Forsythia suspensa Protects against Bone Loss in Ovariectomized Mice

In traditional oriental medicine, the fruit of Forsythia suspensa has been used as a nutritional supplement to alleviate inflammation and treat gastrointestinal diseases. However, there is no information available on its beneficial effects on bone. We investigated the beneficial effects of F. suspensa water extract (WFS) on osteoclast differentiation and bone loss. The microarchitecture of trabecular bone was analyzed by micro-computed tomography. Osteoclast differentiation was evaluated based on tartrate-resistant alkaline phosphatase activity, and bone resorption activity was examined on a bone-like mineral surface. The mechanism of action of WFS was assessed by evaluating the expression and activation of signaling molecules. Phytochemical constituents were identified and quantitated by ultrahigh-performance liquid chromatography–tandem mass spectrometry. WFS reduced ovariectomy-induced trabecular bone loss and inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation and resorption activity. WFS suppressed RANKL-induced expression of nuclear factor of activated T cells cytoplasmic 1, a crucial transcription factor for osteoclast differentiation by decreasing c-Fos protein levels and suppressing the activation of p38 and c-Jun-N-terminal kinase. We also identified 12 phytochemicals in WFS including lignans, phenylethanoids, and flavonoids. Collectively, these results suggest that WFS inhibits osteoclast differentiation and can potentially be used to treat postmenopausal osteoporosis.

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Water Extract of Lysimachia christinae Inhibits Trabecular Bone Loss and Fat Accumulation in Ovariectomized Mice

Nutrients ◽

10.3390/nu12071927 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1927

Author(s):

Ki-Shuk Shim ◽

Youn-Hwan Hwang ◽

Seon-A Jang ◽

Taesoo Kim ◽

Hyunil Ha

Keyword(s):

Bone Loss ◽

Trabecular Bone ◽

Body Weight Gain ◽

Osteoclast Differentiation ◽

Water Extract ◽

Mitogen Activated Protein Kinase ◽

Nuclear Factor ◽

Fat Accumulation ◽

Ovariectomized Mice ◽

Trabecular Bone Loss

In Asia, extracts of Lysimachia christinae have been used for liver or urinogenital system-related diseases in traditional medicine. In this study, we investigated the effects of the water extract of L. christinae (WELC) on receptor activator of nuclear factor-kappa Β ligand (RANKL)-induced osteoclastic differentiation of bone marrow macrophages, and on osteoporosis and obesity in ovariectomy mice. RANK signaling pathways related to osteoclast differentiation were examined by real-time polymerase chain reaction (PCR) and western blot analysis. Additionally, we performed micro-computed tomography to assess trabecular bone loss, histological analysis for fat accumulation in adipose, liver, and bone tissues, and phytochemical profiling for WELC characterization. WELC significantly inhibited osteoclast differentiation by downregulating RANKL-induced mitogen-activated protein kinase (MAPK)/c-Fos/nuclear factor of activated T-cells (NFAT) signaling in osteoclast precursors and ovariectomy-induced trabecular loss by suppressing osteolcastic bone resorption. WELC markedly decreased ovariectomy-induced body weight gain and fat accumulation in adipose, liver, and bone tissues. Furthermore, ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) identified 16 phytochemicals in WELC when compared with the mass fragmentation of standard chemicals. Collectively, these results suggest that WELC might possess beneficial effects on postmenopausal osteoporosis by inhibiting osteoclast differentiation and obesity by suppressing fat accumulation.

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Anti-Osteoporotic Effects of Commiphora Myrrha and Its Poly-Saccharide via Osteoclastogenesis Inhibition

Plants ◽

10.3390/plants10050945 ◽

2021 ◽

Vol 10 (5) ◽

pp. 945

Author(s):

Youn-Hwan Hwang ◽

Ami Lee ◽

Taesoo Kim ◽

Seon-A Jang ◽

Hyunil Ha

Keyword(s):

Bone Loss ◽

Osteoclast Differentiation ◽

Water Extract ◽

Nuclear Factor Κb ◽

Herbal Remedies ◽

Specific Gene ◽

Nuclear Factor ◽

Activated T Cells ◽

Herbal Products ◽

Marrow Cavity

In traditional oriental medicines, Commiphora myrrha and its resinous exudate (i.e., myrrh) are used as herbal remedies to treat various inflammatory and metabolic disorders. Until now, C. myrrha-derived herbal products are considered useful source for bioactive compounds to manage numerous human diseases. This study investigated the effects of water extract of C. myrrha resin (WCM) and its polysaccharide (WCM-PE) on modulatory effects of osteoclast differentiation and/or ovariectomized-induced bone loss. Oral administration of WCM (200 and 500 mg/kg/day for four weeks) notably decreased trabecular bone loss and lipid accumulation in the bone marrow cavity. WCM and WCM-PE dose-dependently inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis and suppressed RANKL-mediated overexpression of c-Fos and nuclear factor of activated T cells, cytoplasmic 1, thereby downregulating osteoclast-specific gene (Atp6v0d2, DC-STAMP and cathepsin K) expression. Thus, our results suggest that WCM and WCM-PE are promising nutraceutical candidates for the management of osteoporosis in postmenopausal women.

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Water Extract of Agastache rugosa Prevents Ovariectomy-Induced Bone Loss by Inhibiting Osteoclastogenesis

Foods ◽

10.3390/foods9091181 ◽

2020 ◽

Vol 9 (9) ◽

pp. 1181

Author(s):

Seon-A Jang ◽

Youn-Hwan Hwang ◽

Taesoo Kim ◽

Hyun Yang ◽

Jun Lee ◽

...

Keyword(s):

Bone Loss ◽

Postmenopausal Osteoporosis ◽

Osteoclast Differentiation ◽

Water Extract ◽

Nuclear Factor Κb ◽

Estrogen Deficiency ◽

Nuclear Factor ◽

Agastache Rugosa ◽

Activated T Cells ◽

Food Ingredients

Estrogen deficiency in postmenopausal women causes homeostatic imbalance of bone, resulting in bone loss and osteoporosis. Agastache rugosa, a plant belonging to the Lamiaceae family, is an aromatic herb, and the leaves of this herb are widely used as food ingredients. Extracts of A. rugosa have various bioactivities including anti-HIV integration, anti-inflammatory, and anti-atherogenic properties. However, the beneficial effect of A. rugosa on bone has not been studied. Therefore, we investigated the effects of water extract of A. rugosa (WEAR) on osteoclast differentiation and estrogen deficiency-induced bone loss in ovariectomized (OVX) mice as an animal model for postmenopausal osteoporosis. The oral administration of WEAR remarkably improved OVX-induced trabecular bone loss and fat accumulation in the bone marrow. WEAR suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation in osteoclast precursor cells, subsequently inhibiting resorption activity on a bone mimetic surface. WEAR inhibited the expression of cellular oncogene fos (c-Fos) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), key osteoclastogenic transcription factors, by decreasing RANKL-induced activation of mitogen-activated protein kinases (MAPKs), and nuclear factor-κB (NF-κB) pathways. We also identified seventeen phytochemicals present in WEAR, including five phenols and twelve flavonoids, and found eleven bioactive constituents that have anti-osteoclastogenic effects. Collectively, these results suggest that WEAR could be used to treat and prevent postmenopausal osteoporosis by suppressing osteoclastogenesis.

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Poria Cocos Ameliorates Bone Loss in Ovariectomized Mice and Inhibits Osteoclastogenesis In Vitro

Nutrients ◽

10.3390/nu12051383 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1383 ◽

Cited By ~ 1

Author(s):

Youn-Hwan Hwang ◽

Seon-A Jang ◽

Ami Lee ◽

Taesoo Kim ◽

Hyunil Ha

Keyword(s):

Bone Loss ◽

Postmenopausal Osteoporosis ◽

Osteoclast Differentiation ◽

Nuclear Factor ◽

Bone Homeostasis ◽

Estrogen Deprivation ◽

Activated T Cells ◽

Poria Cocos ◽

Ovariectomized Mice

Estrogen deprivation in postmenopausal women causes disruption of bone homeostasis, resulting in bone loss and osteoporosis. Conventional therapies can exert adverse effects. The sclerotum of Poria cocos has been used in traditional medicine and as a nutritional supplement and to treat various diseases. However, the effects of P. cocos on the bone remain largely undetermined. In this study, we examined the effects of P. cocos hydroethanolic extract (PC) on osteoclast differentiation and estrogen-deprivation-induced bone loss in an ovariectomized mouse model of postmenopausal osteoporosis. PC-mediated inhibition of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation and resorption activity suppressed RANKL-induced expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which is a crucial transcription factor for osteoclast differentiation. In ovariectomized mice, PC markedly alleviated trabecular bone loss and reduced the accumulation of lipid droplets in the bone marrow. We additionally identified ten triterpenoid constituents of PC using UPLC-MS/MS analysis. Our results indicate that PC negatively regulated osteoclast differentiation and function, and can potentially be used to manage postmenopausal osteoporosis.

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Water Extract ofDryopteris crassirhizomaAttenuates Bone Loss by Suppressing Osteoclast Differentiation and Function

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/852648 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Hyunil Ha ◽

Ki-Shuk Shim ◽

Taesoo Kim ◽

Hyosun An ◽

Jin Yeul Ma

Keyword(s):

Bone Loss ◽

Protective Effect ◽

Osteoclast Differentiation ◽

Water Extract ◽

Inhibitory Effect ◽

Ring Structure ◽

Nuclear Factor ◽

Actin Ring ◽

Activated T Cells ◽

Osteoclast Precursors

The rhizome ofDryopteris crassirhizomahas been used as a traditional herbal medicine for treating various inflammatory and infectious diseases such as tapeworm infestation and mumps. In the present study, we investigated the bone protective effect of water extract of the rhizome ofDryopteris crassirhizoma(WEDC). We found that WEDC inhibits osteoclast differentiation via directly acting on osteoclast precursors. In osteoclast precursors, WEDC inhibited receptor activator of nuclear factor-κB ligand- (RANKL-) induced expression of c-Fos and nuclear factor of activated T cells cytoplasmic 1, a key downstream target of c-Fos during osteoclast differentiation. We found that WEDC inhibits RNAKL-induced activation of extracellular-regulated kinase and NF-κB that mediates c-Fos expression and osteoclast differentiation. In addition to the inhibitory effect of osteoclast differentiation, WEDC markedly suppressed bon-resorbing activity of mature osteoclasts, which was accompanied by disruption of actin ring structure. Furthermore, administration of WEDC suppressed RANKL-induced trabecular bone loss in mice. Collectively, our results demonstrate that WEDC inhibits not only osteoclast differentiation by inhibiting RANK signaling pathways in osteoclast precursors but also bone resorption by disrupting actin ring in mature osteoclasts, thereby contributing to its protective effect on bone loss.

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Water Extract of Mentha arvensis L. Attenuates Estrogen Deficiency-Induced Bone Loss by Inhibiting Osteoclast Differentiation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.719602 ◽

2021 ◽

Vol 12 ◽

Author(s):

Seon-A Jang ◽

Youn-Hwan Hwang ◽

Hyun Yang ◽

Jin Ah Ryuk ◽

Taesoo Kim ◽

...

Keyword(s):

Bone Loss ◽

Osteoclast Differentiation ◽

Water Extract ◽

Nuclear Factor Κb ◽

Osteoclast Formation ◽

Nuclear Factor ◽

Mentha Arvensis ◽

Activated T Cells ◽

Mitogen Activated Protein

Mentha arvensis L., is an aromatic herb that belongs to the Lamiaceae family and is widely used in medicinal applications, essential oil applications, and food flavoring. The extract of M. arvensis has been reported to exert sedative-hypnotic, anti-inflammatory, anti-fungal, and anti-bacterial effects. However, its effects on bone metabolism have not yet been studied. Here, we investigated the effects of the water extract of M. arvensis (WEMA) on osteoclast formation in vitro and bone loss in an ovariectomized mouse model. We found that WEMA inhibited osteoclast differentiation by directly acting on osteoclast precursor cells. WEMA inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced the expression of cellular oncogene fos (c-Fos) and nuclear factor of activated T cells c1 (NFATc1), crucial transcription factors for osteoclast differentiation, by suppressing RANKL-induced activation of early signaling pathways such as those of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In addition, oral administration of WEMA suppressed ovariectomy-induced trabecular bone loss in mice. We additionally identified phytochemicals in WEMA that are known to have anti-osteoclastogenic or anti-osteoporotic properties. Collectively, these results suggest that WEMA is a promising herbal candidate that can be used to prevent or treat postmenopausal osteoporosis.

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The key royal jelly component 10-hydroxy-2-decenoic acid protects against bone loss by inhibiting NF-κB signaling downstream of FFAR4

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013821 ◽

2020 ◽

Vol 295 (34) ◽

pp. 12224-12232 ◽

Cited By ~ 1

Author(s):

Yosuke Tsuchiya ◽

Mikihito Hayashi ◽

Katashi Nagamatsu ◽

Takehito Ono ◽

Masaki Kamakura ◽

...

Keyword(s):

Bone Loss ◽

Royal Jelly ◽

Osteoclast Differentiation ◽

Nuclear Factor Κb ◽

Spectrometric Analysis ◽

Nuclear Factor ◽

Decenoic Acid ◽

Activated T Cells ◽

Ovariectomized Mice ◽

Free Fatty Acid Receptor

The supplementation of royal jelly (RJ) is known to provide a variety of health benefits, including anti-inflammatory and anti-obesity effects. RJ treatment also reportedly protects against bone loss, but no single factor in RJ has yet been identified as an anti-osteoporosis agent. Here we fractionated RJ and identified 10-hydroxy-2-decenoic acid (10H2DA) as a key component involved in inhibiting osteoclastogenesis based on mass spectrometric analysis. We further demonstrated free fatty acid receptor 4 (FFAR4) as directly interacting with 10H2DA; binding of 10H2DA to FFAR4 on osteoclasts inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced activation of NF-κB signaling, thereby attenuating the induction of nuclear factor of activated T cells (NFAT) c1, a key transcription factor for osteoclastogenesis. Oral administration of 10H2DA attenuated bone resorption in ovariectomized mice. These results suggest a potential therapeutic approach of targeting osteoclast differentiation by the supplementation of RJ, and specifically 10H2DA, in cases of pathological bone loss such as occur in postmenopausal osteoporosis.

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Orostachys japonicus Suppresses Osteoclast Differentiation by Inhibiting NFATc1 Expression

The American Journal of Chinese Medicine ◽

10.1142/s0192415x15500585 ◽

2015 ◽

Vol 43 (05) ◽

pp. 1013-1030 ◽

Cited By ~ 2

Author(s):

Ki-Shuk Shim ◽

Hyunil Ha ◽

Taesoo Kim ◽

Chung-Jo Lee ◽

Jin Yeul Ma

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Therapeutic Potential ◽

Osteoclast Differentiation ◽

Water Extract ◽

Bone Diseases ◽

Tartrate Resistant Acid Phosphatase ◽

Dependent Manner ◽

Nuclear Factor ◽

Activated T Cells

The herb Orostachys japonicus has been traditionally used to treat chronic diseases, such as hepatitis, hemorrhoids, and cancer, in Asia. In this study, we investigated the effect of Orostachys japonicus water extract (OJWE) on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and bone loss. We found that OJWE inhibited RANKL-induced osteoclast differentiation in a dose-dependent manner without affecting bone resorption in bone marrow-derived macrophage cells. Interestingly, OJWE significantly reduced serum levels of C-terminal telopeptide of type 1 collagen and tartrate-resistant acid phosphatase (TRAP) 5b, markers of bone resorption and osteoclast number, respectively, in an animal model of bone loss. Furthermore, OJWE suppressed the RANKL-induced up-regulation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression, and activation of the p38 signaling pathway, but prevented the RANKL-mediated down-regulation of interferon regulatory factor-8 (IRF-8), which is known to be an anti-osteoclastogenic factor that represses NFATc1 expression. We also identified gallic acid and quercetin-3-O-β-D-glucoside as the OJWE components that inhibit RANKL-induced osteoclast differentiation. These results suggest that OJWE inhibits osteoclast differentiation by inhibiting RANKL-induced NFATc1 expression, which prevents osteoclast differentiation and bone loss. The present study elucidated a mechanism of action underlying the inhibitory effect of OJWE on osteoclast differentiation. Our findings suggest that O. japonicus has therapeutic potential for use in the treatment of bone diseases.

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Inhibition of Osteoclastogenesis by Thioredoxin-Interacting Protein-Derived Peptide (TN13)

Journal of Clinical Medicine ◽

10.3390/jcm8040431 ◽

2019 ◽

Vol 8 (4) ◽

pp. 431 ◽

Cited By ~ 2

Author(s):

Mi Kim ◽

Won Kim ◽

Jae-Eun Byun ◽

Jung Choi ◽

Suk Yoon ◽

...

Keyword(s):

Bone Loss ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

Raw 264.7 Cells ◽

Tartrate Resistant Acid Phosphatase ◽

Nuclear Factor ◽

Activated T Cells ◽

Interacting Protein ◽

Hematopoietic Stem ◽

Thioredoxin Interacting Protein

Overactivated osteoclasts lead to many bone diseases, including osteoporosis and rheumatoid arthritis. The p38 MAPK (p38) is an essential regulator of the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone loss. We previously reported TAT conjugated thioredoxin-interacting protein-derived peptide (TAT-TN13) as an inhibitor of p38 in hematopoietic stem cells (HSCs). Here, we examined the role of TAT-TN13 in the differentiation and function of osteoclasts. TAT-TN13 significantly suppressed RANKL-mediated differentiation of RAW 264.7 cells and bone marrow macrophages (BMMs) into osteoclasts. TAT-TN13 also inhibited the RANKL-induced activation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), leading to the decreased expression of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP) and Cathepsin K. Additionally, TAT-TN13 treatment protected bone loss in ovariectomized (OVX) mice. Taken together, these results suggest that TAT-TN13 inhibits osteoclast differentiation by regulating the p38 and NF-κB signaling pathway; thus, it may be a useful agent for preventing or treating osteoporosis.

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Fucoidan Prevents RANKL-Stimulated Osteoclastogenesis and LPS-Induced Inflammatory Bone Loss via Regulation of Akt/GSK3β/PTEN/NFATc1 Signaling Pathway and Calcineurin Activity

Marine Drugs ◽

10.3390/md17060345 ◽

2019 ◽

Vol 17 (6) ◽

pp. 345 ◽

Cited By ~ 5

Author(s):

Sheng-Hua Lu ◽

Yi-Jan Hsia ◽

Kuang-Chung Shih ◽

Tz-Chong Chou

Keyword(s):

Bone Loss ◽

Molecular Mechanisms ◽

Bone Erosion ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

Nuclear Factor ◽

Activated T Cells ◽

Calcineurin Activity

Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca2+ level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca2+/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.

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