Roburic acid attenuates osteoclastogenesis and bone resorption by targeting RANKL-induced intracellular signaling pathways.

Abstract

Excessive activity of osteoclasts contributes to skeletal diseases such as osteoporosis and osteolysis. However, current drugs targeting osteoclast have various deficiencies, placing natural compounds as substitutions of great potential. Roburic acid (RA) is a triterpenoid exacted from Radix Gentianae Macrophyllae, which exhibits inhibitory effects on inflammation and oxidation. By employing an in vitro osteoclastogenesis model, this study investigates the effects and mechanisms of RA on intracellular signaling induced by receptor activator of nuclear factor-κB ligand (RANKL). As expected, RA at a concentration scope from 1 to 10 μM dampened the osteoclast differentiation of bone marrow macrophages (BMMs) but without cell toxicity. Interestingly, RA showed no effect on osteoblastogenesis in vitro. Furthermore, RA mitigated F-actin ring formation, hydroxyapatite resorption, and gene expression in osteoclasts. Mechanistically, RA suppressed TNF receptor-associated factor 6 (TRAF6), the crucial adaptor protein following RANKL-RANK binding. On the one hand, RA downregulated the nuclear factor-κB (NF-κB) activity, extracellular regulated protein kinases (ERK) phosphorylation, and calcium oscillations. On the other hand, RA upregulated the antioxidative response element (ARE) response and the protein expression of heme oxygenase (HO)-1. These upstream alterations eventually led to the suppression of the nuclear factor of activated T cells 1 (NFATc1) activity and the expression of proteins involved in osteoclastogenesis and bone resorption. Furthermore, by using an ovariectomized (OVX) mice model, RA was found to have therapeutic effects against bone loss. On account of these findings, RA could be used to restrain osteoclasts for treating osteoporosis and other osteolytic diseases.

• Authors: Gang Wang, Kai Chen, Chao Ma, Chao Wang, Delong Chen, Jianbo He, Yuhao Liu, Tao Jiang, Jinbo Yuan, Leilei Chen, Wei He, Jiake Xu
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 237 Issue 3 Pg. 1790-1803 (03 2022) ISSN: 1097-4652 [Electronic] United States
• PMID: 34796915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• NF-kappa B
• NFATC Transcription Factors
• RANK Ligand

Topics

• Animals
• Bone Resorption (drug therapy, metabolism)
• Calcium Signaling
• Cell Differentiation
• Female
• Humans
• Mice
• NF-kappa B (metabolism)
• NFATC Transcription Factors (metabolism)
• Osteoclasts (metabolism)
• Osteogenesis
• Osteoporosis (drug therapy, metabolism)
• Ovariectomy
• RANK Ligand (metabolism, pharmacology)