Gefitinib enhances healing of long bone fractures in rats via inhibition of the epidermal growth factor receptor signal pathway

Abstract

Purpose: To investigate the influence of gefitinib on healing of long bone fractures in rats, and the involvement of epidermal growth factor receptor (EGFR) signal route in the process. Methods: A model of long bone fracture was established in 30 Sprague-Dawley (SD) rats which were allocated to control and study groups (n = 15/group). Rats in study group received gefitinib (100 mg/kg per day) via gavage, while control rats were given 0.55 % methylcellulose daily for 7 - 42 days. Fracture healing, maximum callus diameter, serum levels of bone markers and mRNA levels of bone turnover indices in the callus, were determined. Results: Following 1 week of therapy, fracture lines were clear in both groups, and callus was produced. On days 7, 14, 21, and 28, maximum callus diameter of study group was significantly higher than that of control group (p < 0.05). However, there was no significant difference in the maximum callus diameter between the two groups after 42 days (p > 0.05). On days 7, 14 and 21, there were significantly higher BALP and PINP levels, and TRACP-5b and CTX values in study group than in control (p < 0.05). On days 7 and 14, study group COLa1 mRNA and osteocalcin (OC) mRNA was significantly raised, relative to control values. On days 7, 14 and 21, COL10 mRNA expression was significantly up-regulated in study group relative to controls (p < 0.05). However, mRNA expression levels of COLa1, OC, COL10, and COL2A1 were similar in both groups at other time points. Conclusion: Gefitinib enhances the healing of long bone fractures and callus formation in rats, probably through inhibition of EGFR signaling pathway. Therefore, gefitinib is beneficial in bone formation in rats.