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

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-TNF alpha treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFa 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-TNFa 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-TNFa 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-TNFa treatment; this finding may have pathogenic and clinical implications. (C) 2015 Elsevier Inc. All rights reserved.