Abstract
Osteoclasts are multinuclear giant cells that have unique ability to degrade bone. The search for new medicines that modulate the formation and function of osteoclasts is a potential approach for treating osteoclast-related bone diseases. Piceatannol (PIC) is a natural organic polyphenolic stilbene compound found in diverse plants with a strong antioxidant and anti-inflammatory effect. However, the effect of PIC on bone health has not been scrutinized systematically. In this study, we used RAW264.7, an osteoclast lineage of cells of murine macrophages, to investigate the effects and the underlying mechanisms of PIC on osteoclasts. Here, we demonstrated that PIC treatment ranging from 0 to 40 µM strongly inhibited osteoclast formation and bone resorption in a dose-dependent manner. Furthermore, the inhibitory effect of PIC was accompanied by the decrease of osteoclast-specific genes. At the molecular level, PIC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2), NF-κB p65, IκBα and AKT. Besides, PIC promoted the apoptosis of mature osteoclasts by inducing caspase-3 expression. In conclusion, our results suggested that PIC inhibited RANKL-induced osteoclastogenesis and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promoted caspase3-mediated apoptosis of mature osteoclasts, which might contribute to the treatment of bone diseases characterized by excessive bone resorption.
Highlights
Bone homeostasis is maintained by the precise balance between bone formation and bone resorption, which are carried out by osteoblasts and osteoclasts, respectively [1]
NFATc1 plays an important role in osteoclast formation and function by regulating a number of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase 9 (MMP-9) and dendritic cell-specific transmembrane protein (DC-STAMP) [11]
Ke et al [20] demonstrated that PIC decreased the expression of miR-183, resulting in suppressed osteoclastogenesis. These findings have provided an understanding of the effects of PIC on osteoclast formation, the precise underlying mechanism of PIC on osteoclast differentiation and bone resorption from receptor activator of NF-kB ligand (RANKL)-induced RAW264.7 cells remains unclear
Summary
Bone homeostasis is maintained by the precise balance between bone formation and bone resorption, which are carried out by osteoblasts and osteoclasts, respectively [1]. Mouse monocyte/macrophage cell lineage (RAW264.7) can be induced to differentiate into osteoclasts by RANKL in the absence of M-CSF [9,10]. The binding of RANKL to its receptor RANK leads to the recruitment of tumour necrosis factor receptor-associated factor 6 (TRAF6), which activates several downstream signalling pathways including NF-kB, MAPKs (ERK, JNK and p38) and Src/PI3K/AKT [11]. These events lead to the expression of NFATc1, a master regulator for osteoclastogenesis [12]. The agents that suppress RANKL-mediated signalling pathways can be a potential therapeutic target
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