Abstract
Osteoclasts, bone-specialized multinucleated cells, are responsible for bone destructive diseases such as rheumatoid arthritis and osteoporosis. Natural plant-derived products have received substantial attention given their potential therapeutic and preventive activities against bone destructive diseases. In the present study, we investigated the effects of total saponin (TS) from Anemone flaccida Fr. Schmidt, on receptor activator of nuclear factor-κB ligand (RANKL)-induced in vitro osteoclast differentiation. We observed that TS concentration-dependently inhibited RANKL-induced osteoclast formation from RAW 264.7 cell and bone marrow-derived macrophages (BMMs), as well as decreased extent of actin ring formation and lacunar resorption. The RANKL-stimulated expression of osteoclast-related transcription factors were also diminished by TS. Moreover, TS blocked the RANKL-triggered TRAF6 expression, phosphorylation of mitogen-activated protein kinases (MAPKs) and IκB-α, and inhibited NF-κB p65 DNA binding activity. Furthermore, TS almost abrogated the nuclear factor of activated T cells (NFATc1) and c-Fos expression. Taken together, our results demonstrated that TS suppresses RANKL-induced osteoclast differentiation and inflammatory bone loss via the down-regulation of TRAF6 level, suppression of JNK and p38 MAPKs and NF-κB activation, and subsequent decreased expression of c-Fos and NFATc1. Therefore, TS may be a potential agent and needs to be more evaluated in vivo or in clinical trials to become a therapeutic for lytic bone diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0440-1) contains supplementary material, which is available to authorized users.
Highlights
Bone remodeling depends on the balance between bone resorption and bone formation [1]
total saponin (TS) suppresses RANKL-induced osteoclast differentiation Since RAW 264.7 macrophage-like cells can differentiate into OCL cells as described elsewhere [19], the effect of TS on RANKL-induced osteoclast formation was examined using these cells
RAW 264.7 cells cultured in the presence of RANKL form multinucleated Tartrateresistant acid phosphatase (TRAP)-positive OCL cells (Figure 1A)
Summary
Bone remodeling depends on the balance between bone resorption and bone formation [1]. An imbalance in favor of bone resorption, most often due to excess osteoclastic activity, leads to bone loss in pathological conditions such as rheumatoid arthritis (RA) and osteoporosis [2]. Osteoclasts are the primary cells responsible for bone resorption and play crucial roles in maintaining bone homeostasis and in development of pathological conditions such as joint destruction in RA [4,5,6]. The interaction of receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast differentiation and activation [7]. The binding of RANKL and RANK on osteoclast progenitor cells triggers the activation of tumor necrosis factor receptor-associated factor 6 (TRAF6) and subsequently the activation of NF-κB and mitogen-activated protein kinases (MAPKs), such as extracellular signalregulated kinase 1/2 (ERK1/2), p38 and c-Jun Nterminal kinase (JNK) [8,9,10]. The binding of RANKL and RANK on osteoclast progenitor cells triggers the activation of tumor necrosis factor receptor-associated factor 6 (TRAF6) and subsequently the activation of NF-κB and mitogen-activated protein kinases (MAPKs), such as extracellular signalregulated kinase 1/2 (ERK1/2), p38 and c-Jun Nterminal kinase (JNK) [8,9,10]. c-Fos and Nuclear factor
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