Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis

Abstract

Objectives We investigated whether inhibition of hedgehog (Hh) signal by cyclopamine attenuated inflammation and cartilage damage in adjuvant-induced arthritis (AIA) rats. Methods Cyclopamine (2.5, 5, 10 mg/kg) was given by intraperitoneal injection once daily from day 12 to 21 after AIA induction. Paw swelling (volume changes), serum pro-inflammatory cytokines levels (ELISA), histological analysis of joint damage (H&E staining), proteoglycans expression (Alcian blue staining), mRNA levels of sonic Hh (Shh), glioma-associated oncogene homologue 1 (Gli1), type II collagen (COII) and aggrecan in cartilage (real-time PCR) and articular chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) were measured respectively. Key findings Cyclopamine effectively attenuated inflammation and cartilage damage of AIA rats, as evidenced by reduced paw swelling, serum levels of tumor necrosis factors (TNF)-α, IL-1β, IL-6 and histological scores of joint damage, increased proteoglycans expression and mRNA levels of COII and aggrecan in articular cartilage. Shh or Gli1 mRNA level was correlated negatively with COII and aggrecan mRNA levels, suggesting Hh signal inhibition was associated with promotion of cartilage extracellular matrix production. Furthermore, cyclopamine decreased the number of apoptotic articular chondrocytes of AIA rats, which might be partly related to its mechanisms on relieving cartilage damage. Conclusions Our findings present some experimental evidence that Hh signal inhibition might be of potential clinical interest in rheumatoid arthritis treatment.