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1
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Madel MB, Ibáñez L, Ciucci T, Halper J, Boutin A, Beldi G, Lavanant AC, Garchon HJ, Rouleau M, Mueller CG, Peyrin-Biroulet L, Moulin D, Blin-Wakkach C, Wakkach A. Dysregulated myeloid differentiation in colitis is induced by inflammatory osteoclasts in a TNFα-dependent manner. Mucosal Immunol 2025; 18:90-104. [PMID: 39332768 DOI: 10.1016/j.mucimm.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 09/14/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by very severe intestinal inflammation associated with extra-intestinal manifestations. One of the most critical ones is bone destruction, which remains a major cause of morbidity and a risk factor for osteopenia and osteoporosis in IBD patients. In various mouse models of IBD, we and other have demonstrated concomitant bone loss due to a significant increase in osteoclast activity. Besides bone resorption, osteoclasts are known to control hematopoietic niches in vivo and modulate inflammatory responses in vitro, suggesting they may participate in chronic inflammation in vivo. Here, using different models of colitis, we showed that osteoclast inhibition significantly reduced disease severity and that induction of osteoclast differentiation by RANKL contributed to disease worsening. Our results demonstrate a direct link between osteoclast activity and myeloid cell accumulation in the intestine during colitis. RNAseq analysis of osteoclasts from colitic mice revealed overexpression of genes involved in the remodeling of hematopoietic stem cell niches. We also demonstrated that osteoclasts induced hematopoietic progenitor proliferation accompanied by a myeloid skewing in the early phases of colitis, which was confirmed in a model of RANKL-induced osteoclastogenesis. Mechanistically, inhibition of TNF-α reduced the induction of myeloid skewing by OCL both in vitro and in vivo. Lastly, we observed that osteoclastic activity and the proportion of myeloid cells in the blood are positively correlated in patients with Crohn's disease. Collectively, our results shed light on a new role of osteoclasts in colitis in vivo, demonstrating they exert their colitogenic activity through an early action on hematopoiesis, leading to an increase in myelopoiesis sustaining gut inflammation.
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Affiliation(s)
| | - Lidia Ibáñez
- Université Côte d'Azur, CNRS, LP2M, Nice, France
| | - Thomas Ciucci
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Julia Halper
- Université Côte d'Azur, CNRS, LP2M, Nice, France
| | | | - Ghada Beldi
- Université Côte d'Azur, CNRS, LP2M, Nice, France
| | - Alice C Lavanant
- CNRS UPR 3572, IBMC, University of Strasbourg, 67000 Strasbourg, France
| | - Henri-Jean Garchon
- Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, 78180 Montigny-Le-Bretonneux, France
| | | | | | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, IHU INFINY, CHRU Nancy, F-54500 Vandœuvre-lès-Nancy, France; Université de Lorraine, INSERM, NGERE, F-54500 Vandoeuvre les Nancy, France
| | - David Moulin
- Université de Lorraine, CNRS, IMoPA, F-54500 Vandœuvre Les Nancy, France; IHU INFINY, Contrat d'interface, CHRU Nancy, France
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2
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Zeytin IC, Alkan B, Ozdemir C, Cetinkaya DU, Okur FV. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:310-321. [PMID: 35356978 PMCID: PMC8969067 DOI: 10.1093/stcltm/szab019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/07/2021] [Indexed: 11/22/2022] Open
Abstract
Osteopetrosis is a rare inherited disease characterized by impaired osteoclast activity causing defective bone resorption and bone marrow aplasia. It is fatal in early childhood unless hematopoietic stem cell transplantation is performed. But, the transplant course is complicated with engraftment failure. Recently, osteoclasts have been described as the potential regulators of hematopoietic stem cell (HSC) niche. Here we investigated the alterations in the HSC and mesenchymal stromal cell (MSC) components of osteopetrotic niche and their interactions to mimic the stem cell dynamics/trafficking in the BM niche after HSC transplantation. Induced pluripotent stem cells were generated from peripheral blood mononuclear cells of patients with osteopetrosis carrying TCIRG1 mutation. iPSC lines were differentiated into hematopoietic and myeloid progenitors, then into osteoclasts using a step-wise protocol. We first demonstrated a shift toward monocyte-macrophages lineage regarding hematopoietic differentiation potential of osteopetrotic iPSC-derived hematopoietic progenitors (HPCs) and phenotypically normal and functionally defective osteoclast formation. The expression of the genes involved in HSC homing and maintenance (Sdf-1, Jagged-1, Kit-L, and Opn) in osteopetrotic MSCs recovered significantly after coculture with healthy HPCs. Similarly, the restoration of phenotype, impaired differentiation, and migratory potential of osteopetrotic iHPCs were observed upon interaction with healthy MSCs. Our results establish significant alterations in both MSC and HPC compartments of the osteopetrotic niche, and support the impact of functionally impaired osteoclasts in defective niche formation.
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Affiliation(s)
- Inci Cevher Zeytin
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Berna Alkan
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Cansu Ozdemir
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
| | - Duygu Uckan Cetinkaya
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
- Department of Pediatrics, Division of Pediatric Hematology and Bone Marrow Transplantation Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey
- Corresponding authors: Duygu Uckan Cetinkaya and Fatma Visal Okur, Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Turkey, (F.V.O.), (D.U.C.)
| | - Fatma Visal Okur
- Center for Stem Cell Research and Development PEDI-STEM, Hacettepe University, Ankara, Turkey
- Department of Stem Cell Sciences, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
- Department of Pediatrics, Division of Pediatric Hematology and Bone Marrow Transplantation Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey
- Corresponding authors: Duygu Uckan Cetinkaya and Fatma Visal Okur, Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Turkey, (F.V.O.), (D.U.C.)
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3
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Yu J, Adapala NS, Doherty L, Sanjay A. Cbl-PI3K interaction regulates Cathepsin K secretion in osteoclasts. Bone 2019; 127:376-385. [PMID: 31299383 PMCID: PMC6708784 DOI: 10.1016/j.bone.2019.07.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 07/06/2019] [Accepted: 07/08/2019] [Indexed: 10/26/2022]
Abstract
Effective bone resorption by osteoclasts is critical for balanced bone remodeling. We have previously reported that mice harboring a substitution mutation of tyrosine 737 to phenylalanine in the adapter protein Cbl (CblY737F, YF) have increased bone volume partly due to decreased osteoclast-mediated bone resorption. The CblY737F mutation abrogates interaction between Cbl and the p85 subunit of PI3K. Here, we studied the mechanism for defective resorptive function of YF mutant osteoclasts. The YF osteoclasts had intact actin cytoskeletons and sealing zones. Expression and localization of proteins needed for acidification of the resorptive lacunae were also comparable between the WT and YF osteoclasts. In contrast, secretion of Cathepsin K, a major protease needed to degrade collagen, was diminished in the conditioned media derived from YF osteoclasts. The targeting of Cathepsin K into LAMP2-positive vesicles was also compromised due to decreased number of LAMP2-positive vesicles in YF osteoclasts. Further, we found that in contrast to WT, conditioned media derived from YF osteoclasts promoted increased numbers of alkaline phosphatase positive colonies, and increased expression of osteogenic markers in WT calvarial cultures. Cumulatively, our results suggest that the Cbl-PI3K interaction regulates Cathepsin K secretion required for proper bone resorption, and secretion of factors which promote osteogenesis.
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Affiliation(s)
- Jungeun Yu
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, United States of America
| | - Naga Suresh Adapala
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, United States of America
| | - Laura Doherty
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, United States of America
| | - Archana Sanjay
- Department of Orthopaedic Surgery, UConn Health, Farmington, CT 06030, United States of America.
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4
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Madel MB, Ibáñez L, Wakkach A, de Vries TJ, Teti A, Apparailly F, Blin-Wakkach C. Immune Function and Diversity of Osteoclasts in Normal and Pathological Conditions. Front Immunol 2019; 10:1408. [PMID: 31275328 PMCID: PMC6594198 DOI: 10.3389/fimmu.2019.01408] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 06/04/2019] [Indexed: 12/31/2022] Open
Abstract
Osteoclasts (OCLs) are key players in controlling bone remodeling. Modifications in their differentiation or bone resorbing activity are associated with a number of pathologies ranging from osteopetrosis to osteoporosis, chronic inflammation and cancer, that are all characterized by immunological alterations. Therefore, the 2000s were marked by the emergence of osteoimmunology and by a growing number of studies focused on the control of OCL differentiation and function by the immune system. At the same time, it was discovered that OCLs are much more than bone resorbing cells. As monocytic lineage-derived cells, they belong to a family of cells that displays a wide heterogeneity and plasticity and that is involved in phagocytosis and innate immune responses. However, while OCLs have been extensively studied for their bone resorption capacity, their implication as immune cells was neglected for a long time. In recent years, new evidence pointed out that OCLs play important roles in the modulation of immune responses toward immune suppression or inflammation. They unlocked their capacity to modulate T cell activation, to efficiently process and present antigens as well as their ability to activate T cell responses in an antigen-dependent manner. Moreover, similar to other monocytic lineage cells such as macrophages, monocytes and dendritic cells, OCLs display a phenotypic and functional plasticity participating to their anti-inflammatory or pro-inflammatory effect depending on their cell origin and environment. This review will address this novel vision of the OCL, not only as a phagocyte specialized in bone resorption, but also as innate immune cell participating in the control of immune responses.
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Affiliation(s)
- Maria-Bernadette Madel
- CNRS, Laboratoire de PhysioMédecine Moléculaire, Faculté de Médecine, UMR7370, Nice, France.,Faculé de Médecine, Université Côte d'Azur, Nice, France
| | - Lidia Ibáñez
- Department of Pharmacy, Cardenal Herrera-CEU University, València, Spain
| | - Abdelilah Wakkach
- CNRS, Laboratoire de PhysioMédecine Moléculaire, Faculté de Médecine, UMR7370, Nice, France.,Faculé de Médecine, Université Côte d'Azur, Nice, France
| | - Teun J de Vries
- Department of Periodontology, Academic Centre of Dentistry Amsterdam, University of Amsterdam and Vrije Univeristeit, Amsterdam, Netherlands
| | - Anna Teti
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | | | - Claudine Blin-Wakkach
- CNRS, Laboratoire de PhysioMédecine Moléculaire, Faculté de Médecine, UMR7370, Nice, France.,Faculé de Médecine, Université Côte d'Azur, Nice, France
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5
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Das P, Veazey KJ, Van HT, Kaushik S, Lin K, Lu Y, Ishii M, Kikuta J, Ge K, Nussenzweig A, Santos MA. Histone methylation regulator PTIP is required to maintain normal and leukemic bone marrow niches. Proc Natl Acad Sci U S A 2018; 115:E10137-E10146. [PMID: 30297393 PMCID: PMC6205459 DOI: 10.1073/pnas.1806019115] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
The bone is essential for locomotion, calcium storage, and harboring the hematopoietic stem cells (HSCs) that supply the body with mature blood cells throughout life. HSCs reside at the interface of the bone and bone marrow (BM), where active bone remodeling takes place. Although the cellular components of the BM niche have been characterized, little is known about its epigenetic regulation. Here we find that the histone methylation regulator PTIP (Pax interaction with transcription-activation domain protein-1) is required to maintain the integrity of the BM niche by promoting osteoclast differentiation. PTIP directly promotes chromatin changes required for the expression of Pparγ (peroxisome proliferator-activated receptor-γ), a transcription factor essential for osteoclastogenesis. PTIP deletion leads to a drastic reduction of HSCs in the BM and induces extramedullary hematopoiesis. Furthermore, exposure of acute myeloid leukemia cells to a PTIP-deficient BM microenvironment leads to a reduction in leukemia-initiating cells and increased survival upon transplantation. Taken together, our data identify PTIP as an epigenetic regulator of osteoclastogenesis that is required for the integrity of the BM niche to sustain both normal hematopoiesis and leukemia.
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Affiliation(s)
- Prosun Das
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Kylee J Veazey
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Hieu T Van
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Saakshi Kaushik
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030
- Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030
- Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
| | - Kai Ge
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
| | - Andre Nussenzweig
- Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Margarida A Santos
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
- Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030
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6
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Kook SH, Sim HJ, Hwang JW, Baek YH, Kim CC, Lee JH, Cho ES, Lee JC. Genetic overexpression of COMP-Ang1 impairs BM microenvironment and induces senescence of BM HSCs. Biochem Biophys Res Commun 2018; 499:669-674. [PMID: 29604278 DOI: 10.1016/j.bbrc.2018.03.210] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 03/28/2018] [Indexed: 12/27/2022]
Abstract
Supplemental Angiopoietin 1 (Ang1) exerts its therapeutic potential on microvascular regression-associated diseases, and this potential is linked with the function of hematopoietic stem cells (HSCs). However, the underlying mechanisms of the effect of enhanced angiogenesis on the modulation of HSCs are not yet defined. Here, we generated transgenic mice expressing Cartilage Oligomeric Matrix Protein (COMP)-Ang1 in keratin 14-expressing cells. The mutant animals expressed excessive angiogenic characteristics in the skin and bone marrow (BM) along with redder skin with more numerous and branched vessels compared with their wild-type (WT) littermates. The mutants displayed reduced long bone formation and osteoclast activity than did WT littermates and had fewer CD150+CD48-Lineage-Sca-1+c-Kit+ (LSK) cells in the BM. The mutants also exhibited greater senescence-associated (SA) β-gal activity, p16INK4a protein expression, and superoxide anion levels in CD150+CD48-LSK cells in the BM. Furthermore, transplantation assay revealed that the mutant-derived LSK cells were inferior to the cells derived from WT littermate in inducing competitive repopulating capacity in the recipients. Collectively, our results demonstrate that persistent and prolonged administration of COMP-Ang1 by inducible transgenic expression mediates excessive angiogenesis in the body and impairs BM microenvironment, eventually leading to senescence of BM HSCs.
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Affiliation(s)
- Sung-Ho Kook
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Chonbuk National University, Jeonju, 54896, South Korea; Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea
| | - Hyun-Jaung Sim
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Chonbuk National University, Jeonju, 54896, South Korea; Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea
| | - Jae-Won Hwang
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea
| | - Young-Hyun Baek
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea
| | - Chun-Chu Kim
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea
| | - Jeong-Hoon Lee
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea.
| | - Jeong-Chae Lee
- Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Chonbuk National University, Jeonju, 54896, South Korea; Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and School of Dentistry, Chonbuk National University, Jeonju, 54896, South Korea.
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7
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Pleyer L, Valent P, Greil R. Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis-Masters of Survival and Clonality? Int J Mol Sci 2016; 17:ijms17071009. [PMID: 27355944 PMCID: PMC4964385 DOI: 10.3390/ijms17071009] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Revised: 05/20/2016] [Accepted: 06/08/2016] [Indexed: 02/07/2023] Open
Abstract
Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the “reprogramming” of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs.
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Affiliation(s)
- Lisa Pleyer
- 3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
- Center for Clinical Cancer and Immunology Trials at Salzburg Cancer Research Institute, 5020 Salzburg, Austria.
- 3rd Medical Department, Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology & Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria.
| | - Richard Greil
- 3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
- Center for Clinical Cancer and Immunology Trials at Salzburg Cancer Research Institute, 5020 Salzburg, Austria.
- 3rd Medical Department, Cancer Cluster Salzburg, 5020 Salzburg, Austria.
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8
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Drissi H, Sanjay A. The Multifaceted Osteoclast; Far and Beyond Bone Resorption. J Cell Biochem 2016; 117:1753-6. [PMID: 27019318 DOI: 10.1002/jcb.25560] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 03/24/2016] [Indexed: 01/21/2023]
Abstract
The accepted function of the bone resorbing cell, osteoclast, has been linked to bone remodeling and pathological osteolysis. Emerging evidence points to novel functions of osteoclasts in controlling bone formation and angiogenesis. Thus, while the concept of a "clastokine" with the potential to regulate osteogenesis during remodeling did not come as a surprise, new evidence provided unique insight into the mechanisms underlying osteoclastic control of bone formation. The question still remains as to whether osteoclast precursors or a unique trap positive mononuclear cell, can govern any aspect of bone formation. The novel paradigm eloquently proposed by leaders in the field brings together the concept of clastokines and osteoclast precursor-mediated bone formation, potentially though enhanced angiogenesis. These fascinating advances in osteoclast biology have motivated this short review, in which we discuss these new roles of osteoclasts. J. Cell. Biochem. 117: 1753-1756, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Hicham Drissi
- University of Connecticut Health Center, Orthopaedics Surgery, 263 Farmington Ave, Farmington 06034, Connecticut
| | - Archana Sanjay
- University of Connecticut Health Center, Orthopaedics Surgery, 263 Farmington Ave, Farmington 06034, Connecticut
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9
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Affiliation(s)
- Won-Ju Jeong
- Department of Orthopedic Surgery, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ha-Jeong Kim
- Department of Physiology, Kyungpook National University School of Medicine, Daegu, Korea
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10
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Catelain C, Michelet F, Hattabi A, Poirault-Chassac S, Kortulewski T, Tronik-Le Roux D, Vainchenker W, Lauret E. The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network. Stem Cell Res 2014; 13:431-41. [PMID: 25460604 DOI: 10.1016/j.scr.2014.10.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 09/17/2014] [Accepted: 10/01/2014] [Indexed: 12/14/2022] Open
Abstract
Understanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self-renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta-4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta-4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, -D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and -2, as part of the stem signature associated with the Delta-4/Notch signalling pathway.
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Affiliation(s)
- Cyril Catelain
- Inserm U974, CNRS (UMR 7215), UM 76, Institut de Myologie, Paris F-75013, France; Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France.
| | - Fabio Michelet
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France
| | - Aurore Hattabi
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France
| | - Sonia Poirault-Chassac
- Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France
| | | | | | - William Vainchenker
- Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France
| | - Evelyne Lauret
- Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France
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11
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Abstract
Blood is renewed throughout the entire life. The stem cells of the blood, called hematopoietic stem cells (HSCs), are responsible for maintaining a supply of all types of fresh blood cells. In contrast to other stem cells, the clinical application of these cells is well established and HSC transplantation is an established life-saving therapy for patients suffering from haematological disorders. Despite their efficient functionality throughout life in vivo, controlling HSC behaviour in vitro (including their proliferation and differentiation) is still a major task that has not been resolved with standard cell culture systems. Targeted HSC multiplication in vitro could be beneficial for many patients, because HSC supply is limited. The biology of these cells and their natural microenvironment - their niche - remain a matter of ongoing research. In recent years, evidence has come to light that HSCs are susceptible to physical stimuli. This makes the regulation of HSCs by engineering physical parameters a promising approach for the targeted manipulation of these cells for clinical applications. Nevertheless, the biophysical regulation of these cells is still poorly understood. This review sheds light on the role of biophysical parameters in HSC biology and outlines which knowledge on biophysical regulation identified in other cell types could be applied to HSCs.
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Affiliation(s)
- C Lee-Thedieck
- Karlsruhe Institute of Technology (KIT), Institute of Functional Interfaces, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
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12
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Blin-Wakkach C, Rouleau M, Wakkach A. Roles of osteoclasts in the control of medullary hematopoietic niches. Arch Biochem Biophys 2014; 561:29-37. [PMID: 24998177 DOI: 10.1016/j.abb.2014.06.032] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 06/23/2014] [Accepted: 06/25/2014] [Indexed: 12/23/2022]
Abstract
Bone marrow is the major site of hematopoiesis in mammals. The bone marrow environment plays an essential role in the regulation of hematopoietic stem and progenitor cells by providing specialized niches in which these cells are maintained. Many cell types participate to the composition and regulation of hematopoietic stem cell (HSC) niches, integrating complex signals from the bone, immune and nervous systems. Among these cells, the bone-resorbing osteoclasts (OCLs) have been described as main regulators of HSC niches. They are not limited to carving space for HSCs, but they also provide signals that affect the molecular and cellular niche components. However, their exact role in HSC niches remains unclear because of the variety of models, signals and conditions used to address the question. The present review will discuss the importance of the implication of OCLs focusing on the formation of HSC niches, the maintenance of HSCs in these niches and the mobilization of HSCs from the bone marrow. It will underline the importance of OCLs in HSC niches.
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Affiliation(s)
- Claudine Blin-Wakkach
- CNRS UMR7370, LP2M, Faculty of Medicine, 28 Av de Valombrose, 06107 Nice, France; University Nice Sophia Antipolis, Faculty of Sciences, Parc Valrose, 06100 Nice, France.
| | - Matthieu Rouleau
- CNRS UMR7370, LP2M, Faculty of Medicine, 28 Av de Valombrose, 06107 Nice, France; University Nice Sophia Antipolis, Faculty of Sciences, Parc Valrose, 06100 Nice, France
| | - Abdelilah Wakkach
- CNRS UMR7370, LP2M, Faculty of Medicine, 28 Av de Valombrose, 06107 Nice, France; University Nice Sophia Antipolis, Faculty of Sciences, Parc Valrose, 06100 Nice, France
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Miyamoto T. Role of osteoclasts in regulating hematopoietic stem and progenitor cells. World J Orthop 2013; 4:198-206. [PMID: 24147255 PMCID: PMC3801239 DOI: 10.5312/wjo.v4.i4.198] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Revised: 12/19/2012] [Accepted: 01/21/2013] [Indexed: 02/06/2023] Open
Abstract
Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed “niche” to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization.
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Lacombe J, Karsenty G, Ferron M. Regulation of lysosome biogenesis and functions in osteoclasts. Cell Cycle 2013; 12:2744-52. [PMID: 23966172 DOI: 10.4161/cc.25825] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In order to resorb the mineralized bone extracellular matrix, the osteoclast relies on the generation of a resorption lacuna characterized by the presence of specific proteases and a low pH. Hence, bone resorption by osteoclasts is highly dependent on lysosomes, the organelles specialized in intra- and extracellular material degradation. This is best illustrated by the fact that multiple forms of human osteopetrosis are caused by mutations in genes encoding for lysosomal proteins. Yet, until recently, the molecular mechanisms regulating lysosomal biogenesis and function in osteoclasts were poorly understood. Here we review the latest developments in the study of lysosomal biogenesis and function in osteoclasts with an emphasis on the transcriptional control of these processes.
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Affiliation(s)
- Julie Lacombe
- Institut de Recherches Cliniques de Montréal; Montréal, Québec, Canada
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Le Goff B, Berthelot JM, Maugars Y, Heymann D. Osteoclasts in RA: diverse origins and functions. Joint Bone Spine 2013; 80:586-91. [PMID: 23731635 DOI: 10.1016/j.jbspin.2013.04.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2013] [Indexed: 01/01/2023]
Abstract
Osteoclasts were recognized in the late 1990s as the cells responsible for generalized and focal bone loss in rheumatoid arthritis (RA). Concepts about osteoclast biology have changed radically based on recent evidence of considerable diversity in both the origins and the functions of osteoclasts. In addition, the role for osteoclasts is not confined to bone resorption but may also include active contributions to inflammatory and autoimmune responses. Thus, in RA, osteoclast progenitors may arise from both circulating cells and cells developed within the rheumatoid synovium or subchondral bone. Within the inflamed synovium, osteoclasts are activated by factors such as cytokines, immune complexes, or activators of the toll-like receptors, which are not found in healthy bone tissue. Finally, recent data suggest that osteoclasts may be capable of antigen presentation to T cells via major histocompatibility complex class I and class II molecules. Confirmation of this suggestion by future studies would indicate that osteoclasts might be involved not only in bone resorption, but also in autoimmune responses and antigen presentation. These data highlight the considerable complexity of interactions between bone tissue and the immune system. Research into these interactions may identify new targets for treatments against the bone abnormalities associated with chronic inflammatory disease.
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Affiliation(s)
- Benoit Le Goff
- Service de rhumatologie, Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes cedex 1, France; LUNAM université, 44000 Nantes, France; Inserm, UMR957, physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, 44035 Nantes, France; Université de Nantes, Nantes atlantique universités, 44035 Nantes, France.
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