Xiang Zhu MD, Junjie Gao BSc, Pei Y. Ng PhD, An Qin MD, PhD, James H. Steer BSc, Nathan J. Pavlos PhD, Ming H. Zheng MD, PhD, ARCPA, FRACSPath, Yang Dong MD and Tak S. Cheng PhD
Aseptic loosening and periprosthetic infection leading to inflammatory osteolysis is a major complication associated with total joint arthroplasty (TJA). The liberation of bacterial products and/or implant-derived wear particles activates immune cells which produce pro-osteoclastogenic cytokines that enhances osteoclast recruitment and activity leading to bone destruction and osteolysis. Therefore agents which prevent the inflammatory response and/or attenuate excessive osteoclast (OC) formation and bone resorption offer therapeutic potential by prolonging the life of TJA implants. Alexidine dihydrochloride (AD) is a bisbiguanide compound commonly used as an oral disinfectant and in contact lens solutions. It possesses anti-microbial, anti-inflammatory and anti-cancer properties however its effects on OC biology are poorly described. Here, we demonstrate that AD inhibits OC formation and bone resorption in vitro and exert prophylatic protection against LPS-induced osteolysis in vivo. Biochemical analysis demonstrated that AD suppressed RANKL-induced activation of MAPKs (ERK, p38 and JNK) leading to the downregulation of NFATc1. Furthermore, AD disrupted F-actin ring formation and attenuated the ability of mature OC to resorb bone. Collectively our findings suggest that AD may be a promising prophylactic anti-osteoclastic/resorptive agent for the treatment of osteolytic diseases caused by excessive OC formation and function.