scholarly journals Myelofibrosis osteoclasts are clonal and functionally impaired

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2320-2324 ◽  
Author(s):  
Ivo Veletic ◽  
Taghi Manshouri ◽  
Asha S. Multani ◽  
C. Cameron Yin ◽  
Lei Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Remodeling ◽  
Chromosomal Abnormalities ◽  
Cathepsin K ◽  
Janus Kinase ◽  
Tartrate Resistant Acid Phosphatase ◽  
Healthy Individuals ◽  
Functionally Impaired ◽  
Calr Mutations ◽  
Mineral Resorption

Abstract Bone marrow (BM) sclerosis is commonly found in patients with late-stage myelofibrosis (MF). Because osteoclasts (OCs) and osteoblasts play a key role in bone remodeling, and MF monocytes, the OC precursors, are derived from the neoplastic clone, we wondered whether decreased OC numbers or impairment in their osteolytic function affects the development of osteosclerosis. Analysis of BM biopsies from 50 MF patients showed increased numbers of multinucleated tartrate-resistant acid phosphatase (TRAP)/cathepsin K+ OCs expressing phosphorylated Janus kinase 2 (JAK2). Randomly microdissected TRAP+ OCs from 16 MF patients harbored JAK2 or calreticulin (CALR) mutations, confirming MF OCs are clonal. To study OC function, CD14+ monocytes from MF patients and healthy individuals were cultured and differentiated into OCs. Unlike normal OCs, MF OCs appeared small and round, with few protrusions, and carried the mutations and chromosomal abnormalities of neoplastic clones. In addition, MF OCs lacked F-actin–rich ring-like structures and had fewer nuclei and reduced colocalization signals, compatible with decreased fusion events, and their mineral resorption capacity was significantly reduced, indicating impaired osteolytic function. Taken together, our data suggest that, although the numbers of MF OCs are increased, their impaired osteolytic activity distorts bone remodeling and contributes to the induction of osteosclerosis.

scholarly journals Translocation t(3;12)(q26;q21) In Jak2V617F Point Mutation Negative Chronic Idiopathic Myelofibrosis: A Case Report

2014 ◽  
Vol 17 (1) ◽  
pp. 63-67
Author(s):  
Mešanović S. ◽  
Šahović H. ◽  
Perić M.
Keyword(s):  
Bone Marrow ◽  
Structural Changes ◽  
Chromosomal Abnormalities ◽  
Chromosomal Translocation ◽  
Diagnostic Algorithm ◽  
Janus Kinase ◽  
Chromosomal Anomalies ◽  
Idiopathic Myelofibrosis ◽  
Jak2 Mutation ◽  
Chronic Idiopathic Myelofibrosis

Abstract The myeloproliferative diseases (MPDs) or myelo-proliferative neoplasms (MPNs) are a group of diseases of the bone marrow in which excess cells are produced. Chronic idiopathic myelofibrosis (CIMF) is a stem cell defect characterized by splenomegaly with multiorgan extramedullary hematopoiesis, immature peripheral blood granulocytes and erythrocytes and progressive bone marrow fibrosis. The most common chromosomal abnormalities seen in CIMF patients include numerical changes of chromosomes 7, 8 and 9, and structural changes of 1q, 5q, 13q and 20q. At least 75.0% of patients with bone marrow abnormalities have one or more of these chromosomal anomalies. Detection of the Janus kinase 2 (JAK2) mutation may be a potential major breakthrough for understanding the pathobiology of MPNs, and is an essential part of the diagnostic algorithm. In this study, we describe a JAK2V617F mutation negative CIMF patient who has the chromosomal translocation t(3;12)(q26;q21) in her karyotype.

scholarly journals Effects and Interaction of Icariin, Curculigoside, and Berberine in Er-Xian Decoction, a Traditional Chinese Medicinal Formula, on Osteoclastic Bone Resorption

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Liming Xue ◽  
Lei Jiao ◽  
Yin Wang ◽  
Yan Nie ◽  
Ting Han ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Cathepsin K ◽  
Osteoclastic Bone Resorption ◽  
Tartrate Resistant Acid Phosphatase ◽  
Inhibitory Effects ◽  
Dihydroxyvitamin D ◽  
Marrow Cells

Er-Xian decoction (EXD), a traditional Chinese medicine, has been reported to have a protective effect against bone loss in ovariectomized osteoporotic rats, and the inclusion of icariin (I), curculigoside (C), and berberine (B) in EXD displays inhibitory effects on osteoclastic bone resorption. In the present paper, we investigated the interaction and effects of I, C, B, and their combination on bone resorption activityin vitroon osteoclasts derived from rat bone marrow cells. ICB synergistically decreased the formation of bone resorption pits, the number of multinucleated osteoclasts, and the activity of tartrate-resistant acid phosphatase (TRAP) and showed antagonistic or additive effects on cathepsin K activity in the coculture system of osteoblasts and bone marrow cells in the presence of 1, 25-dihydroxyvitamin D3and dexamethasone. The combination of ICB also enhanced the inhibitory effects on the formation of F-actin ring, a cytoskeleton structure of osteoclasts induced from bone marrow cells with macrophage colony stimulation factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). In addition, ICB synergistically improved the ratio of protein expression of osteoprotegerin (OPG) and RANKL in osteoblasts and interfered with the mitogen-activated protein kinases (MAPKs) pathway in osteoclast. These results clearly show that I, C, B, and their combination in EXD exert effects of mutual reinforcement. However, IBC does not show an intensified adverse effect in the ovariectomized murine model, as revealed by change in body and uterine weight, confirming the safety of EXD. These observations are in agreement with the rationality of the formula used in this paper.

JAK2 V617F Mutation Is Infrequent in “5q-Syndrome” and 5q-Associated MDS.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4833-4833
Author(s):  
Ling Zhang ◽  
Saskia Gueller ◽  
Sophie Raynaud ◽  
Phillip H. Koeffler ◽  
Stephen Lee
Keyword(s):  
Bone Marrow ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Aspiration ◽  
K562 Cells ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Wild Type ◽  
Jak2 Mutation ◽  
V617f Mutation

Abstract Background: V617F mutation in Janus Kinase 2 (JAK2) gene has been found in chronic myeloproliferative disorders (MPD) including polycythemia vera (90%), essential thrombocythemia and chronic idiopathic myelofibrosis (30–50%), and occasionally in myelodysplastic syndromes (MDS). “5q- Syndrome” is a MDS that shares features with MPD and characterized by an atypical megakaryocytic hyperplasia in bone marrow and usually thrombocytosis in peripheral blood. The most common deleted region for this syndrome is 5q13.3q33.1. An interstitial deletion with variable proximal (5q12-14) and distal (5q31-33) breakpoints has been found in other MDS with/without additional chromosomal abnormalities beyond “5q- Syndrome”. To date, JAK2 mutation was detected in 6/97(6.2%) of patients having diagnosis of MDS with “5q- Syndrome”. Design: In our study 21 MDS patients (10 with “5q- Syndrome” and 11 MDS with isolated or complex 5q-) whose diagnosis by both bone marrow aspiration/biopsy and conventional chromosomal analysis were confirmed. Materials and Method: Primers were created to amplify a 460 bp fragment containing the site of JAK2 V617F mutation. Forty-five cycles of PCR were performed at an annealing temperature of 57°C. Resulting PCR product was digested with 2 U BsaXI for 16 hours and with an additional 2 U BsaXI for another 16 hours at 37°C, then analyzed on a 2% agarose gel. The mutant allele remained undigested whereas the wild-type allele was digested into 241 bp, 189 bp and 30 bp fragments. All experiments included a positive (HEL cells) and negative (K562 cells) control. Results: PCR results showed clear wild type PCR patterns in all 21 cases. Conclusion: No JAK2 mutations were detected in 21 patients either with “5q- Syndrome” or other 5q- associated MDS suggesting that JAK2 mutations are infrequent in these MDS patients.

scholarly journals Isofraxidin Inhibits Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis in Bone Marrow–Derived Macrophages Isolated from Sprague–Dawley Rats by Regulating NF-κB/NFATc1 and Akt/NFATc1 Signaling Pathways

2021 ◽  
Vol 30 ◽  
pp. 096368972199032
Author(s):  
Wei Wang ◽  
Bo Wang
Keyword(s):  
Bone Marrow ◽  
Signaling Pathways ◽  
Cathepsin K ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Luciferase Reporter ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Receptor Activator

Osteoporosis is a common bone disease that is characterized by decreased bone mass and fragility fractures. Isofraxidin is a hydroxy coumarin with several biological and pharmacological activities including an anti-osteoarthritis effect. However, the role of isofraxidin in osteoporosis has not yet been investigated. In the present study, we used receptor activator of nuclear factor-κB ligand (RANKL) to induce osteoclast formation in primary bone marrow macrophages (BMMs). Our results showed that RANKL treatment significantly increased tartrate-resistant acid phosphatase (TRAP) activity, as well as the expression of osteoclastogenesis-related markers including MMP-9, c-Src, and cathepsin K at both mRNA and protein levels; however, these effects were inhibited by isofraxidin in BMMs. In addition, luciferase reporter assay demonstrated that isofraxidin treatment suppressed the RANKL-induced an increase in nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) transcriptional activity. Besides, the decreased expression level of IκBα and increased levels of p-p65, p-IκBα, and p-Akt in RANKL-induced BMMs were attenuated by isofraxidin. Moreover, NFATc1 overexpression rescued the anti-osteoclastogenic effect of isofraxidin with increased expression levels of MMP-9, c-Src, and cathepsin K. Taken together, these findings indicated that isofraxidin inhibited RANKL-induced osteoclast formation in BMMs via inhibiting the activation of NF-κB/NFATc1 and Akt/NFATc1 signaling pathways. Thus, isofraxidin might be a therapeutic agent for the treatment of osteoporosis.

scholarly journals Antibodies to Citrullinated Proteins (ACPA) Associate with Markers of Osteoclast Activation and Bone Destruction in the Bone Marrow of Patients with Rheumatoid Arthritis

2021 ◽  
Vol 10 (8) ◽  
pp. 1778
Author(s):  
Weronika Kurowska ◽  
Iwona Slowinska ◽  
Zbigniew Krogulec ◽  
Piotr Syrowka ◽  
Wlodzimierz Maslinski
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Marrow ◽  
Bone Resorption ◽  
Peripheral Blood ◽  
Bone Destruction ◽  
Cathepsin K ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Osteoclast Activation ◽  
Citrullinated Protein

Normalizing bone metabolism is a challenge in rheumatoid arthritis (RA). Studies in mice suggest that anti-citrullinated protein antibodies (ACPAs) can trigger osteoclast activation and bone resorption in the bone marrow. However, data on the presence and role of ACPAs in human bone marrow are scarce. We investigated whether ACPAs can contribute to osteoclast activation and bone erosion in RA bone marrow. Anti-cyclic citrullinated peptide antibodies (anti-CCP Abs), osteoclast activation indicators–the tartrate-resistant acid phosphatase 5b (TRAP5b) and cathepsin K, and bone degradation marker–C-terminal telopeptide of type I collagen (CTX-I) were measured in the bone marrow and peripheral blood of RA patients using ELISAs. We found that ACPAs present in RA bone marrow was associated with increased amounts of TRAP5b, cathepsin K and CTX-I in this location. Levels of IL-8, the key mediator of anti-citrullinated protein antibody (ACPA)-induced bone resorption, were also elevated in bone marrow containing anti-CCP Abs and positively correlated with TRAP5b and cathepsin K concentrations. Higher levels of TRAP5b, cathepsin K, CTX-I and IL-8 in bone marrow compared to peripheral blood indicate local generation of these molecules. Our results complement data from animal studies and highlight the relevance of ACPAs and bone marrow in bone resorption in RA.

Hematological and toxicological evaluation of formaldehyde as a potential cause of human leukemia

2010 ◽  
Vol 30 (7) ◽  
pp. 725-735 ◽  
Author(s):  
Bernard D Goldstein
Keyword(s):  
Bone Marrow ◽  
Chromosomal Abnormalities ◽  
Species Difference ◽  
The Body ◽  
Myelogenous Leukemia ◽  
Laboratory Animals ◽  
Human Leukemia ◽  
Toxicological Evaluation ◽  
Hematopoietic Stem ◽  
Hematological Cancers

Epidemiological findings suggesting that formaldehyde exposure is associated with a higher risk of acute myelogenous leukemia (AML) and other hematological cancers have led to consideration of the potential mechanism of action by which inhalation of this rapidly reactive agent can cause bone marrow cancer. Two major mechanism-based arguments against formaldehyde as a leukemogen have been the difficulty in envisioning how inhaled formaldehyde might penetrate to the bone marrow; and the lack of similarity of non-cancer effects to other known human myeloleukemogens, particularly the absence of pancytopenia in humans or laboratory animals exposed to high levels. However, both of these arguments have been addressed by the recent finding of a pancytopenic effect and chromosomal abnormalities in heavily exposed Chinese workers which, if replicated, are indicative of a genotoxic effect of formaldehyde on hematopoietic stem cells that is in keeping with other known human leukemogens. Review of the body of evidence suggests an apparent discrepancy between studies in laboratory animals, which generally fail to show evidence of penetration of formaldehyde into the blood or evidence of blood or bone marrow genotoxicity, and studies of exposed humans in which there tends to be evidence of genotoxicity in circulating blood cells. One possible explanation for this discrepancy is species difference. Another possible explanation is that myeloid precursors within the nasal mucosa may be the site for leukemogenesis. However, chloromas, which are local collections of myeloid tumor cells, are rarely if ever found in the nose. Other proposed mechanisms for formaldehyde leukemogenesis are reviewed, and dose issues at the interface between the epidemiological and hematotoxicological findings are explored.

scholarly journals Hemophagocytic Lymphohistiocytosis Complicating Erythroleukemia in a Child with Monosomy 7: A Case Report and Review of the Literature

2013 ◽  
Vol 2013 ◽  
pp. 1-3
Author(s):  
Samin Alavi ◽  
Maryam Ebadi ◽  
Alireza Jenabzadeh ◽  
M. T. Arzanian ◽  
Sh. Shamsian
Keyword(s):  
Bone Marrow ◽  
Case Report ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Aspiration ◽  
Review Of The Literature ◽  
Monosomy 7 ◽  
Persistent Fever ◽  
First Case ◽  
Erythroid Precursors

Herein, the first case of childhood erythrophagocytosis following chemotherapy for erythroleukemia in a child with monosomy 7 is reported. A 5-year-old boy presented with anemia, thrombocytopenia, and hepatosplenomegaly in whom erythroleukemia was diagnosed. Prolonged pancytopenia accompanied by persistent fever and huge splenomegaly and hepatomegaly became evident after 2 courses of chemotherapy. On bone marrow aspiration, macrophages phagocytosing erythroid precursors were observed and the diagnosis of HLH was established; additionally, monosomy 7 was detected on bone marrow cytogenetic examination. In conclusion, monosomy 7 can lead to erythrophagocytosis associated with erythroid leukemia and should be considered among the chromosomal abnormalities contributing to the association.

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.

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