scholarly journals Anti–IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss

2011 ◽  
Vol 208 (9) ◽  
pp. 1849-1861 ◽  
Author(s):  
Yu-Hsiang Hsu ◽  
Wei-Yu Chen ◽  
Chien-Hui Chan ◽  
Chih-Hsing Wu ◽  
Zih-Jie Sun ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Loss ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Osteoporotic Bone ◽  
Mineral Density

IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about the role of IL-20 in bone destruction. We explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of anti–IL-20 monoclonal antibody 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteopenia and osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by up-regulating the receptor activator of NF-κB (RANK) expression in osteoclast precursor cells and RANK ligand (RANKL) in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by macrophage colony-stimulating factor (M-CSF) and RANKL in vitro and protected mice from OVX-induced bone loss in vivo. Furthermore, IL-20R1–deficient mice had significantly higher bone mineral density (BMD) than did wild-type controls. IL-20R1 deficiency also abolished IL-20–induced osteoclastogenesis and increased BMD in OVX mice. We have identified a pivotal role of IL-20 in osteoclast differentiation, and we conclude that anti–IL-20 monoclonal antibody is a potential therapeutic for protecting against osteoporotic bone loss.

scholarly journals Crataegus pinnatifida Bunge Inhibits RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells and Prevents Bone Loss in an Ovariectomized Rat Model

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Minsun Kim ◽  
MinBeom Kim ◽  
Jae-Hyun Kim ◽  
SooYeon Hong ◽  
Dong Hee Kim ◽  
...  
Keyword(s):  
Bone Loss ◽  
Rat Model ◽  
Osteoclast Differentiation ◽  
Ovariectomized Rat ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mineral Density ◽  
Crataegus Pinnatifida

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

scholarly journals The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 55
Author(s):  
Zamzam Awida ◽  
Almog Bachar ◽  
Hussam Saed ◽  
Anton Gorodov ◽  
Nathalie Ben-Califa ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Mineral Density ◽  
Female Mice ◽  
Epo Receptor

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

Identification and Functional Characterization of Metabolites for Bone Mass in Peri-/Post-menopausal Chinese Women

2021 ◽  
Author(s):  
Rui Gong ◽  
Hong-Mei Xiao ◽  
Yin-Hua Zhang ◽  
Qi Zhao ◽  
Kuan-Jui Su ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Dodecanoic Acid ◽  
Mineral Density ◽  
Ovariectomized Mice ◽  
Post Menopausal ◽  
Functional Mechanisms

Abstract Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri-/post-menopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares (PLS) regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module, causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. DA treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (e.g.,10, 100μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

scholarly journals Scopolin Attenuates Osteoporotic Bone Loss in Ovariectomized Mice

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3565
Author(s):  
Eunkuk Park ◽  
Jeonghyun Kim ◽  
Hyun-Seok Jin ◽  
Chun Whan Choi ◽  
Tae Hyun Choi ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Osteoporotic Bone ◽  
Nodule Formation ◽  
Mineral Density ◽  
Bone Mineral Density Loss ◽  
Treatment And Prevention ◽  
Ovariectomized Mice ◽  
Bioactive Constituent

Bone remodeling is a renewal process regulated by bone synthesis (osteoblasts) and bone destruction (osteoclasts). A previous study demonstrated that Lycii radicis cortex (LRC) extract inhibited ovariectomized (OVX)-induced bone loss in mice. This study investigated the anti-osteoporotic effects of bioactive constituent(s) from the LRC extract. The effective compound(s) were screened, and a single compound, scopolin, which acts as a phytoalexin, was chosen as a candidate component. Scopolin treatment enhanced alkaline phosphatase activity and increased mineralized nodule formation in MC3T3-E1 pre-osteoblastic cells. However, osteoclast differentiation in primary-cultured monocytes was reduced by treatment with scopolin. Consistently, scopolin treatment increased osteoblast differentiation in the co-culture of monocytes (osteoclasts) and MC3T3-E1 (osteoblast) cells. Scopolin treatment prevented bone mineral density loss in OVX-induced osteoporotic mice. These results suggest that scopolin could be a therapeutic bioactive constituent for the treatment and prevention of osteoporosis.

scholarly journals Circaea Mollis Siebold & Zucc. Prevents Bone Loss in a Mouse Postmenopausal Osteoporosis Model by Promoting of Osteoblast Differentiation (P06-130-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Gyhye Yoo ◽  
Ji-Hye Park ◽  
Yang-Ju Son ◽  
Chang Ho Lee ◽  
Chu Won Nho
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Bone Loss ◽  
Postmenopausal Osteoporosis ◽  
Osteoclast Differentiation ◽  
Mineral Density ◽  
Promising Alternative ◽  
Ovariectomized Mice

Abstract Objectives Postmenopausal osteoporosis, a condition of low bone density consequent to decreased estrogen levels after menopause in women, is generally treated with hormone replacement therapy. However, long-term hormone use may cause critical side effects including breast cancer. Alternatively, phytoestrogens, which have similar structures to steroid hormones, are reported to cure postmenopausal symptoms with fewer side effects. Here, we investigated the effects of EtOH extract of Circaea mollis Siebold & Zucc. (EECM), a traditional herbal medicine in Asia that exhibits anti-arthritic activities, on postmenopausal osteoporosis. Methods In vitro model: MCF7 breast cancer cells and MC3T3-E1 pre-osteoblast cells were utilized to estimate estrogenic and osteogenic activity. Osteoblastic markers were measured by western blot and real-time PCR. In vivo model: Female mature C57BL/6 mice were ovariectomized and oral administrated with 10 mg/kg and 40 mg/kg of EECM respectively. Results EECM increased alkaline phosphatase activity and osteoblastic markers including osteoprotegerin at day 6 during mouse preosteoblast differentiation. EECM inhibited osteoclast differentiation and bone resorption in an osteoblast-osteoclast primary co-culture system via osteoprotegerin-mediated RANK/RANKL signaling. In ovariectomized mice, EECM prevented bone mineral density decrease and recovered osteoblastic molecules. Conclusions EECM enhanced the differentiation of osteoblasts via osteogenic markers and modulated RANK/RANKL signaling via an elevation of OPG from osteoblasts in vitro and in vivo. Therefore, EECM may be effective in preventing bone loss and offers a promising alternative for the nutritional management of postmenopausal osteoporosis. Funding Sources This work was supported by the Center Project for the Korea-Mongolia Science and Technology Cooperation (2U06170). Supporting Tables, Images and/or Graphs

scholarly journals Anti-Osteoporotic Effects of Combined Extract of Lycii Radicis Cortex and Achyranthes japonica in Osteoblast and Osteoclast Cells and Ovariectomized Mice

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2716 ◽  
Author(s):  
Eunkuk Park ◽  
Jeonghyun Kim ◽  
Subin Yeo ◽  
Eunguk Lim ◽  
Chun Whan Choi ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Osteoporotic Bone ◽  
Osteoblastic Cell ◽  
Mouse Bone Marrow ◽  
Osteoblastic Cell Line ◽  
Ovariectomized Mice ◽  
Achyranthes Japonica

Osteoporosis is characterized by low bone density and quality with high risk of bone fracture. Here, we investigated anti-osteoporotic effects of natural plants (Lycii Radicis Cortex (LRC) and Achyranthes japonica (AJ)) in osteoblast and osteoclast cells in vitro and ovariectomized mice in vivo. Combined LRC and AJ enhanced osteoblast differentiation and mineralized bone-forming osteoblasts by the up-regulation of bone metabolic markers (Alpl, Runx2 and Bglap) in the osteoblastic cell line MC3T3-E1. However, LRC and AJ inhibited osteoclast differentiation of monocytes isolated from mouse bone marrow. In vivo experiments showed that treatment of LRC+AJ extract prevented OVX-induced trabecular bone loss and osteoclastogenesis in an osteoporotic animal model. These results suggest that LRC+AJ extract may be a good therapeutic agent for the treatment and prevention of osteoporotic bone loss.

scholarly journals Eleutherococcus sessiliflorus Inhibits Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)-Induced Osteoclast Differentiation and Prevents Ovariectomy (OVX)-Induced Bone Loss

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1886
Author(s):  
Sang-Yong Han ◽  
June-Hyun Kim ◽  
Eun-Heui Jo ◽  
Yun-Kyung Kim
Keyword(s):  
Bone Loss ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Mapk Signaling ◽  
Root Bark ◽  
Nuclear Factor ◽  
Mineral Density ◽  
Trabecular Thickness

The aim of this study was to evaluate the effects of root bark of Eleutherococcus sessiliflorus (ES) on osteoclast differentiation and function in vitro and in vivo. In vitro, we found that ES significantly inhibited the RANKL-induced formation of TRAP-positive multinucleated osteoclasts and osteoclastic bone resorption without cytotoxic effects. ES markedly downregulated the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1); c-Fos; and osteoclast-related marker genes, such as TRAP, osteoclast-associated receptor (OSCAR), matrix metalloproteinase-9 (MMP-9), calcitonin receptor, cathepsin K, the 38 kDa d2 subunit of the vacuolar H+-transporting lysosomal ATPase (Atp6v0d2), dendritic cell-specific transmembrane protein (DC-STAMP), and osteoclast-stimulatory transmembrane protein (OC-STAMP). These effects were achieved by inhibiting the RANKL-mediated activation of MAPK signaling pathway proteins, including p38, ERK, and JNK. In vivo, ES attenuated OVX-induced decrease in bone volume to tissue volume ratio (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and bone mineral density, but increased trabecular separation (Tb.Sp) in the femur. Collectively, our findings showed that ES inhibited RANKL-activated osteoclast differentiation in bone marrow macrophages and prevented OVX-mediated bone loss in rats. These findings suggest that ES has the potential to be used as a therapeutic agent for bone-related diseases, such as osteoporosis.

scholarly journals Disruption of claudin-18 diminishes ovariectomy-induced bone loss in mice

2013 ◽  
Vol 304 (5) ◽  
pp. E531-E537 ◽  
Author(s):  
Ha-Young Kim ◽  
Catrina Alarcon ◽  
Sheila Pourteymour ◽  
Jon E. Wergedal ◽  
Subburaman Mohan
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Negative Regulator ◽  
Skeletal Phenotype ◽  
Estrogen Effects ◽  
Total Body ◽  
Deficient Mice

Claudin-18 (Cldn-18), a member of the tight junction family of proteins, is a negative regulator of RANKL-induced osteoclast differentiation and bone resorption (BR) in vivo. Since estrogen deficiency decreases bone mass in part by a RANKL-mediated increase in BR, we evaluated whether estrogen regulates Cldn-18 expression in bone. We found that Cldn-18 expression was reduced in the bones of estrogen deficient mice, whereas it was increased by estrogen treatment in osteoblasts and osteoclasts in vitro. We next evaluated the role of Cldn-18 in mediating estrogen-induced bone loss. Cldn-18 knockout (KO) and littermate wild-type (WT) mice were ovariectomized (OVX) or sham operated at 6 wk of age, and the skeletal phenotype was evaluated at 14 wk of age. PIXImus revealed that total body, femur, and lumbar BMD were reduced 8–13% ( P < 0.05) after 8 wk of OVX compared with sham in WT mice. As expected, total body, femur, and lumbar BMD were reduced 14–21% ( P < 0.05) in Cldn-18 KO sham mice compared with sham WT mice. However, ovariectomy failed to induce significant changes in BMD of total body, femur, or vertebra in the Cldn-18 KO mice. μCT analysis of the distal femur revealed that trabecular (Tb) bone volume was decreased 50% in the OVX WT mice compared with sham that was caused by a 26% decrease in Tb number and a 30% increase in Tb separation (all P < 0.05). By contrast, none of the Tb parameters were significantly different in OVX Cldn-18 KO mice compared with sham KO mice. Histomorphometric analyses at the Tb site revealed that neither osteoclast surface nor osteoclast perimeter was increased significantly as a consequence of OVX in either genotype at the time point examined. Based on our findings, we conclude that the estrogen effects on osteoclasts may in part be mediated via regulation of Cldn-18 signaling.

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.

Taxifolin Inhibits Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis of Human Bone Marrow-Derived Macrophages in vitro and Prevents Lipopolysaccharide-Induced Bone Loss in vivo

Pharmacology ◽  
2018 ◽  
Vol 103 (1-2) ◽  
pp. 101-109 ◽  
Author(s):  
Hong-Qi Zhang ◽  
Yun-Jia Wang ◽  
Guan-Teng Yang ◽  
Qi-Le Gao ◽  
Ming-Xing Tang
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Tartrate Resistant Acid Phosphatase ◽  
Receptor Activator

It has been reported that taxifolin inhibit osteoclastogenesis in RAW264.7 cells. In our research, the inhibition effects of taxifolin on the osteoclastogenesis of human bone marrow-derived macrophages (BMMs) induced by receptor activator of NF-κB ligand (RANKL) as well as the protection effects in lipopolysaccharide-induced bone lysis mouse model have been demonstrated. In vitro, taxifolin inhibited RANKL-induced osteoclast differentiation of human BMMs without cytotoxicity. Moreover, taxifolin significantly suppressed RANKL-induced gene expression, including tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T cells 1 and cathepsin K, and F-actin ring formation. Further studies showed that taxifolin inhibit osteoclastogenesis via the suppression of the NF-κB signaling pathway. In vivo, taxifolin prevented bone loss in mouse calvarial osteolysis model. In conclusion, the results suggested that taxifolin has a therapeutic potential for osteoclastogenesis-related diseases such as osteoporosis, osteolysis, and rheumatoid arthritis.

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