Inhibition of Osteoclast Differentiation by Ginsenoside Rg3 in RAW264.7 Cells via RANKL, JNK and p38 MAPK Pathways Through a Modulation of Cathepsin K: An In Silico and In Vitro Study

Abstract

Various studies have demonstrated that overexpression of cathepsin K (Cat-K) causes excessive bone loss, which ultimately leads to a variety of bone diseases including osteoporosis. Therefore, inhibition of Cat-K signifies a potential therapeutic target in osteoporosis treatment. Ginsenoside Rg3 is one of the most promising compound of Panax ginseng Meyer (P. ginseng) with numerous biological activities. Thus, in recent study the inhibitory effect of Rg3 isolated from P. ginseng was investigated in order to impede the osteoclast activity by an in silico approach followed by in vitro study validation using RAW264.7 cells through the investigation of different biological activity prediction such as absorption distribution metabolism and excretion (ADMET) properties against Cat-K protein. The docking results of our study showed that Rg3 is a non-toxic compound and may act as a drug-like molecule. Additionally, the molecular interaction of Rg3 with the active residues of Cat-K markedly describes its inhibitory effects on osteoclastogenesis. Findings of the present study exhibited that Rg3 significantly reduced receptor activator of nuclear factor kappa B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP) activity, pit formation (actin rings), and TRAP-positive multinucleated cells development in RAW264.7 cells. Furthermore, Rg3 dose-dependently reduced the mRNA expression levels of osteoclast-specific markers such as RANK, TRAP, and Cat-K induced by RANKL through the down regulation of p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase (JNK) pathways. In conclusion, in silico docking study and in vitro validation together suggested that Rg3 inhibits osteoclastogenesis and reduces bone resorption through the inhibition of Cat-K. Therefore, Rg3 might be a useful therapeutic agent for the treatment of osteoporosis and proper bone formation. Copyright © 2015 John Wiley & Sons, Ltd.

Effects of cathepsin K on Emdogain-induced hard tissue formation by human periodontal ligament stem cells

“…The particular cell morphology changes indicated that mesenchymal cells differentiated into epithelial cells (osteoblasts/cementoblasts in the present study); thus, CTSK affected the differentiation of PDLSCs. Previous studies on the role of CTSK in cell differentiation have mainly focused on osteoclast differentiation (Siddiqi et al ., ). In addition, CTSK regulates adipogenic (Han et al ., ) and osteogenic differentiation (Morko et al ., ).…”

Ginsenosides induce extensive changes in gene expression and inhibit oxidative stress-induced apoptosis in human lens epithelial cells

“…RAD23B, MAPK8 and TLK2 have been shown to be involved in DNA damage response [18]. Effect of ginsenosides on MAPK has been well documented [19][20][21]. A Chinese herbal medicine containing ginsenosides was found to attenuate H 2 O 2 -induced injury in PC12 cells by inhibiting Akt and MAPK signaling pathways [22].…”

Bromo-honaucin A inhibits osteoclastogenic differentiation in RAW 264.7 cells via Akt and ERK signaling pathways

“…Over expression of cathepsin K causes excessive bone loss (Siddiqi et al, 2015; Zhuoet al, 2014). In this study, we found that Br-H A reduced the RANKL-induced expression of cathepsin K. TRAP is an iron-binding protein that is highly expressed in osteoclasts and also induced in differentiation of osteoclasts (Reddy et al, 1995).…”