scholarly journals Network-based Transcriptome-wide Expression Study for Postmenopausal Osteoporosis

2020 ◽  
Vol 105 (8) ◽  
pp. 2678-2691
Author(s):  
Lan Zhang ◽  
Tian-Liu Peng ◽  
Le Wang ◽  
Xiang-He Meng ◽  
Wei Zhu ◽  
...  
Keyword(s):  
Postmenopausal Osteoporosis ◽  
Human Peripheral Blood ◽  
Osteoclast Differentiation ◽  
Cell Receptor ◽  
Osteoclast Formation ◽  
Blood Monocytes ◽  
Mineral Density ◽  
Gene Sets ◽  
Relationship Of

Abstract Purpose Menopause is a crucial physiological transition during a woman’s life, and it occurs with growing risks of health issues like osteoporosis. To identify postmenopausal osteoporosis-related genes, we performed transcriptome-wide expression analyses for human peripheral blood monocytes (PBMs) using Affymetrix 1.0 ST arrays in 40 Caucasian postmenopausal women with discordant bone mineral density (BMD) levels. Methods We performed multiscale embedded gene coexpression network analysis (MEGENA) to study functionally orchestrating clusters of differentially expressed genes in the form of functional networks. Gene sets net correlations analysis (GSNCA) was applied to assess how the coexpression structure of a predefined gene set differs in high and low BMD groups. Bayesian network (BN) analysis was used to identify important regulation patterns between potential risk genes for osteoporosis. A small interfering ribonucleic acid (siRNA)-based gene silencing in vitro experiment was performed to validate the findings from BN analysis. Result MEGENA showed that the “T cell receptor signaling pathway” and the “osteoclast differentiation pathway” were significantly enriched in the identified compact network, which is significantly correlated with BMD variation. GSNCA revealed that the coexpression structure of the “Signaling by TGF-beta receptor complex pathway” is significantly different between the 2 BMD discordant groups; the hub genes in the postmenopausal low and high BMD group are FURIN and SMAD3 respectively. With siRNA in vitro experiments, we confirmed the regulation relationship of TGFBR2–SMAD7 and TGFBR1–SMURF2. Main Conclusion The present study suggests that biological signals involved in monocyte recruitment, monocyte/macrophage lineage development, osteoclast formation, and osteoclast differentiation might function together in PBMs that contribute to the pathogenesis of postmenopausal 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 Overexpression of PIK3R1 Promotes Bone Formation by Regulating Osteoblast Differentiation and Osteoclast Formation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Haitao Zhu ◽  
Hua Chen ◽  
Degang Ding ◽  
Shui Wang ◽  
Xiaofeng Dai ◽  
...  
Keyword(s):  
Bone Formation ◽  
Signaling Pathway ◽  
Differentially Expressed Genes ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Differentially Expressed ◽  
Estrogen Signaling ◽  
Mineral Density

In an effort to bolster our understanding of regulation of bone formation in the context of osteoporosis, we screened out differentially expressed genes in osteoporosis patients with high and low bone mineral density by bioinformatics analysis. PIK3R1 is increasingly being nominated as a pivotal mediator in the differentiation of osteoblasts and osteoclasts that is closely related to bone formation. However, the specific mechanisms underlying the way that PIK3R1 affects bone metabolism are not fully elucidated. We intended to examine the potential mechanism by which PIK3R1 regulates osteoblast differentiation. Enrichment analysis was therefore carried out for differentially expressed genes. We noted that the estrogen signaling pathway, TNF signaling pathway, and osteoclast differentiation were markedly associated with ossification, and they displayed enrichment in PIK3R1. Based on western blot, qRT-PCR, and differentiation analysis in vitro, we found that upregulation of PIK3R1 enhanced osteoblastic differentiation, as evidenced by increased levels of investigated osteoblast-related genes as well as activities of ALP and ARS, while it notably decreased levels of investigated osteoclast-related genes. On the contrary, downregulation of PIK3R1 decreased levels of osteoblast-related genes and increased levels of osteoclast-related genes. Besides, in vitro experiments revealed that PIK3R1 facilitated proliferation and repressed apoptosis of osteoblasts but had an opposite impact on osteoclasts. In summary, PIK3R1 exhibits an osteoprotective effect via regulating osteoblast differentiation, which can be represented as a promising therapeutic target for osteoporosis.

scholarly journals Immobilization of Denosumab on Titanium Affects Osteoclastogenesis of Human Peripheral Blood Monocytes

2019 ◽  
Vol 20 (5) ◽  
pp. 1002
Author(s):  
Felicitas Beck ◽  
Eliza Hartmann ◽  
Miriam Koehler ◽  
Julia Redeker ◽  
Sabine Schluessel ◽  
...  
Keyword(s):  
Human Peripheral Blood ◽  
Binding Capacity ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Blood Monocytes ◽  
Noncoding Dna ◽  
Continuous Release ◽  
Dna Oligonucleotides ◽  
Peripheral Mononuclear Blood ◽  
Titanium Surfaces

Immobilization of proteins has been examined to improve implant surfaces. In this study, titanium surfaces were modified with nanofunctionalized denosumab (cDMAB), a human monoclonal anti-RANKL IgG. Noncoding DNA oligonucleotides (ODN) served as linker molecules between titanium and DMAB. Binding and release experiments demonstrated a high binding capacity of cDMAB and continuous release. Human peripheral mononuclear blood cells (PBMCs) were cultured in the presence of RANKL/MCSF for 28 days and differentiated into osteoclasts. Adding soluble DMAB to the medium inhibited osteoclast differentiation. On nanofunctionalized titanium specimens, the osteoclast-specific TRAP5b protein was monitored and showed a significantly decreased amount on cDMAB-titanium in PBMCs + RANKL/MCSF. PBMCs on cDMAB-titanium also changed SEM cell morphology. In conclusion, the results indicate that cDMAB reduces osteoclast formation and has the potential to reduce osteoclastogenesis on titanium surfaces.

Ultrastructural Changes in Tumor Cells During Human Peripheral Blood Monocyte-Mediated Cytotoxicity

1981 ◽  
Vol 39 ◽  
pp. 452-453
Author(s):  
K. E. Muse ◽  
D. G. Fischer ◽  
H. S. Koren
Keyword(s):  
Target Cell ◽  
Human Peripheral Blood ◽  
Mononuclear Phagocytes ◽  
Ultrastructural Changes ◽  
Target Cells ◽  
Limited Information ◽  
Blood Monocytes ◽  
Tumoricidal Activity ◽  
Activated State

Mononuclear phagocytes, a pluripotential cell line, manifest an array of basic extracellular functions. Among these physiological regulatory functions is the expression of spontaneous cytolytic potential against tumor cell targets.The limited observations on human cells, almost exclusively blood monocytes, initially reported limited or a lack of tumoricidal activity in the absence of antibody. More recently, freshly obtained monocytes have been reported to spontaneously impair the biability of tumor target cells in vitro (Harowitz et al., 1979; Montavani et al., 1979; Hammerstrom, 1979). Although the mechanism by which effector cells express cytotoxicity is poorly understood, discrete steps can be distinguished in the process of cell mediated cytotoxicity: recognition and binding of effector to target cells,a lethal-hit stage, and subsequent lysis of the target cell. Other important parameters in monocyte-mediated cytotoxicity include, activated state of the monocyte, effector cell concentrations, and target cell suseptibility. However, limited information is available with regard to the ultrastructural changes accompanying monocyte-mediated cytotoxicity.

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.

Osteoclast and osteoblast response to strontium-doped struvite coatings on titanium for improved bone integration

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Claus Moseke ◽  
Katharina Wimmer ◽  
Markus Meininger ◽  
Julia Zerweck ◽  
Cornelia Wolf-Brandstetter ◽  
...  
Keyword(s):  
Bone Ingrowth ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Strontium Nitrate ◽  
Bone Implant ◽  
Electrochemically Deposited ◽  
Bone Integration ◽  
Titanium Substrates

AbstractTo develop implants with improved bone ingrowth, titanium substrates were coated with homogeneous and dense struvite (MgNH4PO4·6H2O) layers by means of electrochemically assisted deposition. Strontium nitrate was added to the coating electrolyte in various concentrations, in order to fabricate Sr-doped struvite coatings with Sr loading ranging from 10.6 to 115 μg/cm2. It was expected and observed that osteoclast activity surrounding the implant was inhibited. The cytocompatibility of the coatings and the effect of Sr-ions in different concentrations on osteoclast formation were analyzed in vitro. Osteoclast differentiation was elucidated on morphological, biochemical as well as on gene expression level. It could be shown that moderate concentrations of Sr2+ had an inhibitory effect on osteoclast formation, while the growth of osteoblastic cells was not negatively influenced compared to pure struvite surfaces. In summary, the electrochemically deposited Sr-doped struvite coatings are a promising approach to improve bone implant ingrowth.

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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