scholarly journals Reduced miR-144-3p expression in serum and bone mediates osteoporosis pathogenesis by targeting RANK

2018 ◽  
Vol 96 (5) ◽  
pp. 627-635 ◽  
Author(s):  
Chunqing Wang ◽  
Hanliang He ◽  
Liang Wang ◽  
Yu Jiang ◽  
Youjia Xu
Keyword(s):  
Mononuclear Cells ◽  
Osteoclast Differentiation ◽  
Cathepsin K ◽  
Osteoclast Formation ◽  
Bone Homeostasis ◽  
Serum Samples ◽  
Peripheral Blood Mononuclear ◽  
Altered Expression ◽  
Rna Molecules ◽  
Non Coding Rna

Osteoblasts and osteoclasts are responsible for the formation and resorption of bone, respectively. An imbalance between these two processes results in a disease called osteoporosis, in which a decreased level of bone strength increases the risk of a bone fracture. MicroRNAs (miRNAs) are small non-coding RNA molecules of 18–25 nucleotides that have been previously shown to control bone metabolism by regulating osteoblast and osteoclast differentiation. In this study, we detected the expression pattern of 10 miRNAs in serum samples from patients with osteoporosis, and identified the altered expression of 6 miRNAs by comparison with patients without osteoporosis. We selected miR-144-3p for further investigation, and showed that it regulates osteoclastogenesis by targeting RANK, and that it is conserved amongst vertebrates. Disrupted expression of miR-144-3p in CD14+ peripheral blood mononuclear cells changed TRAP activity and the osteoclast-specific genes TRAP, cathepsin K (CTSK), and NFATC. TRAP staining, CCK-8, and flow cytometry analyses revealed that miR-144-3p also affects osteoclast formation, proliferation, and apoptosis. Together, these results indicate that miR-144-3p critically mediates bone homeostasis, and thus, represents a promising novel therapeutic candidate for the treatment of this disease.

Cell-cell fusion: human multinucleated osteoclasts

2009 ◽  
Vol 4 (4) ◽  
pp. 543-548 ◽  
Author(s):  
Zhi-Yong Zeng ◽  
Jun-Min Chen
Keyword(s):  
Cell Fusion ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Cell Cell

AbstractOsteoclasts are known to be formed by fusion of circulating mononuclear precursor cells which originate from haematopoietic stem cells. The precise mechanisms regulating the cell-cell fusion of these circulating cells to multinucleated osteoclasts remain unclear. In the present study, human peripheral blood mononuclear cells (PBMNCs) from healthy donors were treated with the macrophagecolony stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-κB ligand (RANKL) to induce osteoclast differentiation. Osteoclast formation and resorption activity were investigated through the use of tartrate-resistant acid phosphatase (TRAP) staining and lacunar resorption on dentine slices respectively. Real-time reverse-transcription polymerase chain reaction (PCR) was used to detect expression of dendritic cell-specific transmembrane protein (DC-STAMP) in these cells. The results showed that under the treatment of M-CSF and RANKL, PBMNCs differentiated into multinucleated osteoclasts through cell-cell fusion of mononucleated cells. These osteoclasts were TRAP positive and capable of resorbing the bone. Expression of DC-STAMP was much higher in the cells treated with both M-CSF and RANKL than those treated with M-CSF alone. We concluded that human PBMNCs might differentiate into active osteoclasts under certain conditions and the DC-STAMP, which is believed critical for osteoclast development, will be a possible therapeutic target for osteoclast related diseases in future.

scholarly journals I-BET151 suppresses osteoclast formation and inflammatory cytokines secretion by targetting BRD4 in multiple myeloma

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Ning-Hong Guo ◽  
Ji-Fu Zheng ◽  
Fu-Ming Zi ◽  
Jing Cheng
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Mononuclear Cells ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Cytokine Secretion ◽  
Raw 264.7 ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Brd4 Inhibition

Abstract Background: Multiple myeloma (MM) is an incurable hematologic cancer, accompanied by excessive osteoclast formation and inflammatory cytokine secretion. The mechanisms by which bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 regulates osteoclast differentiation and inflammatory cytokine secretion in MM are largely unknown. Methods: The isolated peripheral blood mononuclear cells from normal or patients with MM were treated with receptor activator of NF-κB ligand (RANKL) and M-CSF to induce osteoclast differentiation. RAW 264.7 cells were treated with RANKL. I-BET151 was applied to investigate the effects of BRD4 inhibition on osteoclast formation and inflammatory cytokine secretion. Osteoclast formation was determined by tartrate-resistant acid phosphatase (TRACP) staining. The expression of osteoclast-specific genes TRACP, matrix metalloproteinase-9 (MMP-9), cathepsin K (Ctsk), and c-Src was tested using quantitative real-time PCR. And the level of inflammatory cytokines TNF-α, IL-1β, and IL-6 was assessed by ELISA. Tumor necrosis factor receptor-associated factor 6 (TRAF6), BRD4, nuclear and cytoplasm p65, IκB-α, nuclear factor of activated T cells cytoplasmic (NFATc1), and osteoprotegerin (OPG) expression were measured by Western blotting. RNAi technology was applied to knock down BET family member BRD4. Results: I-BET151 dose-dependently suppressed osteoclast formation, inhibited the levels of osteoclast-specific genes TRACP, MMP-9, Ctsk, and c-Src and inflammatory cytokines TNF-α, IL-1β, and IL-6 secretion in peripheral blood mononuclear cells and RAW 264.7. I-BET151 inhibited the protein levels of BRD4 and NFATc1, increased OPG expression, and suppressed IκB-α degradation and p65 nuclear translocation. Further, the effects of I-BET151 on osteoclast formation, osteoclast-specific genes expression, inflammatory cytokine secretion, and NF-κB inhibition were promoted by BRD4 knockdown. Conclusion: I-BET151 inhibits osteoclast formation and inflammatory cytokine secretion by targetting BRD4-mediated RANKL-NF-κB signal pathway and BRD4 inhibition might be beneficial for MM treatment.

scholarly journals Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nan Xiao ◽  
Meng Nie ◽  
Huanhuan Pang ◽  
Bohong Wang ◽  
Jieli Hu ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Fatal Outcome ◽  
Organ Injury ◽  
Cytokine Release ◽  
Serum Samples ◽  
Peripheral Blood Mononuclear

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

Cells in regenerating deer antler cartilage provide a microenvironment that supports osteoclast differentiation

2001 ◽  
Vol 204 (3) ◽  
pp. 443-455
Author(s):  
C. Faucheux ◽  
S. Nesbitt ◽  
M. Horton ◽  
J. Price
Keyword(s):  
Type I Collagen ◽  
Mononuclear Cells ◽  
Osteoclast Differentiation ◽  
Cathepsin K ◽  
Collagen Matrix ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Deer Antler

Deer antlers are a rare example of mammalian epimorphic regeneration. Each year, the antlers re-grow by a modified endochondral ossification process that involves extensive remodelling of cartilage by osteoclasts. This study identified regenerating antler cartilage as a site of osteoclastogenesis in vivo. An in vitro model was then developed to study antler osteoclast differentiation. Cultured as a high-density micromass, cells from non-mineralised cartilage supported the differentiation of large numbers of osteoclast-like multinucleated cells (MNCs) in the absence of factors normally required for osteoclastogenesis. After 48 h of culture, tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells (osteoclast precursors) were visible, and by day 14 a large number of TRAP-positive MNCs had formed (783+/−200 per well, mean +/− s.e.m., N=4). Reverse transcriptase/polymerase chain reaction (RT-PCR) showed that receptor activator of NF κ B ligand (RANKL) and macrophage colony stimulating factor (M-CSF) mRNAs were expressed in micromass cultures. Antler MNCs have the phenotype of osteoclasts from mammalian bone; they expressed TRAP, vitronectin and calcitonin receptors and, when cultured on dentine, formed F-actin rings and large resorption pits. When cultured on glass, antler MNCs appeared to digest the matrix of the micromass and endocytose type I collagen. Matrix metalloproteinase-9 (MMP-9) may play a role in the resorption of this non-mineralised matrix since it is highly expressed in 100 % of MNCs. In contrast, cathepsin K, another enzyme expressed in osteoclasts from bone, is only highly expressed in resorbing MNCs cultured on dentine. This study identifies the deer antler as a valuable model that can be used to study the differentiation and function of osteoclasts in adult regenerating mineralised tissues.

scholarly journals A mikro-RNS-ek patogenetikai és diagnosztikai szerepe mellékvesekéreg-carcinomában

2018 ◽  
Vol 159 (7) ◽  
pp. 245-251 ◽  
Author(s):  
Zoltán Nagy ◽  
Ábel Decmann ◽  
Pál Perge ◽  
Péter Igaz
Keyword(s):  
Posttranscriptional Regulation ◽  
Regulation Of Gene Expression ◽  
Adrenocortical Cancer ◽  
Altered Expression ◽  
Rna Molecules ◽  
Adrenocortical Adenomas ◽  
Non Coding Rna ◽  
Adrenocortical Tumours ◽  
Clinical Consequences ◽  
Advanced Stages

Abstract: Adrenocortical tumours are quite prevalent. Most of these tumours are benign, hormonally inactive adrenocortical adenomas. Rare hormone-secreting adrenocortical adenomas are associated with severe clinical consequences, whereas the prognosis of the rare adrenocortical cancer is rather poor in its advanced stages. The pathogenesis of these tumours is only partly elucidated. MicroRNAs are small, non-coding RNA molecules that are pivotal in the regulation of several basic cell biological processes via the posttranscriptional regulation of gene expression. Their altered expression has been described in many tumours. Several tissue microRNAs, such as miR-483-5p, miR-503, miR-210, miR-335 and miR-195 were found to be differentially expressed among benign and malignant adrenocortical tumours, and these could also have pathogenic relevance. Due to their tissue specific and stable expression, microRNAs can be exploited in diagnostics as well. As the histological diagnosis of adrenocortical malignancy is difficult, microRNAs might be of help in the establishment of malignancy. Novel data show that microRNAs are secreted in various body fluids, projecting their applicability as biomarkers as part of liquid biopsy. In this review, we attempt to present a synopsis on the pathogenic relevance of microRNAs in adrenocortical tumours and their potential diagnostic applicability. Orv Hetil. 2018; 159(7): 245–251.

scholarly journals Regulation of Transcription Factor E2-2 in Human Plasmacytoid Dendritic Cells by Monocyte-Derived TNFα

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 162 ◽  
Author(s):  
Hannah K. Dewald ◽  
Harry J. Hurley ◽  
Patricia Fitzgerald-Bocarsly
Keyword(s):  
Dendritic Cells ◽  
Transcription Factor ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Plasmacytoid Dendritic Cells ◽  
Cytokine Signaling ◽  
Regulation Of Transcription ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Altered Expression

Plasmacytoid dendritic cells (pDCs) are innate immune cells and potent producers of interferon alpha (IFNα). Regulation of pDCs is crucial for prevention of aberrant IFN production. Transcription factor E2-2 (TCF4) regulates pDC development and function, but mechanisms of E2-2 control have not been investigated. We used freshly-isolated human peripheral blood mononuclear cells stimulated with toll-like receptor 7, 9, and 4 agonists to determine which factors regulate E2-2. After activation, pDCs decreased E2-2 expression. E2-2 downregulation occurred during the upregulation of costimulatory markers, after maximal IFN production. In congruence with previous reports in mice, we found that primary human pDCs that maintained high E2-2 levels produced more IFN, and had less expression of costimulatory markers. Stimulation of purified pDCs did not lead to E2-2 downregulation; therefore, we investigated if cytokine signaling regulates E2-2 expression. We found that tumor necrosis factor alpha (TNFα) produced by monocytes caused decreased E2-2 expression. All together, we established that primary human pDCs decrease E2-2 in response to TNFα and E2-2 low pDCs produce less IFN but exhibit more costimulatory molecules. Altered expression of E2-2 may represent a mechanism to attenuate IFN production and increase activation of the adaptive immune compartment.

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