scholarly journals MicroRNA-29a represses osteoclast formation and protects against osteoporosis by regulating PCAF-mediated RANKL and CXCL12

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Wei-Shiung Lian ◽  
Jih-Yang Ko ◽  
Yu-Shan Chen ◽  
Huei-Jing Ke ◽  
Chin-Kuei Hsieh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Estrogen Deficiency ◽  
Biomechanical Property ◽  
Mineral Density ◽  
Cxcl12 Expression ◽  
Osteogenic Cells

Abstract Osteoporosis deteriorates bone mass and biomechanical strength, becoming a life-threatening cause to the elderly. MicroRNA is known to regulate tissue remodeling; however, its role in the development of osteoporosis remains elusive. In this study, we uncovered that silencing miR-29a expression decreased mineralized matrix production in osteogenic cells, whereas osteoclast differentiation and pit formation were upregulated in bone marrow macrophages as co-incubated with the osteogenic cells in transwell plates. In vivo, decreased miR-29a expression occurred in ovariectomy-mediated osteoporotic skeletons. Mice overexpressing miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg/OCN) displayed higher bone mineral density, trabecular volume and mineral acquisition than wild-type mice. The estrogen deficiency-induced loss of bone mass, trabecular morphometry, mechanical properties, mineral accretion and osteogenesis of bone marrow mesenchymal cells were compromised in miR-29aTg/OCN mice. miR-29a overexpression also attenuated the estrogen loss-mediated excessive osteoclast surface histopathology, osteoclast formation of bone marrow macrophages, receptor activator nuclear factor-κ ligand (RANKL) and C–X–C motif chemokine ligand 12 (CXCL12) expression. Treatment with miR-29a precursor improved the ovariectomy-mediated skeletal deterioration and biomechanical property loss. Mechanistically, miR-29a inhibited RANKL secretion in osteoblasts through binding to 3′-UTR of RANKL. It also suppressed the histone acetyltransferase PCAF-mediated acetylation of lysine 27 in histone 3 (H3K27ac) and decreased the H3K27ac enrichment in CXCL12 promoters. Taken together, miR-29a signaling in osteogenic cells protects bone tissue from osteoporosis through repressing osteoclast regulators RANKL and CXCL12 to reduce osteoclastogenic differentiation. Arrays of analyses shed new light on the miR-29a regulation of crosstalk between osteogenic and osteoclastogenic cells. We also highlight that increasing miR-29a function in osteoblasts is beneficial for bone anabolism to fend off estrogen deficiency-induced excessive osteoclastic resorption and osteoporosis.

scholarly journals Ethanolic Extract of Rubus coreanus Fruits Inhibits Bone Marrow-Derived Osteoclast Differentiation and Lipopolysaccharide-Induced Bone Loss

2017 ◽  
Vol 12 (12) ◽  
pp. 1934578X1701201
Author(s):  
Tae-Ho Kim ◽  
Chae Gyeong Jeong ◽  
Hyeong-U Son ◽  
Man-Il Huh ◽  
Shin-Yoon Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Ethanolic Extract ◽  
Type I ◽  
Mineral Density ◽  
Induced Differentiation ◽  
Rubus Coreanus

The inhibition of osteoclast differentiation/bone resorption is a well-known therapeutic strategy for controlling pathological and postmenopausal bone loss. Natural products that specifically inhibit osteoclastogenesis could therefore be developed as antiresorptive drugs for the treatment of metabolic bone disorders characterized by excessive osteoclastic bone resorption. We therefore examined the effects of Rubus coreanus extract (eeRc) on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced differentiation of bone marrow macrophages (BMMs) into osteoclasts and pit formation in vitro. Additionally, the in vivo effects of the eeRc were observed in mice with lipopolysaccharide (LPS)-induced bone erosion. In this study, we found that the ethanolic extract of Rubus coreanus fruits considerably suppressed the RANKL-induced differentiation of primary BMMs into osteoclasts and bone-resorbing activity of mature osteoclasts. Oral administration of eeRc attenuated LPS-induced bone loss in vivo, as demonstrated by the reversal of LPS-induced reduction in bone volume per tissue volume, bone mineral density, and trabecular number to some extent in eeRc-treated mice. In addition, eeRc slightly decreased the serum levels of C-terminal telopeptide fragments of type I collagen, the collagen-breakdown product generated by osteoclasts. Collectively, our results indicate that eeRc has the potential to inhibit bone loss by blocking osteoclast differentiation and could therefore be a promising natural product for the prevention and/or treatment of inflammatory bone loss.

Melatonin inhibits osteoclastogenesis and bone loss in ovariectomized mice by regulating PRMT1-mediated signaling

Endocrinology ◽  
2021 ◽  
Author(s):  
Joo-Hee Choi ◽  
Ah-Ra Jang ◽  
Min-Jung Park ◽  
Dong-il Kim ◽  
Jong-Hwan Park
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Tumor Necrosis Factor Receptor ◽  
Estrogen Deficiency ◽  
Melatonin Receptors ◽  
Mineral Density ◽  
Melatonin Treatment ◽  
Ovariectomized Mice

Abstract Melatonin, a pineal gland hormone, has been suggested to treat postmenopausal osteoporosis due to its inhibitory effect on osteoclast differentiation. We previously reported that protein arginine methyltransferase 1 (PRMT1) was an important mediator of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the relationship between melatonin and PRMT1 in osteoclast differentiation and estrogen deficiency-induced osteoporosis is unclear. In this study, we investigated the inhibitory mechanisms of melatonin in vitro and in vivo by focusing on PRMT1. Melatonin treatment effectively blocked RANKL-induced osteoclastogenesis by inhibiting PRMT1 and asymmetric dimethylarginine (ADMA) expression. RANKL-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) and the phosphorylation of JNK were also suppressed by melatonin, and TRAF6 siRNA attenuated RANKL-induced p-JNK and PRMT1 production. Melatonin inhibited the transcriptional activity of NF-κB by interfering with the binding of PRMT1 and NF-κB subunit p65 in RANKL-treated BMDMs. Our results also revealed that melatonin inhibits RANKL-induced PRMT1 expression through receptors-independent pathway. Thus, the anti-osteoclastogenic effect of melatonin was mediated by a cascade of inhibition of RANKL-induced TRAF6, JNK, PRMT1, and NF-κB signaling in melatonin receptors-independent pathway. In vivo, ovariectomy caused significant decreases in bone mineral density, but melatonin treatment alleviated the ovariectomized (OVX)-induced bone loss by inhibiting bone resorption. Furthermore, the expression PRMT1 and TRAP mRNA was upregulated in OVX-femurs, but effectively suppressed by melatonin injection. These findings suggest that melatonin inhibited osteoclast differentiation and estrogen deficiency-induced osteoporosis by suppressing RANKL-induced TRAF6, JNK, PRMT1, and NF-κB signaling cascades in melatonin receptors-independent pathway.

scholarly journals Osthole Inhibits Osteoclast Formation and Enhances Bone Mass of Bone Marrow Mesenchymal Stem cells by Activating β-catenin-OPG Signaling Pathway

2020 ◽  
Author(s):  
Zhen-Xiong Jin ◽  
Xin-Yuan Liao ◽  
Wei-Wei Da ◽  
Yong-Jian Zhao ◽  
Xiao-Feng Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Mass ◽  
Osteoclast Formation ◽  
Therapeutic Applications ◽  
Protein Levels ◽  
Inhibit Bone Resorption

Abstract Summary Osthole has potential therapeutic applications due to its antiosteoporotic. Our study suggested that osthole attenuates osteoclast formation by stimulating the activation of β-catenin-OPG signaling and could be a potential agent to inhibit bone resorption. Introduction Osthole has potential therapeutic applications due to its antiosteoporotic. we performed study to test if OPG is the target gene of osthole-attenuated osteoclastogenesis. Methods In vivo, using 12-month-old male mice to evaluate the effect of osthole on bone mass. In vitro, Bone marrow stem cells (BMSCs) were isolated, extracted from 3-month-old C57BL/6J mice, 3-month-old β-cateninfx/fx mice, or 3-month-old OPG−/− mice and its littermates of OPG+/+ mice. Results we found that osthole significantly increased the gene and protein levels of OPG expression in primary BMSCs dose-dependently. The deletion of the OPG gene did not affect β-catenin expression and the deletion of the β-catenin gene inhibited OPG expression in BMSCs, which indicated that osthole stimulated the expression of OPG through activation of β-catenin signaling. Conclusion Osthole attenuates osteoclast formation by stimulating the activation of β-catenin-OPG signaling and could be a potential agent to inhibit bone resorption.

scholarly journals Osteoprotective Effects of Loganic Acid on Osteoblastic and Osteoclastic Cells and Osteoporosis-Induced Mice

2020 ◽  
Vol 22 (1) ◽  
pp. 233
Author(s):  
Eunkuk Park ◽  
Chang Gun Lee ◽  
Eunguk Lim ◽  
Seokjin Hwang ◽  
Seung Hee Yun ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Osteoblastic Differentiation ◽  
Common Disease ◽  
Root Extract ◽  
Mouse Bone Marrow ◽  
Mineral Density ◽  
Bone Mineral Density Loss ◽  
In Vivo Experiments

Osteoporosis is a common disease caused by an imbalance of processes between bone resorption by osteoclasts and bone formation by osteoblasts in postmenopausal women. The roots of Gentiana lutea L. (GL) are reported to have beneficial effects on various human diseases related to liver functions and gastrointestinal motility, as well as on arthritis. Here, we fractionated and isolated bioactive constituent(s) responsible for anti-osteoporotic effects of GL root extract. A single phytochemical compound, loganic acid, was identified as a candidate osteoprotective agent. Its anti-osteoporotic effects were examined in vitro and in vivo. Treatment with loganic acid significantly increased osteoblastic differentiation in preosteoblast MC3T3-E1 cells by promoting alkaline phosphatase activity and increasing mRNA expression levels of bone metabolic markers such as Alpl, Bglap, and Sp7. However, loganic acid inhibited osteoclast differentiation of primary-cultured monocytes derived from mouse bone marrow. For in vivo experiments, the effect of loganic acid on ovariectomized (OVX) mice was examined for 12 weeks. Loganic acid prevented OVX-induced bone mineral density loss and improved bone structural properties in osteoporotic model mice. These results suggest that loganic acid may be a potential therapeutic candidate for treatment of osteoporosis.

scholarly journals Biological Effects of β-Glucans on Osteoclastogenesis

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1982
Author(s):  
Wataru Ariyoshi ◽  
Shiika Hara ◽  
Ayaka Koga ◽  
Yoshie Nagai-Yoshioka ◽  
Ryota Yamasaki
Keyword(s):  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Biological Effects ◽  
Osteoclast Differentiation ◽  
Treatment Strategies ◽  
Alcaligenes Faecalis ◽  
Osteoclast Formation ◽  
Osteoclast Precursors

Although the anti-tumor and anti-infective properties of β-glucans have been well-discussed, their role in bone metabolism has not been reviewed so far. This review discusses the biological effects of β-glucans on bone metabolisms, especially on bone-resorbing osteoclasts, which are differentiated from hematopoietic precursors. Multiple immunoreceptors that can recognize β-glucans were reported to be expressed in osteoclast precursors. Coordinated co-stimulatory signals mediated by these immunoreceptors are important for the regulation of osteoclastogenesis and bone remodeling. Curdlan from the bacterium Alcaligenes faecalis negatively regulates osteoclast differentiation in vitro by affecting both the osteoclast precursors and osteoclast-supporting cells. We also showed that laminarin, lichenan, and glucan from baker’s yeast, as well as β-1,3-glucan from Euglema gracilisas, inhibit the osteoclast formation in bone marrow cells. Consistent with these findings, systemic and local administration of β-glucan derived from Aureobasidium pullulans and Saccharomyces cerevisiae suppressed bone resorption in vivo. However, zymosan derived from S. cerevisiae stimulated the bone resorption activity and is widely used to induce arthritis in animal models. Additional research concerning the relationship between the molecular structure of β-glucan and its effect on osteoclastic bone resorption will be beneficial for the development of novel treatment strategies for bone-related diseases.

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.

scholarly journals GPR109A mediates the effects of hippuric acid on regulating osteoclastogenesis and bone resorption in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jin-Ran Chen ◽  
Haijun Zhao ◽  
Umesh D. Wankhade ◽  
Sree V. Chintapalli ◽  
Can Li ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Mass ◽  
Hippuric Acid ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Osteoclast Differentiation ◽  
Bone Homeostasis ◽  
Wild Type ◽  
Osteoclast Precursors

AbstractThe G protein-coupled receptor 109 A (GPR109A) is robustly expressed in osteoclastic precursor macrophages. Previous studies suggested that GPR109A mediates effects of diet-derived phenolic acids such as hippuric acid (HA) and 3-(3-hydroxyphenyl) propionic acid (3-3-PPA) on promoting bone formation. However, the role of GPR109A in metabolic bone homeostasis and osteoclast differentiation has not been investigated. Using densitometric, bone histologic and molecular signaling analytic methods, we uncovered that bone mass and strength were significantly higher in tibia and spine of standard rodent diet weaned 4-week-old and 6-month-old GPR109A gene deletion (GPR109A−/−) mice, compared to their wild type controls. Osteoclast numbers in bone and in ex vivo bone marrow cell cultures were significantly decreased in GPR109A−/− mice compared to wild type controls. In accordance with these data, CTX-1 in bone marrow plasma and gene expression of bone resorption markers (TNFα, TRAP, Cathepsin K) were significantly decreased in GPR109A−/− mice, while on the other hand, P1NP was increased in serum from both male and female GPR109A−/− mice compared to their respective controls. GPR109A deletion led to suppressed Wnt/β-catenin signaling in osteoclast precursors to inhibit osteoclast differentiation and activity. Indeed, HA and 3-3-PPA substantially inhibited RANKL-induced GPR109A expression and Wnt/β-catenin signaling in osteoclast precursors and osteoclast differentiation. Resultantly, HA significantly inhibited bone resorption and increased bone mass in wild type mice, but had no additional effects on bone in GPR109A−/− mice compared with their respective untreated control mice. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption mediating effects of HA and 3-3-PPA on inhibiting bone resorption during skeletal development.

Reconstitution of the host holobiont in germ-free born male rats acutely increases bone growth and affects marrow cellular content

2021 ◽  
Author(s):  
Piotr J Czernik ◽  
Rachel M. Golonka ◽  
Saroj Chakraborty ◽  
Beng San Yeoh ◽  
Ahmed A Abokor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Growth ◽  
Elevated Serum ◽  
Male Rats ◽  
Bone Lengthening ◽  
Mineral Density ◽  
Germ Free ◽  
Hepatic Expression ◽  
Gut Colonization

Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiologic interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-week-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, while the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Further, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.

scholarly journals Effects of Nrf2 Deficiency on Bone Microarchitecture in an Experimental Model of Osteoporosis

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Lidia Ibáñez ◽  
María Luisa Ferrándiz ◽  
Rita Brines ◽  
David Guede ◽  
Antonio Cuadrado ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Bone Metabolism ◽  
Bone Microarchitecture ◽  
Related Factor ◽  
Mineral Density ◽  
Trabecular Bone Mineral Density ◽  
Bone Marrow Derived Cells

Objective. Redox imbalance contributes to bone fragility. We have evaluated the in vivo role of nuclear factor erythroid derived 2-related factor-2 (Nrf2), an important regulator of cellular responses to oxidative stress, in bone metabolism using a model of postmenopausal osteoporosis.Methods. Ovariectomy was performed in both wild-type and mice deficient in Nrf2 (Nrf2−/−). Bone microarchitecture was analyzed byμCT. Serum markers of bone metabolism were also measured. Reactive oxygen species production was determined using dihydrorhodamine 123.Results. Sham-operated or ovariectomized Nrf2−/−mice exhibit a loss in trabecular bone mineral density in femur, accompanied by a reduction in cortical area in vertebrae. Nrf2 deficiency tended to increase osteoblastic markers and significantly enhanced osteoclastic markers in sham-operated animals indicating an increased bone turnover with a main effect on bone resorption. We have also shown an increased production of oxidative stress in bone marrow-derived cells from sham-operated or ovariectomized Nrf2−/−mice and a higher responsiveness of bone marrow-derived cells to osteoclastogenic stimuli in vitro.Conclusion. We have demonstrated in vivo a key role of Nrf2 in the maintenance of bone microarchitecture.

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.

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