Abstract
Osteoblasts and osteoclasts play a pivotal role in maintaining bone homeostasis, of which excessive bone resorption by osteoclasts can cause osteoporosis and various bone diseases. However, current osteoporosis treatments have many side effects, and research on new treatments that can replace these treatments is ongoing. Therefore, in this study, the roles of ligustroside (LGS) and oleoside dimethylester (ODE), a natural product-derived compound isolated from Syringa oblata subsp. dilatata as a novel, natural product-derived osteoporosis treatments were investigated. In the results of this study, LGS and ODE inhibited the differentiation of receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced RAW264.7 cells into osteoclasts without cytotoxicity, and down-regulated the activity of TRAP, a specific biomarker of osteoclasts. In addition, it inhibited bone resorption and actin ring formation, which are important functions and features of osteoclasts. Also, the effects of LGS and ODE on the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and phosphoinositide 3-kinases (PI3K)/ protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) signaling pathways that play important roles in osteoclast differentiation were evaluated. In the results, LGS and ODE downregulated the phosphorylation of RANKL-induced MAPK and PI3K/Akt/mTOR proteins in a concentration-dependent manner, translocation of NF-κB into the nucleus was inhibited. As a result, the compounds LGS and ODE isolated from S. oblate subsp. dilatata effectively regulated the differentiation of RANKL-induced osteoclasts and inhibited the phosphorylation of signaling pathways that play a pivotal role in osteoclast differentiation. Therefore, these results suggest the possibility of LGS and ODE as new natural product treatments for bone diseases caused by excessive osteoclasts.
Highlights
Osteoporosis affects men as well as postmenopausal women, and most fractures occur mainly in the hip, spine, and wrist [1]
The receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK) pathway plays a critical role in bone remodeling and a pathway associated with osteoclast and osteoblast, and when progenitor cells such as macrophage are stimulated with RANKL and M-CSF, differentiation into osteoclasts occurs [12]
In our recent chemical investigation of S. olbata subsp. dilatata, we identified 15 secoiridoid glucosides, including two new secoiridoid glucosides, ligustroside (LGS) and oleoside dimethylester (ODE), which were evaluated for their effects on the induction of nerve growth factor (NGF) secretion in a C6 rat glioma cell line and their cytotoxicity against several cancer cell lines [18]
Summary
Osteoporosis affects men as well as postmenopausal women, and most fractures occur mainly in the hip, spine, and wrist [1]. An important role in the treatment of osteoporosis is directly related to the recovery of bone cells, and osteoporosis is mainly caused by excessive bone resorption due to excessive osteoclast formation [11]. The receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK) pathway plays a critical role in bone remodeling and a pathway associated with osteoclast and osteoblast, and when progenitor cells such as macrophage are stimulated with RANKL and M-CSF, differentiation into osteoclasts occurs [12]. In this study, the effects of LGS and ODE on osteoclast differentiation in RAW264.7 macrophages induced osteoclast differentiation with RANKL were investigated
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