title: Anti-TNFα treatment decreases the previously increased serum Indian Hedgehog levels in patients with ankylosing spondylitis and affects the expression of functional Hedgehog pathway target genes.
abstract: OBJECTIVE
  Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton-the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation.
  
  
  METHODS
  Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model.
  
  
  RESULTS
  Patients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment.
  
  
  CONCLUSIONS
  Ihh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications.
authors.affiliation: Department of Rheumatology, University of Patras Medical School, Patras University Hospital, Rion 26504, Patras, Greece. Electronic address: jimdaoussis@hotmail.com.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Daoussis
authors.affiliation: Department of Rheumatology, University of Patras Medical School, Patras University Hospital, Rion 26504, Patras, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Filippopoulou
authors.affiliation: Department of Rheumatology, University of Patras Medical School, Patras University Hospital, Rion 26504, Patras, Greece.
authors.forename: Stamatis-Nick
authors.initials: SN
authors.lastname: Liossis
authors.affiliation: Clinical and Molecular Oncology Laboratoty, University of Patras Medical School, Patras University Hospital, Rion, Patras, Greece.
authors.forename: Chaido
authors.initials: C
authors.lastname: Sirinian
authors.affiliation: Department of Rheumatology, University of Patras Medical School, Patras University Hospital, Rion 26504, Patras, Greece.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Klavdianou
authors.affiliation: Department of Chemistry, University of Patras, Rion, Patras, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Bouris
authors.affiliation: Department of Chemistry, University of Patras, Rion, Patras, Greece.
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.affiliation: Department of Rheumatology, University of Patras Medical School, Patras University Hospital, Rion 26504, Patras, Greece.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Andonopoulos
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D016022:Case-Control Studies; D002460:Cell Line; D000068800:Etanercept / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010006:Osteoblasts; D010012:Osteogenesis / Q000235:genetics; D015398:Signal Transduction; D013167:Spondylitis, Ankylosing / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D053823:Hedgehog Proteins; C509246:IHH protein, human; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab; D000068800:Etanercept
keywords: Ankylosing spondylitis; Anti-TNFα treatment; Endochondral ossification; Indian Hedgehog; New bone formation; TNFα blockers