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.
Highlights
Bone formation by osteoblasts and bone resorption by osteoclasts are balanced to maintain bone homeostasis
We previously reported that rhinacanthin C is a strong inhibitor of RANKL-stimulated Tartrate-resistant acid phosphatase (TRAP)-positive doi:10.1371/journal.pone.0130174.g001
We investigated the effects of rhinacanthin C on osteoclast differentiation and bone resorption pit formation
Summary
Bone formation by osteoblasts and bone resorption by osteoclasts are balanced to maintain bone homeostasis. Receptor activator of nuclear factor-κB ligand (RANKL), proinflammatory cytokines (TNF-α, IL-1), and lipopolysaccharide (LPS) induce osteoclast differentiation and activation [1,2,3,4]. RANKL, which is produced by osteoblasts and bone marrow stromal cells, binds to RANK on monocyte/macrophages followed by receptor oligomerization and recruitment of signaling adapter molecules such as TNF receptor-associated factor-κB ligand 6 (TRAF6). Subsequent TRAF6-TAK1 association activates the downstream signaling pathways NF-κB and activator protein 1 (AP-1) (c-Fos/c-Jun dimer) and induces expression of NFATc1, which is the master osteoclast regulator [1,5]. Interference with these signaling pathways may prevent excessive osteoclast formation and pathological bone loss
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