment of SF to cartilage, promoting proteoglycan loss and subsequently cartilage degradation in chronic inflammatory arthritis.
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. stefan.waeldele@web.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wäldele
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. christinawunrau@gmx.de.
authors.forename: Christina
authors.initials: C
authors.lastname: Koers-Wunrau
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. denise.beckmann@uni-muenster.de.
authors.forename: Denise
authors.initials: D
authors.lastname: Beckmann
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. korba@uni-muenster.de.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Korb-Pap
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. cwehmeye@uni-muenster.de.
authors.forename: Corinna
authors.initials: C
authors.lastname: Wehmeyer
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. thomas.pap@uni-muenster.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Bldg. D3, Muenster, D-48149, Germany. dankbarb@uni-muenster.de.
authors.forename: Berno
authors.initials: B
authors.lastname: Dankbar
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology*; D010450:Endopeptidases; D018093:Gelatinases / Q000172:deficiency*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000172:deficiency; D012697:Serine Endopeptidases / Q000172:deficiency*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011509:Proteoglycans; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha