1. Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea
2. HUONS Research Center, Hanyang University in ERICA campus, Ansan 15588, Republic of Korea
3. Division of Rheumatology, Department of Internal Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea
4. Department of Radiology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea
5. Medical Convergence Research Center, Wonkwang University Hospital, 460 Iksandae-ro, Iksan, Jeonbuk 570-749, Republic of Korea
#These authors contributed equally to this work.
Excessive bone resorption plays a central role in the development of inflammatory bone diseases, including osteoporosis and rheumatoid arthritis. Thus, identification of agents that can effectively suppress excessive osteoclast formation and function is crucial for the prevention and treatment of inflammatory bone loss. Umbelliferone (Umb), a derivative of coumarin, is a natural bioactive compound with anti-inflammatory and antioxidant properties. However, the effect of Umb on metabolic bone diseases is unknown. In this study, we found that Umb exhibited a strong inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory bone loss in vivo. Histological analysis confirmed that Umb prevented trabecular bone matrix degradation and osteoclast formation in bone tissue. In addition, Umb suppressed RANKL-induced osteoclast differentiation and abrogated bone resorption. We found that the anti-osteoclastic and anti-resorptive activities of Umb are mediated via suppression of the RANKL-induced Akt-c-Fos-NFATc1 signaling pathway and the attenuation of osteoclast-specific genes, such as TRAP, OSCAR, ATP6v0d2, and CtsK. In particular, Umb downregulated the stability of c-Fos and NFATc1 proteins, but did not suppress the expression of their mRNAs. These results indicate that Umb may be a potential therapeutic agent for inflammatory bone diseases associated with abnormal osteoclast formation and function.
Keywords: umbelliferone, inflammatory bone diseases, osteoclast, Akt-c-Fos-NFATc1 signaling, bone resorption