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 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 Yukmijihwang-Tang Suppresses Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-Induced Osteoclast Differentiation and Prevents Ovariectomy (OVX)-Mediated Bone Loss

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7579
Author(s):  
Sang-Yong Han ◽  
Yun-Kyung Kim
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Kappa B ◽  
Nuclear Translocation ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Receptor Activator

Yukmijihwang-tang (YJ) has been used to treat diabetes mellitus, renal disorders, and cognitive impairment in traditional medicine. This study aimed to evaluate the anti-osteoporotic effect of YJ on ovariectomy (OVX)-induced bone loss in a rat and receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast differentiation in bone marrow macrophages (BMMs). YJ reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) in an osteoclast/osteoblast co-culture system by regulating the ratio of RANKL/osteoprotegerin (OPG) by osteoblasts. Overall, YJ reduced TRAP-positive cell formation and TRAP activity and F-actin ring formation. Analysis of the underlying mechanisms indicated that YJ inhibited the activation of the nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and c-Fos, resulting in the suppression of osteoclast differentiation-related genes such as TRAP, ATPase, H+ transporting, lysosomal 38 kDa, V0 subunit d2, osteoclast-associated receptor, osteoclast-stimulatory transmembrane protein, dendritic cell-specific transmembrane protein, matrix metalloproteinase-9, cathepsin K, and calcitonin receptor. YJ also inhibited the nuclear translocation of NFATc1. Additionally, YJ markedly inhibited RANKL-induced phosphorylation of signaling pathways activated in the early stages of osteoclast differentiation including the p38, JNK, ERK, and NF-κB. Consistent with these in vitro results, the YJ-administered group showed considerably attenuated bone loss in the OVX-mediated rat model. These results provide promising evidence for the potential novel therapeutic application of YJ for bone diseases such as osteoporosis.

An adherent condition is required for formation of multinuclear osteoclasts in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor κB ligand

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4335-4343 ◽  
Author(s):  
Takeshi Miyamoto ◽  
Fumio Arai ◽  
Osamu Ohneda ◽  
Katsumasa Takagi ◽  
Dirk M. Anderson ◽  
...  
Keyword(s):  
Culture Medium ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Precursor Cells ◽  
Osteoclast Precursor ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Multinuclear Cells ◽  
Differentiation And Proliferation

Abstract Identification of receptor activator of nuclear factor-κB (RANK) and RANK-ligand (RANKL) has provided new insights into the osteoclast differentiation pathway. Osteoclast precursor cells were isolated using monoclonal antibodies against c-Fms and RANK, and the effect of adherence on the in vitro differentiation and proliferation of these cells was examined in 2 different types of stromal-cell–free culture systems: a semisolid culture medium (a nonadherent system) and a liquid culture medium (an adherent system). Osteoclast precursor cells were not able to differentiate into mature osteoclasts efficiently in the semisolid culture system. Trimerized RANKL enhanced osteoclast differentiation in semisolid cultures, but not to the extent seen when cells were allowed to adhere to plastic. Initial precursor cells were capable of differentiating into macrophages or osteoclasts. Once these cells were transferred to adherent conditions, striking differentiation was induced. Multinuclear cells were observed even after they had displayed phagocytic activity, which suggests that cell adhesion plays an important role in the differentiation of osteoclast precursor cells. Integrins, especially the arginine-glycine-aspartic acid (RGD)–recognizing integrins αv and β3, were needed for osteoclast-committed precursor cells to proliferate in order to form multinuclear osteoclasts, and the increase in cell density affected the formation of multinuclear cells. A model of osteoclast differentiation with 2 stages of precursor development is proposed: (1) a first stage, in which precursor cells are bipotential and capable of anchorage-independent growth, and (2) a second stage, in which the further proliferation and differentiation of osteoclast-committed precursor cells is anchorage-dependent.

scholarly journals Lack of NOD2 attenuates ovariectomy-induced bone loss via inhibition of osteoclasts

2017 ◽  
Vol 235 (2) ◽  
pp. 85-96 ◽  
Author(s):  
Ke Ke ◽  
Ok-Joo Sul ◽  
Soo-Wol Chung ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Kappa B ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Receptor Activator ◽  
Recognition Receptor ◽  
Oligomerization Domain

Nucleotide-binding oligomerization domain-2 (NOD2) is a pattern recognition receptor of the innate immune system. It interacts with serine–threonine kinases to induce activation of nuclear factor κB (NF-κB), which is important for receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. We tested the idea that NOD2 modulates bone metabolism via an action on osteoclasts (OCs). The absence of NOD2 reduced ovariectomy-induced bone loss in mice, and lowered the area and the activity of OCs, by impairing RANKL signaling. It also reduced the level of reactive oxygen species (ROS), as well as of NF-κB-DNA binding upon RANKL exposure. NOD2 was found to physically interact with nicotinamide adenine dinucleotide phosphate oxidase 1, and this led to increased production of ROS in OCs. Our data suggest that NOD2 contributes to bone loss in estrogen deficiency by elevating ROS levels in OCs.

scholarly journals Interleukin-6 Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclastogenesis by Diverting Cells into the Macrophage Lineage: Key Role of Serine727 Phosphorylation of Signal Transducer and Activator of Transcription 3

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3688-3697 ◽  
Author(s):  
Laurence Duplomb ◽  
Marc Baud’huin ◽  
Céline Charrier ◽  
Martine Berreur ◽  
Valérie Trichet ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Signal Transducer ◽  
Blood Monocytes ◽  
Receptor Activator ◽  
Few Data ◽  
Macrophage Lineage

Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor κB ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT) 3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine727 associated with an absence of phosphorylation on Tyrosine705 is essential for osteoclastogenesis. Furthermore, a decrease of Serine727 phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine705 phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.

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