scholarly journals Role of Synovial Exosomes in Osteoclast Differentiation in Inflammatory Arthritis

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 120
Author(s):  
Ji Eun Song ◽  
Ji Soo Kim ◽  
Ji Hye Shin ◽  
Ki Won Moon ◽  
Jin Kyun Park ◽  
...  
Keyword(s):  
Synovial Fluid ◽  
Inflammatory Arthritis ◽  
Mononuclear Cells ◽  
Osteoclast Differentiation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tartrate Resistant Acid Phosphatase ◽  
Healthy Donors ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

This study aimed to investigate the characteristics of exosomes isolated from synovial fluid and their role in osteoclast differentiation in different types of inflammatory arthritis. Exosomes isolated from synovial fluid of rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, and osteoarthritis (OA) patients were co-incubated with CD14+ mononuclear cells from healthy donors without macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Osteoclast differentiation was evaluated via tartrate-resistant acid phosphatase (TRAP) staining and activity and F-actin ring formation. RANKL expression on synovial exosomes was assessed using flow cytometry and an enzyme-linked immunosorbent assay (ELISA). Synovial exosomes were the lowest in OA patients; these induced osteoclastogenesis in the absence of M-CSF and RANKL. Osteoclastogenesis was significantly higher with more exosomes in RA (p = 0.030) than in OA patients, but not in AS or gout patients. On treating macrophages with a specified number of synovial exosomes from RA/AS patients, exosomes induced greater osteoclastogenesis in RA than in AS patients. Synovial exosomal RANKL levels were significantly higher in RA (p = 0.035) than in AS patients. Synovial exosome numbers vary with the type of inflammatory arthritis. Synovial exosomes from RA patients may bear the disease-specific “synovial signature of osteoclastogenesis.”

scholarly journals Augmenting MNK1/2 activation by c-FMS proteolysis promotes osteoclastogenesis and arthritic bone erosion

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Se Hwan Mun ◽  
Seyeon Bae ◽  
Steven Zeng ◽  
Brian Oh ◽  
Carmen Chai ◽  
...  
Keyword(s):  
Inflammatory Arthritis ◽  
Essential Role ◽  
Inflammatory Responses ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Myeloid Cell ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

AbstractOsteoclasts are bone-resorbing cells that play an essential role in homeostatic bone remodeling and pathological bone erosion. Macrophage colony stimulating factor (M-CSF) is abundant in rheumatoid arthritis (RA). However, the role of M-CSF in arthritic bone erosion is not completely understood. Here, we show that M-CSF can promote osteoclastogenesis by triggering the proteolysis of c-FMS, a receptor for M-CSF, leading to the generation of FMS intracellular domain (FICD) fragments. Increased levels of FICD fragments positively regulated osteoclastogenesis but had no effect on inflammatory responses. Moreover, myeloid cell-specific FICD expression in mice resulted in significantly increased osteoclast-mediated bone resorption in an inflammatory arthritis model. The FICD formed a complex with DAP5, and the FICD/DAP5 axis promoted osteoclast differentiation by activating the MNK1/2/EIF4E pathway and enhancing NFATc1 protein expression. Moreover, targeting the MNK1/2 pathway diminished arthritic bone erosion. These results identified a novel role of c-FMS proteolysis in osteoclastogenesis and the pathogenesis of arthritic bone erosion.

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 Interleukin (IL)-25 suppresses IL-22 induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway

2020 ◽  
Author(s):  
Hong Ki Min ◽  
Ji-Yeon Won ◽  
Bo-Mi Kim ◽  
Kyung-Ann Lee ◽  
Seoung-Joon Lee ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
P38 Mapk ◽  
Human Peripheral Blood ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tartrate Resistant Acid Phosphatase ◽  
Blood Monocytes ◽  
Rankl Expression

Abstract Background The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA). Methods Serum from patients with RA and osteoarthritis (OA), and healthy controls, as well as synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis. Results Serum and synovial IL-25 levels in RA were up-regulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers. Conclusion In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.

Local concentrations of macrophage colony-stimulating factor mediate osteoclastic differentiation

1995 ◽  
Vol 269 (6) ◽  
pp. E1024-E1030 ◽  
Author(s):  
S. L. Perkins ◽  
S. J. Kling
Keyword(s):  
Bone Marrow ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nonspecific Esterase ◽  
Colony Stimulating Factor ◽  
Murine Bone Marrow ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Macrophage colony-stimulating factor (M-CSF) is essential for differentiation of osteoclasts and macrophages from a common bone marrow precursor. Using ST-2 stromal cell/murine bone marrow coculture, we studied the effects of increasing amounts of M-CSF on differentiation of macrophages and osteoclasts. Addition of exogenous M-CSF caused a dose-dependent 98% decrease in tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, accompanied by a 2.5-fold increase in nonspecific esterase-staining macrophages. Similar decrease in osteoclastic functional activity, including 125I-labeled calcitonin binding and calcitonin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production, were observed. Addition of exogenous M-CSF beyond 6 days in coculture had a decreasing ability to inhibit osteoclast formation, suggesting that M-CSF exerts its effects early in osteoclast differentiation, during the proposed proliferative phase of osteoclast formation. Similarly, early addition of neutralizing anti-M-CSF inhibited osteoclast formation, with diminishing effects beyond day 9. These results suggest that local high concentrations of M-CSF may influence the early determination of terminal differentiation into either macrophages or osteoclasts.

scholarly journals Interleukin (IL)-25 suppresses IL-22 induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway

2019 ◽  
Author(s):  
Hong Ki Min ◽  
Ji-Yeon Won ◽  
Bo-Mi Kim ◽  
Kyung-Ann Lee ◽  
Seoung-Joon Lee ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
P38 Mapk ◽  
Human Peripheral Blood ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tartrate Resistant Acid Phosphatase ◽  
Blood Monocytes ◽  
Rankl Expression

Abstract Background The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA).Methods Serum from patients with RA and osteoarthritis (OA), and healthy controls, as well as synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis.Results Serum and synovial IL-25 levels in RA were up-regulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers.Conclusion In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.

scholarly journals Relationships Between Slc1a5 and Osteoclastogenesis

2021 ◽  
Author(s):  
Hideki Tsumura ◽  
Miyuki Shindo ◽  
Morihiro Ito ◽  
Arisa Igarashi ◽  
Kazue Takeda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Osteoclast Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Glutamine Transporter ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Glutamine Uptake ◽  
Marrow Cells

Slc1a5 (ASCT2) encodes a small neutral amino-acid exchanger and is the most well-studied glutamine transporter in cancercells. To investigate the role of Slc1a5 in osteoclastogenesis, we developed Slc1a5-deficient mice by using a conventional gene-targeting approach. The Slc1a5−/− mice showed no obvious abnormalities in growth. Glutamine uptake was assessed in Slc1a5+/+ and Slc1a5−/− bone marrow cells stimulated with RANKL. The rate of glutamine uptake in Slc1a5−/− bone marrow cellswas reduced to 70% of that of cells from Slc1a5+/+ bone marrow. To confirm the involvement of Slc1a5 in osteoclast formation, bone marrow cells derived from Slc1a5+/+ or Slc1a5−/− mice were stimulated with RANKL and macrophage colony-stimulating factor and stained with tartrate-resistant acid phosphatase. The bone resorption activity and actin ring formation of stimulated cells were measured. The formation of multinucleated osteoclasts in bone marrow cells isolated from Slc1a5−/− mice was severely impaired compared with those from Slc1a5+/+ mice. RANKL-induced expression of ERK, NFκB, p70S6K, and NFATc1 was suppressed in Slc1a5−/− osteoclasts. These results show that Slc1a5 plays an important role in osteoclast formation.

scholarly journals Interleukin (IL)-25 suppresses IL-22-induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Hong Ki Min ◽  
Ji-Yeon Won ◽  
Bo-Mi Kim ◽  
Kyung-Ann Lee ◽  
Seoung-Joon Lee ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
P38 Mapk ◽  
Human Peripheral Blood ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tartrate Resistant Acid Phosphatase ◽  
Blood Monocytes ◽  
Rankl Expression

Abstract Background The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA). Methods Serum from patients with RA and osteoarthritis (OA), and healthy controls, and synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis. Results Serum and synovial IL-25 levels in RA were upregulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers. Conclusion In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.

Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis

2019 ◽  
Vol 34 (13) ◽  
pp. 815-819
Author(s):  
Dilara F. Kocacık Uygun ◽  
Vedat Uygun ◽  
Durmuş Burgucu ◽  
Nilüfer Çiçek Ekinci ◽  
Nilgün Sallakçı ◽  
...  
Keyword(s):  
Measles Virus ◽  
Mononuclear Cells ◽  
Inflammatory Mediator ◽  
Subacute Sclerosing Panencephalitis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Mediator Production ◽  
Healthy Donors ◽  
New Strategy ◽  
Ifn Γ

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. In this study, the possible roles of the Th1 (interleukin [IL]-12, interferon [IFN]-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.

scholarly journals Essential role of macrophage colony-stimulating factor in the osteoclast differentiation supported by stromal cells.

1991 ◽  
Vol 173 (5) ◽  
pp. 1291-1294 ◽  
Author(s):  
H Kodama ◽  
M Nose ◽  
S Niida ◽  
A Yamasaki
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Cells ◽  
Osteoclast Differentiation ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Marrow Cells

Severe deficiency of osteoclasts, monocytes, and peritoneal macrophages in osteopetrotic (op/op) mutant mice is caused by the absence of functional macrophage colony-stimulating factor (M-CSF). To clarify the role of M-CSF in the osteoclast differentiation, we established a clonal stromal cell line OP6L7 capable of supporting hemopoiesis from newborn op/op mouse calvaria. Although very few macrophages appeared in the cocultures of bone marrow cells and OP6L7 cells, a 50-fold larger number of macrophages was detected in the day 7 cocultures when purified recombinant human M-CSF (rhM-CSF) was exogenously supplied. Tartrate-resistant acid phosphatase (TRACP; a marker enzyme of osteoclasts)-positive cells appeared only when bone marrow cells were cultured in contact with OP6L7 cells and both rhM-CSF and 1 alpha, 25 (OH)2D3 were added. The TRACP-positive cells became multinucleated with increasing time in culture and expressed the c-fms/M-CSF receptor. These results indicate that both contact with stromal cells and M-CSF are requisite for osteoclast differentiation under physiological conditions.

Role of Endogenous Granulocyte-Macrophage Colony Stimulating Factor Following Stroke and Relationship to Neurological Outcome

2009 ◽  
Vol 6 (4) ◽  
pp. 246-251 ◽  
Author(s):  
Miriam Navarro-Sobrino ◽  
Anna Rosell ◽  
Anna Penalba ◽  
Marc Ribo ◽  
Jose Alvarez-Sabin ◽  
...  
Keyword(s):  
Neurological Outcome ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor
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