Abstract
BackgroundNatural plants, including common vegetables and fruits, have been recognized as essential sources for drug discovery and the development of new, safe, and economical medicaments. Stauntonia hexaphylla (Lardizabalaceae) is widely distributed in Korea, Japan, and China, and is a popular herbal supplement in Korean and Chinese folk medicine owing to its analgesic, sedative, and diuretic properties. However, the exact pharmacological effects of S. hexaphylla extract, particularly its effect on osteoclastogenesis, are not known.MethodsOsteoclast differentiation and function were identified with tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay, and the underling mechanisms were determined by real-time RT-PCR and western blot analysis.ResultsS. hexaphylla was found to inhibit early-stage receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without cytotoxicity and bone-resorbing activity in mature osteoclasts in a dose-dependent manner. This S. hexaphylla-mediated blockade of osteoclastogenesis involved abrogation of the NF-κB, ERK, and c-Src-Btk-PLCγ2 calcium signal pathways. Interestingly, we found that S. hexaphylla down-regulated RANKL-associated c-Fos protein induction by suppressing its translation. Furthermore, ectopic overexpression of c-Fos and NFATc1 rescued the inhibition of osteoclast differentiation by S. hexaphylla. Furthermore, S. hexaphylla inhibited the c-Fos- and NFATc1-regulated expression of genes required for osteoclastogenesis, such as TRAP, OSCAR, β3-integrin, ATP6v0d2, and CtsK.ConclusionsThese findings suggest that S. hexaphylla might be useful for the development of new anti-osteoporosis agents.
Highlights
Natural plants, including common vegetables and fruits, have been recognized as essential sources for drug discovery and the development of new, safe, and economical medicaments
S. hexaphylla suppresses RANKL-induced osteoclast differentiation in bone marrow macrophages (BMMs) and bone resorption by co-cultured mature osteoclast To identify the efficacy of S. hexaphylla on RANKLinduced osteoclastogenesis, BMMs were cultured in the presence of RANKL and macrophage colony-stimulating factor (M-CSF) treated with or without various concentrations of S. hexaphylla
RANKL differentiated the BMMs of the control into TRAPpositive multinucleated cells (MNCs), and S. hexaphylla dose-dependently decreased the formation of tartrate-resistant acid phosphatase (TRAP)- positive MNCs (Fig. 1a and b)
Summary
Natural plants, including common vegetables and fruits, have been recognized as essential sources for drug discovery and the development of new, safe, and economical medicaments. Current anti-osteoporosis drugs such as estrogen, raloxifene, bisphosphonates, and calcitonin have been widely used, and their bone protective mechanisms are based on the inhibition osteoclastic bone resorption. These drugs have numerous side effects, causing many patients to discontinue their use [4,5,6,7]. A more detailed mechanism is still expected to be unveiled, the major signaling events have been elucidated: RANK/RANKL binding activates downstream early signaling pathways, including mitogen-activated protein kinase (MAPK) pathways and NF-κB, by recruitment of TNF-receptor associated factor 6 (TRAF6), which regulates transcription factors involved in osteoclast differentiation [11, 12]. Calcineurin inhibitors, such as FK506 and cyclosporine A, as well as the Ca2+ chelator BAPTA-AM, potently suppress RANKL-induced osteoclastogenesis through inhibition of NFATc1 nuclear translocation [19]
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