Cardiotrophin like cytokine factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway

Bone ◽  
2021 ◽  
pp. 116140
Author(s):  
Shunichi Yokota ◽  
Gen Matsumae ◽  
Tomohiro Shimizu ◽  
Tomoka Hasegawa ◽  
Taku Ebata ◽  
...  
Keyword(s):  
Bone Loss ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Interferon Signaling

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

Plants ◽  
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.

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

Foods ◽  
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.

scholarly journals Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

2016 ◽  
Vol 36 (19) ◽  
pp. 2451-2463 ◽  
Author(s):  
Takashi Iezaki ◽  
Kazuya Fukasawa ◽  
Gyujin Park ◽  
Tetsuhiro Horie ◽  
Takashi Kanayama ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Bone Diseases ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Bone Homeostasis ◽  
Activated T Cells

Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) through activator protein 1. Global deletion of murineIfrd1increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion ofIfrd1in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impairedin vitroinIfrd1-deleted bone marrow macrophages (BMMs).Ifrd1deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-κB-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-κB/NFATc1 axis plays a pivotal role in bone remodelingin vivoand represents a therapeutic target for bone diseases.

scholarly journals The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis by Suppressing Protein Kinase-C α/βII Phosphorylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kyosuke Sakaida ◽  
Kazuhiro Omori ◽  
Masaaki Nakayama ◽  
Hiroki Mandai ◽  
Saki Nakagawa ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Common Disease ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Receptor Activator

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

scholarly journals Ethanol Extracts of FreshDavallia formosana(WL1101) Inhibit Osteoclast Differentiation by Suppressing RANKL-Induced Nuclear Factor-κB Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Tzu-Hung Lin ◽  
Rong-Sen Yang ◽  
Kuan-Chin Wang ◽  
Dai-Hua Lu ◽  
Houng-Chi Liou ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Translocation ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Ovariectomized Rats ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Trabecular Bone Loss ◽  
Ethanol Extracts

The rhizome ofDavallia formosanais commonly used to treat bone disease including bone fracture, arthritis, and osteoporosis in Chinese herbal medicine. Here, we report the effects of WL1101, the ethanol extracts of fresh rhizomes ofDavallia formosanaon ovariectomy-induced osteoporosis. In addition, excess activated bone-resorbing osteoclasts play crucial roles in inflammation-induced bone loss diseases, including rheumatoid arthritis and osteoporosis. In this study, we examined the effects of WL1101 on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Treatment with WL1101 significantly inhibited RANKL-stimulated osteoclastogenesis. Two isolated active compounds, ((−)-epicatechin) or WL14 (4-hydroxy-3-aminobenzoic acid) could also inhibit RANKL-induced osteoclastogenesis. WL1101 suppressed the RANKL-induced nuclear factor-κB (NF-κB) activation and nuclear translocation, which is the key process during osteoclastogenesis, by inhibiting the activation of IκB kinase (IKK) and IκBα. In animal model, oral administration of WL1101 (50 or 200 mg/kg/day) effectively decreased the excess bone resorption and significantly antagonized the trabecular bone loss in ovariectomized rats. Our results demonstrate that the ethanol extracts of fresh rhizomes ofDavallia formosanainhibit osteoclast differentiation via the inhibition of NF-κB activation and effectively ameliorate ovariectomy-induced osteoporosis. WL1101 may thus have therapeutic potential for the treatment of diseases associated with excessive osteoclastic activity.

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

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.

scholarly journals Anti-Osteoporotic Effects of Polysaccharides Isolated from Persimmon Leaves via Osteoclastogenesis Inhibition

Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 901 ◽  
Author(s):  
Youn-Hwan Hwang ◽  
Hyunil Ha ◽  
Rajeong Kim ◽  
Chang-Won Cho ◽  
Young-Ran Song ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
In Vivo Model ◽  
Osteoporotic Bone ◽  
Diospyros Kaki ◽  
Nuclear Factor ◽  
Activated T Cells

Persimmon (Diospyros kaki L.f.) leaves have traditionally been used as a phytomedicine, in health beverages to treat cardiovascular and respiratory disease and to promote maternal health in East Asia. In particular, polysaccharides from persimmon are known to have anti-coagulant, anti-oxidant, and immune-stimulatory activities. However, their beneficial effects against osteoporosis have not been reported. In the present study, we investigated the anti-osteoporotic effects of polysaccharides from persimmon leaves (PLE0) using an in vivo model of ovariectomy (OVX)-induced bone loss and an in vitro system of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. In the OVX mouse model, PLE0 remarkably improved OVX-induced trabecular bone loss by suppressing osteoclast activity. In primary bone marrow-derived macrophages (BMMs), PLE0 dose-dependently inhibited osteoclast differentiation. In addition, PLE0 down-regulated RANKL-induced activation of mitogen-activated protein kinases (MAPKs) such as p38, ERK, and JNK resulting in suppression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) expression. Our results indicate that PLE0 has anti-osteoporotic effects in OVX-induced bone loss via inhibition of osteoclast differentiation. Taken together, PLE0 from persimmon may prevent postmenopausal bone loss and osteoporotic bone fragility.

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

2020 ◽  
Vol 295 (34) ◽  
pp. 12224-12232 ◽  
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.

scholarly journals Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss

2021 ◽  
Vol 22 (5) ◽  
pp. 2303
Author(s):  
Liang Li ◽  
Ming Yang ◽  
Saroj Kumar Shrestha ◽  
Hyoungsu Kim ◽  
William H. Gerwick ◽  
...  
Keyword(s):  
Bone Loss ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Mineral Density ◽  
Multinucleated Cells

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

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