Rhinacanthin C Inhibits Osteoclast Differentiation and Bone Resorption: Roles of TRAF6/TAK1/MAPKs/NF-κB/NFATc1 Signaling.

Abstract

Rhinacanthin C is a naphthoquinone ester with anti-inflammatory activity, found in Rhinacanthus nasutus (L) Kurz (Acanthaceae). We found that rhinacanthin C inhibited osteoclast differentiation stimulated by the receptor activator of nuclear factor-κB ligand (RANKL) in mouse bone marrow macrophage cultures, although the precise molecular mechanisms underlying this phenomenon are unclear. In this study, we investigated the inhibitory mechanisms of rhinacanthin C in osteoclastogenesis. Rhinacanthin C suppressed RANKL-induced nuclear factor of activated T cells c1 (NFATc1) expression. Phosphorylation of ERK, JNK, and NF-κB, but not p38, was inhibited by rhinacanthin C, which also inhibited RANKL-stimulated TRAF6-TAK1 complex formation. Thus, the anti-osteoclastogenic effect of rhinacanthin C is mediated by a cascade of inhibition of RANKL-induced TRAF6-TAK1 association followed by activation of MAPKs/NF-κB; this leads to suppression of c-Fos and NFATc1, which regulate transcription of genes associated with osteoclast differentiation. In vivo, rhinacanthin C also reduced RANKL-induced osteoclast formation and bone resorption in mouse calvaria. Rhinacanthin C also suppressed LPS-stimulated osteoclastogenesis and bone resorption in vitro and in vivo. Rhinacanthin C may provide a novel therapy for abnormal bone lysis that occurs during inflammatory bone resorption.

• Authors: Mineko Tomomura, Ryuichiro Suzuki, Yoshiaki Shirataki, Hiroshi Sakagami, Nobuaki Tamura, Akito Tomomura
• Journal: PloS one (PLoS One) Vol. 10 Issue 6 Pg. e0130174 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26083531 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• NFATC Transcription Factors
• Naphthoquinones
• RANK Ligand
• TNF Receptor-Associated Factor 6
• rhinacanthin-C
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Bone Resorption (chemically induced, drug therapy, pathology)
• Cell Differentiation (drug effects)
• Enzyme Activation (drug effects)
• MAP Kinase Kinase Kinases (metabolism)
• MAP Kinase Signaling System (drug effects)
• Macrophages (cytology)
• Male
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• NFATC Transcription Factors (metabolism)
• Naphthoquinones (pharmacology, therapeutic use)
• Osteoclasts (cytology, drug effects, metabolism)
• RANK Ligand (pharmacology)
• TNF Receptor-Associated Factor 6 (metabolism)