Oleanolic acid acetate inhibits osteoclast differentiation by downregulating PLCγ2–Ca2+-NFATc1 signaling, and suppresses bone loss in mice

Kim, Ju‐Young; Cheon, Yoon‐Hee; Oh, Hyun Mee; Rho, Mun Chual; Erkhembaatar, Munkhsoyol; Kim, Min Seuk; Lee, Chang Hoon; Kim, Jeong Joong; Choi, Min Kyu; Yoon, Kwon‐Ha; Lee, Myeung Su; Oh, Jae‐Min

doi:10.1016/j.bone.2013.12.013

Cited by 56 publications

(51 citation statements)

References 40 publications

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“…All experiments were conducted according to the guidelines of the Institutional Animal Care and Use Committee of Wonkwang University (WKU-14-23; Iksan, Korea). BMMs from mice were cultured as described previously (14). Briefly, to obtain BMMs, BMCs were cultured in α-MEM supplemented with 10% FBS and M-CSF (10 ng/ml) for 1 day.…”

Section: Methodsmentioning

confidence: 99%

Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro

Baek

Ahn

Cheon

et al. 2016

Molecular Medicine Reports

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The adipokine nicotinamide phosphoribosyltransferase (Nampt), also known as pre-B-cell colony-enhancing factor or the insulin-mimetic hormone visfatin, has a crucial role in the conversion of nicotinamide to nicotinamide mononucleotide during biosynthesis of the coenzyme nicotinamide adenine dinucleotide. Previous reports have demonstrated the inhibitory effects of Nampt on osteoclast formation from human peripheral blood mononuclear cells and CD14+ monocytes. However, the effects of Nampt on bone marrow macrophage (BMM)-derived osteoclastogenesis and its precise role in the process remain unclear. The present in vitro study used recombinant Nampt and BMMs as osteoclast precursors demonstrated that Nampt suppresses receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis by decreasing the phosphorylation of various early signal transducers, including c-Jun N-terminal kinase, Akt, glycogen synthase kinase-3 β, Bruton's tyrosine kinase and phospholipase C γ-2. In addition, western blotting and reverse transcription-quantitative polymerase chain reaction analysis indicated that Nampt downregulates the mRNA and protein expression levels of c-Fos and nuclear factor of activated T cells, cytoplasmic 1, leading to a decrease in the expression of osteoclast-specific genes including tartrate-resistant acid phosphatase, osteoclast-associated receptor and cathepsin K. However, the bone-resorbing activity of mature osteoclasts treated with Nampt was similar to untreated control osteoclasts. This finding indicates that Nampt exerts its anti-osteoclastogenic activity by targeting osteoclast precursor cells rather than mature osteoclasts. Consequently, the present study demonstrated that Nampt acts as a negative regulator of RANKL-mediated differentiation of BMMs into osteoclasts, suggesting the potential therapeutic targets to treat bone-related disorders such as osteoporosis.

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Section: Methodsmentioning

confidence: 99%

Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro

Baek

Ahn

Cheon

et al. 2016

Molecular Medicine Reports

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“…Western blot analysis, and quantitative RT-PCR were performed as described previously (Kim et al, 2014c). We performed Western blotting by using 1:1000 dilution of primary antibodies with a source of rabbit or mouse reconstituted at 1 mg/mL and 1:3000 anti-rabbit and -mouse secondary antibodies reconstituted at 0.4 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…Histone deacetylase inhibitors (HDACis) have exerted potent osteogenic potential related to stability of Runx2 by deacetylases (Kim et al, 2011, Jeon et al, 2006). As such there have been a great number of small molecules or natural products that have been shown to affect osteoclastogenesis (Kim et al, 2014a, Kim et al, 2014a, Lee et al, 2014, Kwak et al, 2010). Although the RANKL/RANK axis is the master regulator for osteoclastogenesis, precise underlying mechanisms for contribution of many coupling factors such as SOST, semaphorin, OSCAR, FcR or OC-STAMP to osteoclastogenesis remains to be explored (Honma et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Massive elimination of multinucleated osteoclasts by eupatilin is due to dual inhibition of transcription and cytoskeletal rearrangement

et al. 2015

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Osteoporosis is an aging-associated disease requiring better therapeutic modality. Eupatilin is a major flavonoid from Artemisia plants such as Artemisia princeps and Artemisia argyi which has been reported to possess various beneficial biological effects including anti-inflammation, anti-tumor, anti-cancer, anti-allergy, and anti-oxidation activity. Complete blockade of RANK-dependent osteoclastogenesis was accomplished upon stimulation prior to the receptor activator of nuclear factor κB (RANK)-ligand (RANKL) treatment or post-stimulation of bone marrow macrophages (BMCs) in the presence of RANKL with eupatilin. This blockade was accompanied by inhibition of rapid phosphorylation of Akt, GSK3β, ERK and IκB as well as downregulation of c-Fos and NFATc1 at protein, suggesting that transcriptional suppression is a key mechanism for anti-osteoclastogenesis. Transient reporter assays or gain of function assays confirmed that eupatilin was a potent transcriptional inhibitor in osteoclasts (OC). Surprisingly, when mature osteoclasts were cultured on bone scaffolds in the presence of eupatilin, bone resorption activity was also completely blocked by dismantling the actin rings, suggesting that another major acting site of eupatilin is cytoskeletal rearrangement. The eupatilin-treated mature osteoclasts revealed a shrunken cytoplasm and accumulation of multi-nuclei, eventually becoming fibroblast-like cells. No apoptosis occurred. Inhibition of phosphorylation of cofilin by eupatilin suggests that actin may play an important role in the morphological change of multinucleated cells (MNCs). Human OC similarly responded to eupatilin. However, eupatilin has no effects on osteoblast differentiation and shows cytotoxicity on osteoblast in the concentration of 50 μM. When eupatilin was administered to LPS-induced osteoporotic mice after manifestation of osteoporosis, it prevented bone loss. Ovariectomized (OVX) mice remarkably exhibited bone protection effects. Taken together, eupatilin is an effective versatile therapeutic intervention for osteoporosis via; 1) transcriptional suppression of c-Fos and NFATc1 of differentiating OC and 2) inhibition of actin rearrangement of pathogenic MNCs.

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“…Osteoclast pit assay is based on the previous report [23]. Briefly, BMCs and primary osteoblasts were cocultured in collagen gel-coated culture dishes for 7 days in the presence of 1,25-dihydroxyvitamin D 3 (VitD 3 ) (Sigma) and prostaglandin E 2 (PGE 2 ) (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, numerous studies have been performed to investigate whether various natural extracts or representative compounds from oriental herbs exhibit a dual effect by inhibiting osteoclast differentiation, in addition to enhancing osteoblast differentiation, in order to identify novel therapeutic materials for treating bone disorders such as osteoporosis and rheumatoid arthritis [20–23]. To discover new extracts or functional food that can act as antiosteoporosis agent that promotes bone anabolic activity and inhibits osteoclast differentiation, we screened 20 natural extracts using analysis of TRAP staining and ALP staining and found that Chrysanthemum indicum has stimulatory effects on osteoblast differentiation and inhibitory effects on osteoclast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Dual Effect of Chrysanthemum indicum Extract to Stimulate Osteoblast Differentiation and Inhibit Osteoclast Formation and Resorption In Vitro

Baek

Kim

Cheon

et al. 2014

Evidence-Based Complementary and Alternative Medicine

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The risk of bone-related diseases increases due to the imbalance between bone resorption and bone formation by osteoclasts and osteoblasts, respectively. The goal in the development of antiosteoporotic treatments is an agent that will improve bone through simultaneous osteoblast stimulation and osteoclast inhibition without undesirable side effects. To achieve this goal, numerous studies have been performed to identify novel approaches using natural oriental herbs to treat bone metabolic diseases. In the present study, we investigated the effect of Chrysanthemum indicum extract (CIE) on the differentiation of osteoclastic and osteoblastic cells. CIE inhibited the formation of TRAP-positive mature osteoclasts and of filamentous-actin rings and disrupted the bone-resorbing activity of mature osteoclasts in a dose-dependent manner. CIE strongly inhibited Akt, GSK3β, and IκB phosphorylation in RANKL-stimulated bone marrow macrophages and did not show any effects on MAP kinases, including p38, ERK, and JNK. Interestingly, CIE also enhanced primary osteoblast differentiation via upregulation of the expression of alkaline phosphatase and the level of extracellular calcium concentrations during the early and terminal stages of differentiation, respectively. Our results revealed that CIE could have a potential therapeutic role in bone-related disorders through its dual effects on osteoclast and osteoblast differentiation.

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Oleanolic acid acetate inhibits osteoclast differentiation by downregulating PLCγ2–Ca2+-NFATc1 signaling, and suppresses bone loss in mice

Cited by 56 publications

References 40 publications

Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro

Nicotinamide phosphoribosyltransferase inhibits receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation in vitro

Massive elimination of multinucleated osteoclasts by eupatilin is due to dual inhibition of transcription and cytoskeletal rearrangement

Dual Effect of Chrysanthemum indicum Extract to Stimulate Osteoblast Differentiation and Inhibit Osteoclast Formation and Resorption In Vitro

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