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Sasine JP, Kozlova NY, Valicente L, Dukov J, Tran DH, Himburg HA, Kumar S, Khorsandi S, Chan A, Grohe S, Li M, Kan J, Sehl ME, Schiller GJ, Reinhardt B, Singh BK, Ho R, Yue P, Pasquale EB, Chute JP. Inhibition of Ephrin B2 Reverse Signaling Abolishes Multiple Myeloma Pathogenesis. Cancer Res 2024; 84:919-934. [PMID: 38231476 PMCID: PMC10940855 DOI: 10.1158/0008-5472.can-23-1950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/14/2023] [Accepted: 01/11/2024] [Indexed: 01/18/2024]
Abstract
Bone marrow vascular endothelial cells (BM EC) regulate multiple myeloma pathogenesis. Identification of the mechanisms underlying this interaction could lead to the development of improved strategies for treating multiple myeloma. Here, we performed a transcriptomic analysis of human ECs with high capacity to promote multiple myeloma growth, revealing overexpression of the receptor tyrosine kinases, EPHB1 and EPHB4, in multiple myeloma-supportive ECs. Expression of ephrin B2 (EFNB2), the binding partner for EPHB1 and EPHB4, was significantly increased in multiple myeloma cells. Silencing EPHB1 or EPHB4 in ECs suppressed multiple myeloma growth in coculture. Similarly, loss of EFNB2 in multiple myeloma cells blocked multiple myeloma proliferation and survival in vitro, abrogated multiple myeloma engraftment in immune-deficient mice, and increased multiple myeloma sensitivity to chemotherapy. Administration of an EFNB2-targeted single-chain variable fragment also suppressed multiple myeloma growth in vivo. In contrast, overexpression of EFNB2 in multiple myeloma cells increased STAT5 activation, increased multiple myeloma cell survival and proliferation, and decreased multiple myeloma sensitivity to chemotherapy. Conversely, expression of mutant EFNB2 lacking reverse signaling capacity in multiple myeloma cells increased multiple myeloma cell death and sensitivity to chemotherapy and abolished multiple myeloma growth in vivo. Complementary analysis of multiple myeloma patient data revealed that increased EFNB2 expression is associated with adverse-risk disease and decreased survival. This study suggests that EFNB2 reverse signaling controls multiple myeloma pathogenesis and can be therapeutically targeted to improve multiple myeloma outcomes. SIGNIFICANCE Ephrin B2 reverse signaling mediated by endothelial cells directly regulates multiple myeloma progression and treatment resistance, which can be overcome through targeted inhibition of ephrin B2 to abolish myeloma.
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Affiliation(s)
- Joshua P. Sasine
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California
| | - Natalia Y. Kozlova
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California
| | - Lisa Valicente
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California
| | - Jennifer Dukov
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California
| | - Dana H. Tran
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California
| | - Heather A. Himburg
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Sanjeev Kumar
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California
| | - Sarah Khorsandi
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Aldi Chan
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Samantha Grohe
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Michelle Li
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Jenny Kan
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Mary E. Sehl
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Gary J. Schiller
- Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, California
| | - Bryanna Reinhardt
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Brijesh Kumar Singh
- Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California
| | - Ritchie Ho
- Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, California
| | - Peibin Yue
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Elena B. Pasquale
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, California
| | - John P. Chute
- Division of Hematology & Cellular Therapy, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Mehdi SJ, Ghatak K, Ling W, Johnson SK, Epstein J, Nookaew I, Zangari M, Schinke C, Thanendrarajan S, van Rhee F, Yaccoby S. Growth and dormancy control of myeloma cells by mesenchymal stem cells. Leuk Res 2023; 133:107355. [PMID: 37499483 DOI: 10.1016/j.leukres.2023.107355] [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: 06/08/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023]
Abstract
Bone marrow mesenchymal stem cells (MSCs) may have contrasting impacts on the progression of multiple myeloma (MM). Priming normal MSCs, by culturing them with MM cells, mimics the MSC-induced MM growth. We studied the contrasting effects of conditioned medium (CM) from unprimed or primed MSCs on growth of MM cells from newly diagnosed cases. We elucidated potential molecular pathways using global gene expression profiling and focused on the role of the mTOR2 component, RICTOR, as a novel mediator of dormancy in MM. Primed MSCs CM consistently increased proportions of proliferating cells and supported MM growth in 3-day (n = 20) and 10-day (n = 12) cultures, effects that were partially mediated through the IGF1 axis. In contrast, unprimed MSCs CM inhibited growth of MM cells in cases mainly from stages I/II MM. The genes most overexpressed in MM cells treated with primed MSCs CM were associated with cell cycle, DNA-damage repair, and proliferation; genes most overexpressed in MM cells treated with unprimed MSCs CM were associated with dormancy pathways including RICTOR (mTOR2 pathway), CXCR4, and BCL2. RICTOR protein level was induced by unprimed MSCs CM and was lower in KI67+ proliferating MM cells treated with primed MSCs CM. RICTOR was underexpressed in clinical relapse samples compared with baseline samples of the same patients. Inhibiting RICTOR expression in primary MM cells promoted their growth, and enforced expression of RICTOR in MM cell lines inhibited their growth. Our findings suggest that, after prolonged interactions with MM cells, bone marrow MSCs shift from MM-repressive to MM-permissive. AVAILABILITY OF DATA AND MATERIALS: Our institutional GEP data of MM cells from newly diagnosed patients used to show RICTOR expression have been deposited at Gene Expression Omnibus (GEO: GSE2658, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2658).
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Affiliation(s)
- Syed J Mehdi
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Kalyan Ghatak
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Wen Ling
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sarah K Johnson
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Joshua Epstein
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Intawat Nookaew
- Department of Biomedical Informatics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Maurizio Zangari
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Carolina Schinke
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sharmilan Thanendrarajan
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Frits van Rhee
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Shmuel Yaccoby
- Myeloma Center, Department of Internal Medicine, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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Wang L, Li W, Pan Y. The Eph/Ephrin system in primary bone tumor and bone cancer pain. Aging (Albany NY) 2023; 15:7324-7332. [PMID: 37413995 PMCID: PMC10415561 DOI: 10.18632/aging.204852] [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: 04/14/2023] [Accepted: 06/19/2023] [Indexed: 07/08/2023]
Abstract
The family of Eph receptor tyrosine kinases and their Ephrin ligands system constitutes a bidirectional signaling pathway. Eph/Ephrin system coordinate a wide spectrum of pathologic processes during development, metastasis, prognosis, drug resistance and angiogenesis in carcinogenesis. Chemotherapy, surgery and radiotherapy are the most commonly used clinical treatments for primary bone tumors. Therefore, surgical resection is often unable to completely eliminate the tumor, and this is the main cause of metastasis and postoperative recurrence. A growing body of literature has been published lately revitalizing our scientific interest towards the role of Eph/Ephrins in pathogenesis and the treatment of bone tumor and bone cancer pain. This study mainly reviewed the roles of Eph/Ephrin system that has both tumor-suppressing and -promoting roles in primary bone tumors and bone cancer pain. Understanding the intracellular mechanisms of Eph/Ephrin system in tumorigenesis and metastasis of bone tumors might provide a foundation for the development of Eph/Ephrin targeted anti-cancer therapy.
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Affiliation(s)
- Lujuan Wang
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Wei Li
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
| | - Yong Pan
- Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, China
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Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma. Int J Mol Sci 2022; 23:ijms232415448. [PMID: 36555090 PMCID: PMC9779562 DOI: 10.3390/ijms232415448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/02/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022] Open
Abstract
Multiple myeloma (MM) is a monoclonal gammopathy characterized by biological heterogeneity and unregulated proliferation of plasma cells (PCs) in bone marrow (BM). MM is a multistep process based on genomic instability, epigenetic dysregulation and a tight cross-talk with the BM microenvironment that plays a pivotal role supporting the proliferation, survival, drug-resistance and homing of PCs. The BM microenvironment consists of a hematopoietic and a non-hematopoietic compartment, which cooperate to create a tumor environment. Among the non-hematopoietic component, mesenchymal stromal cells (MSCs) and osteoblasts (OBs) appear transcriptionally and functionally different in MM patients compared to healthy donors (HDs) and to patients with pre-malignant monoclonal gammopathies. Alterations of both MSCs and OBs underly the osteolytic lesions that characterize myeloma-associated bone disease. In this review, we will discuss the different characteristics of MSCs and OBs in MM patients, analyzing the transcriptome, the deregulated molecular pathways and the role performed by miRNAs and exosome in the pathophysiology of MM.
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Gau YC, Yeh TJ, Hsu CM, Hsiao SY, Hsiao HH. Pathogenesis and Treatment of Myeloma-Related Bone Disease. Int J Mol Sci 2022; 23:ijms23063112. [PMID: 35328533 PMCID: PMC8951013 DOI: 10.3390/ijms23063112] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma is a hematologic malignancy of plasma cells that causes bone-destructive lesions and associated skeletal-related events (SREs). The pathogenesis of myeloma-related bone disease (MBD) is the imbalance of the bone-remodeling process, which results from osteoclast activation, osteoblast suppression, and the immunosuppressed bone marrow microenvironment. Many important signaling cascades, including the RANKL/RANK/OPG axis, Notch signaling, the Wnt/β-Catenin signaling pathways, and signaling molecules, such as DKK-1, sclerostin, osteopontin, activin A, chemokines, and interleukins are involved and play critical roles in MBD. Currently, bisphosphonate and denosumab are the gold standard for MBD prevention and treatment. As the molecular mechanisms of MBD become increasingly well understood, novel agents are being thoroughly explored in both preclinical and clinical settings. Herein, we will provide an updated overview of the pathogenesis of MBD, summarize the clinical management and guidelines, and discuss novel bone-modifying therapies for further management of MBD.
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Affiliation(s)
- Yuh-Ching Gau
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tsung-Jang Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chin-Mu Hsu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
| | - Samuel Yien Hsiao
- Department of Biology, University of Rutgers-Camden, Camden, NJ 08102, USA;
| | - Hui-Hua Hsiao
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (Y.-C.G.); (T.-J.Y.); (C.-M.H.)
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +816-7-3162429
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Pan D, Yang F, Zhu S, Li Y, Ning G, Feng S. Inhibition of TGF-β repairs spinal cord injury by attenuating EphrinB2 expressing through inducing miR-484 from fibroblast. Cell Death Discov 2021; 7:319. [PMID: 34711831 PMCID: PMC8553751 DOI: 10.1038/s41420-021-00705-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/27/2021] [Accepted: 10/07/2021] [Indexed: 12/27/2022] Open
Abstract
Spinal cord injury (SCI) can lead to severe loss of motor and sensory function with high disability and mortality. The effective treatment of SCI remains unknown. Here we find systemic injection of TGF-β neutralizing antibody induces the protection of axon growth, survival of neurons, and functional recovery, whereas erythropoietin-producing hepatoma interactor B2 (EphrinB2) expression and fibroblasts distribution are attenuated. Knockout of TGF-β type II receptor in fibroblasts can also decrease EphrinB2 expression and improve spinal cord injury recovery. Moreover, miR-488 was confirmed to be the most upregulated gene related to EphrinB2 releasing in fibroblasts after SCI and miR-488 initiates EphrinB2 expression and physical barrier building through MAPK signaling after SCI. Our study points toward elevated levels of active TGF-β as inducer and promoters of fibroblasts distribution, fibrotic scar formation, and EphrinB2 expression, and deletion of global TGF-β or the receptor of TGF-β in Col1α2 lineage fibroblasts significantly improve functional recovery after SCI, which suggest that TGF-β might be a therapeutic target in SCI.
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Affiliation(s)
- Dayu Pan
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China.,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fuhan Yang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Shibo Zhu
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China.,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yongjin Li
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China.,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Guangzhi Ning
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China. .,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.
| | - Shiqing Feng
- Department of Orthopedics, Tianjin Medical University General Hospital, Heping District, Tianjin, 300052, PR China. .,International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.
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Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease. Int J Mol Sci 2021; 22:ijms22158028. [PMID: 34360793 PMCID: PMC8347368 DOI: 10.3390/ijms22158028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 11/16/2022] Open
Abstract
Tumor–endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2–EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2–EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.
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Wang T, Liu J, Liu H, Lee SR, Gonzalez L, Gorecka J, Shu C, Dardik A. Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae. J Surg Res 2021; 262:224-239. [PMID: 33039109 PMCID: PMC8024410 DOI: 10.1016/j.jss.2020.08.071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 08/26/2020] [Accepted: 08/30/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling. METHODS Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence. RESULTS Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration. CONCLUSIONS Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro. Regulation of EphrinB2 signaling may be a new strategy to improve AVF maturation and patency.
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Affiliation(s)
- Tun Wang
- Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Jia Liu
- Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Haiyang Liu
- The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Shin-Rong Lee
- The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Luis Gonzalez
- The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Jolanta Gorecka
- The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Chang Shu
- Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China; State Key Laboratory of Cardiovascular Disease, Center of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Alan Dardik
- The Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Yale School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, VA Connecticut Healthcare System, West Haven, Connecticut.
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Maiso P, Mogollón P, Ocio EM, Garayoa M. Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression. Cancers (Basel) 2021; 13:2542. [PMID: 34067236 PMCID: PMC8196907 DOI: 10.3390/cancers13112542] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/16/2021] [Accepted: 05/19/2021] [Indexed: 01/01/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.
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Affiliation(s)
- Patricia Maiso
- University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria, 39008 Santander, Spain
| | - Pedro Mogollón
- Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain; (P.M.); (M.G.)
| | - Enrique M. Ocio
- University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria, 39008 Santander, Spain
| | - Mercedes Garayoa
- Cancer Research Center (IBMCC-CSIC-USAL), University Hospital of Salamanca (IBSAL), 37007 Salamanca, Spain; (P.M.); (M.G.)
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10
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Du JS, Yen CH, Hsu CM, Hsiao HH. Management of Myeloma Bone Lesions. Int J Mol Sci 2021; 22:3389. [PMID: 33806209 PMCID: PMC8036461 DOI: 10.3390/ijms22073389] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 01/29/2023] Open
Abstract
Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal plasma-cell proliferation. The survival and prognosis of this condition have been significantly improved by treatment with active anti-MM drugs such as bortezomib or lenalidomide. Further, the discovery of novel agents has recently paved the way for new areas of investigation. However, MM, including myeloma-related bone diseases, remains fatal. Bone disease or bone destruction in MM is a consequence of skeletal involvement with bone pain, spinal cord compression, and bone fracture resulting from osteolytic lesions. These consequences affect disease outcomes, including patients' quality of life and survival. Several studies have sought to better understand MM bone disease (MBD) through the classification of its molecular mechanisms, including osteoclast activation and osteoblast inhibition. Bisphosphonates and the receptor activator of the nuclear factor-kappa B (NF-κB) ligand (RANKL) inhibitor, denosumab, prevent skeletal-related events in MM. In addition, several other bone-targeting agents, including bone-anabolic drugs, are currently used in preclinical and early clinical evaluations. This review summarizes the current knowledge of the pathogenesis of MBD and discusses novel agents that appear very promising and will soon enter clinical development.
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Affiliation(s)
- Jeng-Shiun Du
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-S.D.); (C.-M.H.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chia-Hung Yen
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- National Natural Product Libraries and High-Throughput Screening Core Facility, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Chin-Mu Hsu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-S.D.); (C.-M.H.)
| | - Hui-Hua Hsiao
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan; (J.-S.D.); (C.-M.H.)
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Faculty of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Qu F, Song Y, Wu Y, Huang Y, Zhong Q, Zhang Y, Fan Z, Xu C. The protective role of Ephrin-B2/EphB4 signaling in osteogenic differentiation under inflammatory environment. Exp Cell Res 2021; 400:112505. [PMID: 33516666 DOI: 10.1016/j.yexcr.2021.112505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/21/2021] [Accepted: 01/24/2021] [Indexed: 12/01/2022]
Abstract
Inflammation and alveolar bone destruction constitute the main pathological process of periodontitis. However, the molecular mechanisms of bone destruction under the inflammation environment remain unclear. This study aims to explore the role of Ephrin-B2/EphB4 signaling in osteogenic differentiation under the inflammation environment. Mouse pre-osteoblasts MC3T3-E1 were pretreated with lipopolysaccharide of Porphyromonas gingivalis (Pg-LPS). The Ephrin-B2/EphB4 signaling was activated, and the osteogenic differentiation of cells was examined. The results showed that activation of Ephrin-B2/EphB4 signaling promoted the expression levels of osteogenic differentiation-related genes, and also relieved the inhibitory effect of Pg-LPS on osteogenesis. Noticeably, the effect of Ephrin-B2/EphB4 signaling might be related to the mitogen-activated protein kinase (MAPK) pathway. While applying Ephrin-B2-Fc and EphB4-Fc to periodontitis mice, we observed the reduction of alveolar crest destruction. The current study revealed the possible role of Ephrin-B2/EphB4 signaling in reducing bone destruction in periodontitis and suggested its potential values for further research.
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Affiliation(s)
- Fang Qu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yingshuang Song
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yaqin Wu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yujie Huang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Qi Zhong
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Yifan Zhang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China
| | - Zhen Fan
- Department of Oral Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, No. 399 Yanchang Middle Road, Shanghai, 200072, China.
| | - Chun Xu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, No.639 Zhizaoju Road, Shanghai, 200011, China; National Clinical Research Center for Oral Diseases, No.639 Zhizaoju Road, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, No.639 Zhizaoju Road, Shanghai, 200011, China.
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Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers. Cancers (Basel) 2020; 13:cancers13010068. [PMID: 33383723 PMCID: PMC7794884 DOI: 10.3390/cancers13010068] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/16/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary As for many other cancers, the risk of developing hematologic malignancies increases considerably as people age. In recent years, a growing number of studies have highlighted the influence of the aging microenvironment on hematopoiesis and tumor progression. Mesenchymal stromal cells are a major player in intercellular communication inside the bone marrow microenvironment involved in hematopoiesis support. With aging, their functions may be altered, leading to hematopoiesis disturbances which can lead to hematologic cancers. A good understanding of the mechanisms involved in mesenchymal stem cell aging and the consequences on hematopoiesis and tumor progression is therefore necessary for a better comprehension of hematologic malignancies and for the development of therapeutic approaches. Abstract Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.
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Current Understanding of Myelomatous Mesenchymal Stromal Cells Extended through Advances in Experimental Methods. Cancers (Basel) 2020; 13:cancers13010025. [PMID: 33374627 PMCID: PMC7793501 DOI: 10.3390/cancers13010025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/20/2020] [Accepted: 12/21/2020] [Indexed: 01/03/2023] Open
Abstract
Simple Summary As the amount of information available has grown, now it is known that many types of non-hematopoietic cells, including mesenchymal stem/progenitor cells, mature mesenchymal cells, and endothelial cells, as well as mature hematopoietic cells such as monocytes, macrophages, T-cells, and B-cells, have roles in the pathogenesis of multiple myeloma. This review focuses on the role of mesenchymal cells in the microenvironment of multiple myeloma. We summarize the experimental strategies and current understanding of the biological roles in the pathogenesis of myeloma. Furthermore, we discuss the possible clinical applications targeting mesenchymal cells. Abstract Multiple myeloma is an incurable cancer formed by malignant plasma cells. For the proliferation and survival of myeloma cells, as well as the occurrence of the complications, numerous intra- and extra-cellular mechanisms are involved. The interaction of myeloma cells with the microenvironment is known to be one of the most critical mechanisms. A specific microenvironment could affect the progression and growth of tumor cells, as well as drug resistance. Among various microenvironment components, such as hematological and non-hematological cells, and soluble factors (cytokines, chemokines, and extracellular matrix (ECM) proteins), in this review, we focus on the role of mesenchymal cells. We aimed to summarize the experimental strategies used for conducting studies and current understanding of the biological roles in the pathogenesis of myeloma. Furthermore, we discuss the possible clinical applications targeting mesenchymal cells.
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Broggini T, Piffko A, Hoffmann CJ, Ghori A, Harms C, Adams RH, Vajkoczy P, Czabanka M. Ephrin-B2-EphB4 communication mediates tumor-endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model. Oncogene 2020; 39:7063-7075. [PMID: 32989254 DOI: 10.1038/s41388-020-01473-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 08/21/2020] [Accepted: 09/15/2020] [Indexed: 11/09/2022]
Abstract
Metastases account for the majority of cancer deaths. Bone represents one of the most common sites of distant metastases, and spinal bone metastasis is the most common source of neurological morbidity in cancer patients. During metastatic seeding of cancer cells, endothelial-tumor cell interactions govern extravasation to the bone and potentially represent one of the first points of action for antimetastatic treatment. The ephrin-B2-EphB4 pathway controls cellular interactions by inducing repulsive or adhesive properties, depending on forward or reverse signaling. Here, we report that in an in vivo metastatic melanoma model, ephrin-B2-mediated activation of EphB4 induces tumor cell repulsion from bone endothelium, translating in reduced spinal bone metastatic loci and improved neurological function. Selective ephrin-B2 depletion in endothelial cells or EphB4 inhibition increases bone metastasis and shortens the time window to hind-limb locomotion deficit from spinal cord compression. EphB4 overexpression in melanoma cells ameliorates the metastatic phenotype and improves neurological outcome. Timely harvesting of bone tissue after tumor cell injection and intravital bone microscopy revealed less tumor cells attached to ephrin-B2-positive endothelial cells. These results suggest that ephrin-B2-EphB4 communication influences bone metastasis formation by altering melanoma cell repulsion/adhesion to bone endothelial cells, and represents a molecular target for therapeutic intervention.
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Affiliation(s)
- Thomas Broggini
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany.,Department of Physics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Andras Piffko
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany.,Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany
| | - Christian J Hoffmann
- Department of Experimental Neurology, Center for Stroke Research Berlin, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Adnan Ghori
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Christoph Harms
- Department of Experimental Neurology, Center for Stroke Research Berlin, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Ralf H Adams
- Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, D-48149, Münster, Germany
| | - Peter Vajkoczy
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany
| | - Marcus Czabanka
- Department of Neurosurgery, Universitätsmedizin Charite, D-10117, Berlin, Germany.
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Sharma S, Mahajan A, Mittal A, Gohil R, Sachdeva S, Khan S, Dhillon M. Epigenetic and transcriptional regulation of osteoclastogenesis in the pathogenesis of skeletal diseases: A systematic review. Bone 2020; 138:115507. [PMID: 32610074 DOI: 10.1016/j.bone.2020.115507] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES To identify epigenetic and transcriptional factors controlling osteoclastogenesis (OCG), that have been shown to play a role in the pathogenesis of skeletal diseases. METHODS A systematic review was conducted in accordance with the PRISMA guidelines. The PubMed and EMBASE databases were searched up to 30th April 2020; references of included articles and pertinent review articles were also screened to identify eligible studies. Studies were included if they described epigenetic and/or transcriptional regulation of OCG in a specific skeletal disorder, and quantified alterations in OCG by any well-described experimental method. Risk of bias was assessed by a previously described modification of the CAMARADES tool. RESULTS The combined searches yielded 2265 records. Out of these, 24 studies investigating 12 different skeletal disorders were included in the review. Osteoporosis, followed by osteopetrosis, was the most commonly evaluated disorder. A total of 22 different epigenetic and transcriptional regulators of OCG were identified; key epigenetic regulators included DNA methylation, histone methylation, histone acetylation, miRNAs and lncRNAs. In majority of the disorders, dysregulated OCG was noted to occur at the stage of formation of committed osteoclast from preosteoclast. Dysregulation the stage of formation of the preosteoclast from late monocyte was noted in rheumatoid arthritis and fracture, whereas dysregulation at stage of formation of late monocyte from early monocyte was noted in osteopetrosis and spondyloarthritis. Quality assessment revealed a high risk of bias in domains pertaining to randomization, allocation concealment, blinding of outcome assessors and determination of sample size. CONCLUSIONS A variety of epigenetic and transcriptional factors can result in dysregulated osteoclastogenesis in different skeletal disorders. Dysregulation can occur at any stage; however, the formation of committed osteoclasts from preosteoclasts is the most common target. Although the published literature on this subject seems promising, the overall strength of evidence is limited by the small number of studies evaluating individual skeletal disorders, and also by deficiencies in key aspects of study design.
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Affiliation(s)
- Siddhartha Sharma
- Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Aditi Mahajan
- Department of Biophysics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Anupam Mittal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India..
| | - Riddhi Gohil
- Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunny Sachdeva
- Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shahnawaz Khan
- Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Mandeep Dhillon
- Department of Orthopedics, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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The Recombinant Protein EphB4-Fc Changes the Ti Particle-Mediated Imbalance of OPG/RANKL via EphrinB2/EphB4 Signaling Pathway and Inhibits the Release of Proinflammatory Factors In Vivo. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1404915. [PMID: 32587656 PMCID: PMC7294355 DOI: 10.1155/2020/1404915] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/12/2020] [Accepted: 02/26/2020] [Indexed: 12/18/2022]
Abstract
Aseptic loosening caused by wear particles is one of the common complications after total hip arthroplasty. We investigated the effect of the recombinant protein ephB4-Fc (erythropoietin-producing human hepatocellular receptor 4) on wear particle-mediated inflammatory response. In vitro, ephrinB2 expression was analyzed using siRNA-NFATc1 (nuclear factor of activated T-cells 1) and siRNA-c-Fos. Additionally, we used Tartrate-resistant acid phosphatase (TRAP) staining, bone pit resorption, Enzyme-linked immunosorbent assay (ELISA), as well as ephrinB2 overexpression and knockdown experiments to verify the effect of ephB4-Fc on osteoclast differentiation and function. In vivo, a mouse skull model was constructed to test whether the ephB4-Fc inhibits osteolysis and inhibits inflammation by micro-CT, H&E staining, immunohistochemistry, and immunofluorescence. The gene expression of ephrinB2 was regulated by c-Fos/NFATc1. Titanium wear particles activated this signaling pathway to the promoted expression of the ephrinB2 gene. However, ephrinB2 protein can be activated by osteoblast membrane receptor ephB4 to inhibit osteoclast differentiation. In in vivo experiments, we found that ephB4 could regulate Ti particle-mediated imbalance of OPG/RANKL, and the most important finding was that ephB4 relieved the release of proinflammatory factors. The ephB4-Fc inhibits wear particle-mediated osteolysis and inflammatory response through the ephrinB2/EphB4 bidirectional signaling pathway, and ephrinB2 ligand is expected to become a new clinical drug therapeutic target.
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Cantharidin treatment inhibits hepatocellular carcinoma development by regulating the JAK2/STAT3 and PI3K/Akt pathways in an EphB4-dependent manner. Pharmacol Res 2020; 158:104868. [PMID: 32407961 DOI: 10.1016/j.phrs.2020.104868] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 04/22/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. The tyrosine kinase receptor EphB4 promotes oncogenesis and tumor development and progression. Its inhibition is regarded as an effective strategy for the treatment of solid tumors. In the present study, we identified cantharidin as a novel EphB4 inhibitor for HCC treatment and evaluated the underlying molecular pharmacological mechanisms of action. We observed increased expression levels of EphB4 in HCC patients and a positive correlation between EphB4 and p-JAK2 levels in HCC patient samples. Knockdown of EphB4 using small interfering RNA decreased the expression levels of p-JAK2 and p-STAT3 in HCC cells, suggesting JAK2/STAT3 being a novel downstream signaling target of EphB4. Cell viability experiments revealed that the anti-cancer effect of cantharidin was positively correlated with EphB4 expression levels in HCC cell lines. We confirmed the potent antiproliferative activity of cantharidin on HepG2 cells with high expression of EphB4 and tumor xenograft. Molecular docking assay, immunoblotting assay and quantitative reverse transcription PCR assay indicated that cantharidin bound to EphB4, and thereby resulted in EphB4 suppression at mRNA and protein levels. Hep3B and SMMC-7721 cells were with low expression of EphB4. In EphB4-/HepG2, EphB4+/HepG2, and EphB4+/Hep3B cells, EphB4 knockdown alleviated the cantharidin-induced decrease in cell viability and colony formation ability and increase in apoptosis in HepG2 cells, while its overexpression exacerbated these effects in Hep3B cells and increased the apoptosis of HepG2 cells. In nude mouse models, cantharidin suppressed tumor growth more effectively in EphB4+/SMMC-7721 xenografts than in wild-type SMMC-7721 xenografts. Underlying mechanistic study showed that by targeting EphB4, cantharidin blocked a novel target, the downstream JAK2/STAT3 pathway, and the previously known target, the PI3K/Akt signaling, resulting in intrinsic apoptosis. These results indicated that cantharidin may be a potential candidate for HCC treatment by regulating the EphB4 signaling pathway.
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Lipopolysaccharide inhibits osteogenic differentiation of periodontal ligament stem cells partially through toll-like receptor 4-mediated ephrinB2 downregulation. Clin Oral Investig 2020; 24:3407-3416. [DOI: 10.1007/s00784-020-03211-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 01/09/2020] [Indexed: 01/24/2023]
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Zhu S, Liu Z, Yuan C, Lin Y, Yang Y, Wang H, Zhang C, Wang P, Gu M. Bidirectional ephrinB2‑EphB4 signaling regulates the osteogenic differentiation of canine periodontal ligament stem cells. Int J Mol Med 2020; 45:897-909. [PMID: 31985015 PMCID: PMC7015143 DOI: 10.3892/ijmm.2020.4473] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 12/23/2019] [Indexed: 12/28/2022] Open
Abstract
The aim of the present study was to evaluate the effect of ephrinB2 gene-transfected canine periodontal ligament stem cells (cPDLSCs) on the regulation of osteogenic differentiation. cPDLSCs were transfected with a transgenic null-control green fluorescent protein (GFP) vector (termed Vector-cPDLSCs) or with NFNB2 GFP-Blasticidin (termed EfnB2-cPDLSCs). Subsequently, the osteogenic differentiation of Vector-cPDLSCs and EfnB2-cPDLSCs was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), alkaline phosphatase (ALP) assay and Alizarin Red S staining. The migratory abilities of cPDLSCs, Vector-cPDLSCs and EfnB2-cPDLSCs were also assessed. Following osteogenic induction of Vector-cPDLSCs and EfnB2-cPDLSCs, the protein expression levels of collagen I, Runt-related transcription factor 2, osteocalcin, ephrin type-B receptor 4 (EphB4), phospho-EphB4, ephrinB2 and phosphoephrinB2 were analyzed by western blot assays. Following gene transfection, the RT-qPCR and western blotting results revealed that the mRNA and protein expression levels of ephrinB2, respectively, were significantly increased in EfnB2-cPDLSCs compared with that in Vector-cPDLSCs (P<0.05). ALP and Alizarin Red S staining assays revealed increased ALP activity and mineralization nodules, respectively, in EfnB2-cPDLSCs. Cell proliferation and migration assays revealed that EfnB2-cPDLSCs exhibited enhanced proliferation and migration compared with Vector-cPDLSCs (P<0.05). In conclusion, the findings of the current study indicated that ephrinB2 gene-modified cPDLSCs exhibited enhanced osteogenic differentiation, with the ephrinB2 reverse signaling and EphB4 forward signaling pathways serving a key role in this process. Furthermore, ephrinB2 gene modification was observed to promote the migration and proliferation of cPDLSCs.
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Affiliation(s)
- Shaoyue Zhu
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Zongxiang Liu
- Discipline of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Changyong Yuan
- Discipline of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Yifan Lin
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Yanqi Yang
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Haiming Wang
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Chengfei Zhang
- Department of Endodontology, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
| | - Penglai Wang
- Dental Implant Center, Affiliated Stomatological Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
| | - Min Gu
- Discipline of Orthodontics and Paediatric Dentistry, Faculty of Dentistry, The University of Hong Kong, Hong Kong, SAR 999077, P.R. China
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Myeloma bone disease: from biology findings to treatment approaches. Blood 2019; 133:1534-1539. [PMID: 30760454 DOI: 10.1182/blood-2018-11-852459] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 02/10/2019] [Indexed: 12/16/2022] Open
Abstract
Bone disease is a cardinal complication of multiple myeloma that affects quality of life and survival. Osteocytes have emerged as key players in the development of myeloma-related bone disease. Along with other factors, they participate in increased osteoclast activity, decreased osteoblast function, and immunosuppressed marrow microenvironment, which deregulate bone turnover and result in bone loss and skeletal-related events. Denosumab is a novel alternative to bisphosphonates against myeloma bone disease. Special considerations in this constantly evolving field are thoroughly discussed.
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Mehdi SJ, Johnson SK, Epstein J, Zangari M, Qu P, Hoering A, van Rhee F, Schinke C, Thanendrarajan S, Barlogie B, Davies FE, Morgan GJ, Yaccoby S. Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. Br J Haematol 2018; 184:578-593. [PMID: 30408155 DOI: 10.1111/bjh.15669] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Accepted: 09/25/2018] [Indexed: 02/06/2023]
Abstract
Recent studies suggest that multiple myeloma (MM) induces proliferation and expansion of bone marrow (BM) mesenchymal stem cells (MSCs), but others showed that MM cells induce MSC senescence. To clarify the interaction between MM and MSCs, we exploited our established MSC gene signature to identify gene expression changes in myeloma MSCs and associated functional differences. Single MSCs from patients with MM had changes in expression of genes associated with cellular proliferation and senescence and a higher proportion of senescent cells and lower proliferative potential than those from age-matched healthy donors. Single MSCs from both sources heterogeneously express MSC genes associated with adipogenesis and osteoblastogenesis. We identified the gene encoding insulin-like growth factor-binding protein 2 (IGFBP2), an MSC gene commonly altered in high risk MM, as under-expressed. Morphologically, IGFBP2+ cells are underrepresented in MM BM compared to smouldering MM. Strong IGFBP2 and adiponectin co-expression was detected in a subset of small adipocytes. Co-culturing normal MSCs with myeloma cells suppressed MSC differentiation to adipocytes and osteoblasts, and reduced expression of IGFBP2 and adiponectin. Recombinant IGFBP2 blocked IGF1-mediated myeloma cell growth. Our data demonstrate that myeloma MSCs are less proliferative and that IGFBP2+ small adipocytes are a distinct mesenchymal cell population suppressed by myeloma.
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Affiliation(s)
- Syed J Mehdi
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Sarah K Johnson
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Joshua Epstein
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Maurizio Zangari
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Pingping Qu
- Cancer Research and Biostatistics, Seattle, WA, USA
| | | | - Frits van Rhee
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Carolina Schinke
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | | | - Bart Barlogie
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Faith E Davies
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Gareth J Morgan
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Shmuel Yaccoby
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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22
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Cao C, Huang Y, Tang Q, Zhang C, Shi L, Zhao J, Hu L, Hu Z, Liu Y, Chen L. Bidirectional juxtacrine ephrinB2/Ephs signaling promotes angiogenesis of ECs and maintains self-renewal of MSCs. Biomaterials 2018; 172:1-13. [PMID: 29709731 DOI: 10.1016/j.biomaterials.2018.04.042] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 04/21/2018] [Indexed: 12/17/2022]
Abstract
Co-transplantation of endothelial cells (ECs) and mesenchymal stem cells (MSCs) is an important strategy for repairing complex and large bone defects. However, the ways in which ECs and MSCs interact remain to be fully clarified. We found that forward ephrinB2/Ephs signaling from hBMSCs to hUVECs promoted the tube formation of hUVECs by activating the PI3K/AKT/mTOR pathway. Reverse ephrinB2/Ephs signaling from hUVECs to hBMSCs promoted the proliferation and maintenance of hBMSCs self-renewal via upregulation of OCT4, SOX2, and YAP1. Subcutaneous co-transplantation of ECs and MSCs in nude mice confirmed that forward ephrinB2/Ephs signaling could increase the cross-sectional area of blood vessels in the transplanted area, and reverse ephrinB2/Ephs signaling could maintain the self-renewal of transplanted hBMSCs in vivo. Based on these results, ephrinB2/Ephs bidirectional juxtacrine regulation between ECs and MSCs plays a pivotal role in improving the healing of bone defects by promoting angiogenesis and achieving a sufficient number of MSCs.
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Affiliation(s)
- Cen Cao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ying Huang
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chenguang Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lei Shi
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Jiajia Zhao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Hu
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhewen Hu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Yun Liu
- Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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23
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Morgan GJ, Rasche L. Maintaining therapeutic progress in multiple myeloma by integrating genetic and biological advances into the clinic. Expert Rev Hematol 2018; 11:513-523. [PMID: 29944024 DOI: 10.1080/17474086.2018.1489718] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Utilizing advances in genetic and immunologic analysis to segment and direct treatment is potentially a way of maintaining therapeutic progress toward cure in multiple myeloma (MM). This approach works well using clinical segments but can be optimized using recent genetic and immunologic technologies, which have opened the possibility of enhancing risk stratification and disease subclassification. Areas covered: This position paper discusses strategies to segment myeloma into subgroups with distinct risk profiles and distinct targetable lesions are presented. Expert commentary: Risk stratified treatment of MM is already a clinical reality that can be enhanced by the developmental of unified segmentation and testing approaches. Mutation-targeted treatment has proven to be effective against the RAS pathway, but is compromised by intra-clonal and spatiotemporal heterogeneity. Identifying new disease segments based on tumor biology or immunological content of the microenvironment offers an exciting new way to control and even eradicate myeloma clones. Going forward, risk and biologically stratified therapy for myeloma is a promising way of maintaining therapeutic progress, as is precision immunotherapy directed by the cellular context of the bone marrow.
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Affiliation(s)
- Gareth J Morgan
- a Myeloma Institute , The University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Leo Rasche
- a Myeloma Institute , The University of Arkansas for Medical Sciences , Little Rock , AR , USA
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24
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Rossi M, Botta C, Arbitrio M, Grembiale RD, Tagliaferri P, Tassone P. Mouse models of multiple myeloma: technologic platforms and perspectives. Oncotarget 2018; 9:20119-20133. [PMID: 29732008 PMCID: PMC5929451 DOI: 10.18632/oncotarget.24614] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 02/24/2018] [Indexed: 12/19/2022] Open
Abstract
Murine models of human multiple myeloma (MM) are key tools for the study of disease biology as well as for investigation and selection of novel candidate therapeutics for clinical translation. In the last years, a variety of pre-clinical models have been generated to recapitulate a wide spectrum of biological features of MM. These systems range from spontaneous or transgenic models of murine MM, to subcutaneous or orthothopic xenografts of human MM cell lines in immune compromised animals, to platform allowing the engraftment of primary/bone marrow-dependent MM cells within a human bone marrow milieu to fully recapitulate human disease. Selecting the right model for specific pre-clinical research is essential for the successful completion of investigation. We here review recent and most known pre-clinical murine, transgenic and humanized models of MM, focusing on major advantages and/or weaknesses in the light of different research aims.
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Affiliation(s)
- Marco Rossi
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Cirino Botta
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Mariamena Arbitrio
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | | | - Pierosandro Tagliaferri
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy
| | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro, Catanzaro, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
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25
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Schinke C, Qu P, Mehdi SJ, Hoering A, Epstein J, Johnson SK, van Rhee F, Zangari M, Thanendrarajan S, Barlogie B, Davies FE, Yaccoby S, Morgan GJ. The Pattern of Mesenchymal Stem Cell Expression Is an Independent Marker of Outcome in Multiple Myeloma. Clin Cancer Res 2018; 24:2913-2919. [DOI: 10.1158/1078-0432.ccr-17-2627] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 01/24/2018] [Accepted: 03/13/2018] [Indexed: 11/16/2022]
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26
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Heng BC, Wang S, Gong T, Xu J, Yuan C, Zhang C. EphrinB2 signaling enhances osteogenic/odontogenic differentiation of human dental pulp stem cells. Arch Oral Biol 2018; 87:62-71. [DOI: 10.1016/j.archoralbio.2017.12.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 12/11/2017] [Accepted: 12/13/2017] [Indexed: 01/09/2023]
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27
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Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Dimopoulos MA. Pathogenesis of bone disease in multiple myeloma: from bench to bedside. Blood Cancer J 2018; 8:7. [PMID: 29330358 PMCID: PMC5802524 DOI: 10.1038/s41408-017-0037-4] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 10/13/2017] [Accepted: 10/23/2017] [Indexed: 12/29/2022] Open
Abstract
Osteolytic bone disease is the hallmark of multiple myeloma, which deteriorates the quality of life of myeloma patients, and it affects dramatically their morbidity and mortality. The basis of the pathogenesis of myeloma-related bone disease is the uncoupling of the bone-remodeling process. The interaction between myeloma cells and the bone microenvironment ultimately leads to the activation of osteoclasts and suppression of osteoblasts, resulting in bone loss. Several intracellular and intercellular signaling cascades, including RANK/RANKL/OPG, Notch, Wnt, and numerous chemokines and interleukins are implicated in this complex process. During the last years, osteocytes have emerged as key regulators of bone loss in myeloma through direct interactions with the myeloma cells. The myeloma-induced crosstalk among the molecular pathways establishes a positive feedback that sustains myeloma cell survival and continuous bone destruction, even when a plateau phase of the disease has been achieved. Targeted therapies, based on the better knowledge of the biology, constitute a promising approach in the management of myeloma-related bone disease and several novel agents are currently under investigation. Herein, we provide an insight into the underlying pathogenesis of bone disease and discuss possible directions for future studies.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
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28
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YAMAMOTO M, TODA H, TABATA Y. Studies on Sandwich Culture by Making Use of Biofunctional Hydrogels as a Three-Dimensional Culture Environment. KOBUNSHI RONBUNSHU 2018. [DOI: 10.1295/koron.2017-0067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Masaya YAMAMOTO
- Department of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University
| | - Hiroyuki TODA
- Department of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University
| | - Yasuhiko TABATA
- Department of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University
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29
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Jung JK, Gwon GJ, Neupane S, Sohn WJ, Kim KR, Kim JY, An SY, Kwon TY, An CH, Lee Y, Kim JY, Ha JH. Bortezomib Facilitates Reparative Dentin Formation after Pulp Access Cavity Preparation in Mouse Molar. J Endod 2017; 43:2041-2047. [PMID: 29032823 DOI: 10.1016/j.joen.2017.07.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 07/12/2017] [Accepted: 07/24/2017] [Indexed: 10/18/2022]
Abstract
INTRODUCTION The aim of this study was to evaluate in vitro and ex vivo roles of bortezomib, a proteasome inhibitor that binds to the active site of the 26S proteasome, in tertiary dentin formation. METHODS We established pulpal access cavity preparation that was treated with or without bortezomib before direct pulp capping with a calcium hydroxide-based material. We also analyzed bone morphogenetic protein (Bmp)- and Wnt-related signaling molecules using quantitative real-time polymerase chain reaction. RESULTS In the short-term observation period, the bortezomib-treated pulp specimens showed the period-altered immunolocalization patterns of nestin, CD31, and myeloperoxidase, whereas the control specimens did not. The bortezomib-treated group showed a complete dentin bridge with very few irregular tubules after 42 days. The micro-computed tomographic images showed more apparent dentin bridge structures in the treated specimens than were in the controls. Quantitative real-time polymerase chain reaction analysis showed up-regulated Bmp and Wnt. CONCLUSIONS These findings revealed that treatment with 1 μmol/L bortezomib induced reparative dentin formation that facilitated the maintenance of the integrity of the remaining pulpal tissue via early vascularization and regulation of Bmp and Wnt signaling.
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Affiliation(s)
- Jae-Kwang Jung
- Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu, Korea
| | - Gi-Jeong Gwon
- Department of Biochemistry, School of Dentistry, Institute for Hard Tissue and Bone Regeneration, Kyungpook National University, Daegu, Korea
| | - Sanjiv Neupane
- Department of Biochemistry, School of Dentistry, Institute for Hard Tissue and Bone Regeneration, Kyungpook National University, Daegu, Korea
| | - Wern-Joo Sohn
- Department of Biochemistry, School of Dentistry, Institute for Hard Tissue and Bone Regeneration, Kyungpook National University, Daegu, Korea
| | - Ki-Rim Kim
- Department of Dental Hygiene, Kyungpook National University, Daegu, Korea
| | - Ji-Youn Kim
- Department of Dental Hygiene, Gachon University College of Health Science, Incheon, Seoul, Korea
| | - Seo-Young An
- Department of Oral and Maxillofacial Radiology, Kyungpook National University, Daegu, Korea
| | - Tae-Yub Kwon
- Department of Dental Materials, School of Dentistry, Kyungpook National University, Daegu, Korea
| | - Chang-Hyeon An
- Department of Oral and Maxillofacial Radiology, Kyungpook National University, Daegu, Korea
| | - Youngkyun Lee
- Department of Biochemistry, School of Dentistry, Institute for Hard Tissue and Bone Regeneration, Kyungpook National University, Daegu, Korea
| | - Jae-Young Kim
- Department of Biochemistry, School of Dentistry, Institute for Hard Tissue and Bone Regeneration, Kyungpook National University, Daegu, Korea.
| | - Jung-Hong Ha
- Department of Conservative Dentistry, School of Dentistry, Institute for Hard Tissue and Bone Regeneration, Kyungpook National University, Daegu, Korea.
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30
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Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiol Rev 2017; 97:1295-1349. [DOI: 10.1152/physrev.00036.2016] [Citation(s) in RCA: 369] [Impact Index Per Article: 46.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/29/2017] [Accepted: 04/04/2017] [Indexed: 12/13/2022] Open
Abstract
The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system.
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Affiliation(s)
- Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Tomoki Nakashima
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Masahiro Shinohara
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Takako Negishi-Koga
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Noriko Komatsu
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Asuka Terashima
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Shinichiro Sawa
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Takeshi Nitta
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
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31
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Tosato G. Ephrin ligands and Eph receptors contribution to hematopoiesis. Cell Mol Life Sci 2017; 74:3377-3394. [PMID: 28589441 PMCID: PMC11107787 DOI: 10.1007/s00018-017-2566-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 05/12/2017] [Accepted: 06/01/2017] [Indexed: 12/12/2022]
Abstract
Hematopoietic stem and progenitor cells reside predominantly in the bone marrow. They supply billions of mature blood cells every day during life through maturation into multilineage progenitors and self-renewal. Newly produced mature cells serve to replenish the pool of circulating blood cells at the end of their life-span. These mature blood cells and a few hematopoietic progenitors normally exit the bone marrow through the sinusoidal vessels, a specialized venous vascular system that spreads throughout the bone marrow. Many signals regulate the coordinated mobilization of hematopoietic cells from the bone marrow to the circulation. In this review, we present recent advances on hematopoiesis and hematopoietic cell mobilization with a focus on the role of Ephrin ligands and their Eph receptors. These constitute a large family of transmembrane ligands and receptors that play critical roles in development and postnatally. New insights point to distinct roles of ephrin and Eph in different aspects of hematopoiesis.
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Affiliation(s)
- Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4124, Bethesda, MD, 20892, USA.
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32
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Wang LM, Zhao N, Zhang J, Sun QF, Yang CZ, Yang PS. Tumor necrosis factor-alpha inhibits osteogenic differentiation of pre-osteoblasts by downregulation of EphB4 signaling via activated nuclear factor-kappaB signaling pathway. J Periodontal Res 2017; 53:66-72. [PMID: 28857167 DOI: 10.1111/jre.12488] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND OBJECTIVE The majority of experiments show that tumor necrosis factor-alpha (TNF-α) inhibits osteogenic differentiation of mesenchymal stem cells and pre-osteoblasts by activated nuclear factor-kappaB (NF-κB) signaling. However, the underlying mechanisms by which NF-κB signaling inhibits osteogenic differentiation are not fully understood. The aim of the present study was to investigate whether EphB4 signaling inhibition mediates the effects of TNF-α-activated NF-κB signaling on osteogenic differentiation of pre-osteoblasts. MATERIAL AND METHODS Murine MC3T3-E1 pre-osteoblasts were treated with 10 ng/mL of TNF-α. NF-κB inhibitor, pyrrolidine dithiocarbamate, was used to achieve NF-κB signaling inhibition. EphB4 signaling was activated using ephrinB2-fc. The mRNA expressions of runt related transcription factor 2 (Runx2), bone sialoprotein (BSP) and EphB4 were determined using reverse transcription-polymerase chain reaction. The protein levels of Runx2, BSP, Col Ia1, osteopontin, EphB4, p-NF-κB p65 and NF-κB p65 were evaluated using western blot assays. Alkaline phosphatase (ALP) activity in MC3T3-E1 cells was evaluated by ALP activity kit, and mineral nodule formation was evaluated by Alizarin Red S staining. RESULTS TNF-α inhibited EphB4 expression, while it suppressed Runx2, BSP expression from gene and protein levels as well as ALP activity and mineral nodule formation in MC3T3-E1 cells. Activation of EphB4 signaling by ephrinB2-fc promoted osteogenic differentiation of MC3T3-E1 cells, whereas TNF-α impaired the osteogenic differentiation enhanced by ephrinB2-fc. Pyrrolidine dithiocarbamate blocked the activation of NF-κB signaling induced by TNF-α, while it prevented the downregulation of Runx2, BSP and EphB4, induced by TNF-α. CONCLUSION TNF-α inhibits osteogenic differentiation of pre-osteoblasts by downregulation of EphB4 signaling via activated NF-κB signaling pathway.
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Affiliation(s)
- L M Wang
- Department of Stomatology, Qilu Hospital, and Institute of Stomatology, Shandong University, Jinan, Shandong, China.,Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong, China.,Shandong provincial key laboratory of oral tissue regeneration, Jinan, Shandong, China
| | - N Zhao
- Dezhou keen Stomatology Hospital, Dezhou, Shandong, China
| | - J Zhang
- Department of Endodontics, School of Stomatology, Shandong University, Jinan, Shandong, China
| | - Q F Sun
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong, China
| | - C Z Yang
- Department of Oral & Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, Jinan, Shandong, China
| | - P S Yang
- Department of Periodontology, School of Stomatology, Shandong University, Jinan, Shandong, China.,Shandong provincial key laboratory of oral tissue regeneration, Jinan, Shandong, China
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33
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Zhu S, Yao F, Qiu H, Zhang G, Xu H, Xu J. Coupling factors and exosomal packaging microRNAs involved in the regulation of bone remodelling. Biol Rev Camb Philos Soc 2017; 93:469-480. [PMID: 28795526 DOI: 10.1111/brv.12353] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 06/18/2017] [Accepted: 06/26/2017] [Indexed: 12/31/2022]
Abstract
Bone remodelling is a continuous process by which bone resorption by osteoclasts is followed by bone formation by osteoblasts to maintain skeletal homeostasis. These two forces must be tightly coordinated not only quantitatively, but also in time and space, and its malfunction leads to diseases such as osteoporosis. Recent research focusing on the cross-talk and coupling mechanisms associated with the sequential recruitment of osteoblasts to areas where osteoclasts have removed bone matrix have identified a number of osteogenic factors produced by the osteoclasts themselves. Osteoclast-derived factors and exosomal-containing microRNA (miRNA) can either enhance or inhibit osteoblast differentiation through paracrine and juxtacrine mechanisms, and therefore may have a central coupling role in bone formation. Entwined with angiocrine factors released by vessel-specific endothelial cells and perivascular cells or pericytes, these factors play a critical role in angiogenesis-osteogenesis coupling essential in bone remodelling.
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Affiliation(s)
- Sipin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.,Molecular Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Perth 6009, M504, Australia
| | - Felix Yao
- Molecular Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Perth 6009, M504, Australia
| | - Heng Qiu
- Molecular Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Perth 6009, M504, Australia
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China
| | - Huazi Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China
| | - Jiake Xu
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.,Molecular Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Perth 6009, M504, Australia
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Toda H, Yamamoto M, Uyama H, Tabata Y. Effect of hydrogel elasticity and ephrinB2-immobilized manner on Runx2 expression of human mesenchymal stem cells. Acta Biomater 2017; 58:312-322. [PMID: 28300720 DOI: 10.1016/j.actbio.2017.03.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 02/20/2017] [Accepted: 03/10/2017] [Indexed: 12/22/2022]
Abstract
The objective of this study is to design the manner of ephrinB2 immobilized onto polyacrylamide (PAAm) hydrogels with varied elasticity and evaluate the effect of hydrogels elasticity and the immobilized manner of ephrinB2 on the Runx2 expression of human mesenchymal stem cells (hMSC). The PAAm hydrogels were prepared by the radical polymerization of acrylamide (AAm), and N,N'-methylenebisacrylamide (BIS). By changing the BIS concentration, the elasticity of PAAm hydrogels changed from 1 to 70kPa. For the bio-specific immobilization of ephrinB2, a chimeric protein of ephrinB2 and Fc domain was immobilized onto protein A-conjugated PAAm hydrogels by making use of the bio-specific interaction between the Fc domain and protein A. When hMSC were cultured on the ephrinB2-immobilized PAAm hydrogels with varied elasticity, the morphology of hMSC was of cuboidal shape on the PAAm hydrogels immobilized with ephrinB2 compared with non-conjugated ones, irrespective of the hydrogels elasticity. The bio-specific immobilization of ephrinB2 enhanced the level of Runx2 expression. The expression level was significantly high for the hydrogels of 3.6 and 5.9kPa elasticity with bio-specific immobilization of ephrinB2 compared with other hydrogels with the same elasticity. The hydrogels showed a significantly down-regulated RhoA activity. It is concluded that the Runx2 expression of hMSC is synergistically influenced by the hydrogels elasticity and their immobilized manner of ephrinB2 immobilized. STATEMENT OF SIGNIFICANCE Differentiation fate of mesenchymal stem cells (MSC) is modified by biochemical and biophysical factors, such as elasticity and signal proteins. However, there are few experiments about combinations of them. In this study, to evaluate the synergistic effect of them on cell properties of MSC, we established to design the manner of Eph signal ligand, ephrinB2, immobilized onto polyacrylamide hydrogels with varied elasticity. The gene expression level of an osteogenic maker, Runx2, was enhanced by the immobilized manner, and significantly enhanced for the hydrogels of around 4kPa elasticity with bio-specific immobilization of ephrinB2. This is the novel report describing to demonstrate that the Runx2 expression of MSC is synergistically influenced by the hydrogels elasticity and their manner of ephrinB2 immobilized.
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Heusschen R, Muller J, Duray E, Withofs N, Bolomsky A, Baron F, Beguin Y, Menu E, Ludwig H, Caers J. Molecular mechanisms, current management and next generation therapy in myeloma bone disease. Leuk Lymphoma 2017; 59:14-28. [PMID: 28573897 DOI: 10.1080/10428194.2017.1323272] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Multiple myeloma (MM) bone disease is a major cause of morbidity and mortality in MM patients and persists even in patients in remission. This bone disease is caused by an uncoupling of bone remodeling, with increased osteoclast and decreased osteoblast activity and formation, culminating in lytic bone destruction. Bisphosphonates are the current standard of care but new therapies are needed. As the molecular mechanisms controlling MM bone disease are increasingly well understood, new therapeutic targets are extensively explored in the preclinical setting and initial clinical trials with novel compounds now show promising results. In this review, we will provide a comprehensive overview of the biology of MM bone disease, summarize its current clinical management and discuss preclinical and clinical data on next generation therapies.
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Affiliation(s)
- Roy Heusschen
- a Laboratory of Hematology , University of Liège, GIGA-I3 , Liège , Belgium
| | - Joséphine Muller
- a Laboratory of Hematology , University of Liège, GIGA-I3 , Liège , Belgium
| | - Elodie Duray
- a Laboratory of Hematology , University of Liège, GIGA-I3 , Liège , Belgium
| | - Nadia Withofs
- b Division of Nuclear Medicine and Oncological Imaging, Department of Medical Physics , University and CHU of Liège , Liège , Belgium
| | - Arnold Bolomsky
- c Wilhelminen Cancer Research Institute, Department of Medicine I , Center for Oncology and Hematology, Wilhelminenspital , Vienna , Austria
| | - Frédéric Baron
- a Laboratory of Hematology , University of Liège, GIGA-I3 , Liège , Belgium.,d Division of Hematology, Department of Medicine , University and CHU of Liège , Liège , Belgium
| | - Yves Beguin
- a Laboratory of Hematology , University of Liège, GIGA-I3 , Liège , Belgium.,d Division of Hematology, Department of Medicine , University and CHU of Liège , Liège , Belgium
| | - Eline Menu
- e Department of Hematology and Immunology , Myeloma Center Brussels, Vrije Universiteit Brussel , Brussels , Belgium
| | - Heinz Ludwig
- c Wilhelminen Cancer Research Institute, Department of Medicine I , Center for Oncology and Hematology, Wilhelminenspital , Vienna , Austria
| | - Jo Caers
- a Laboratory of Hematology , University of Liège, GIGA-I3 , Liège , Belgium.,d Division of Hematology, Department of Medicine , University and CHU of Liège , Liège , Belgium
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Morgan GJ, Jones JR. Integration of Genomics Into Treatment: Are We There Yet? Am Soc Clin Oncol Educ Book 2017; 37:569-574. [PMID: 28561666 DOI: 10.1200/edbk_175166] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Using advances in genetic analysis to segment and direct treatment of multiple myeloma (MM) represents a way of maintaining therapeutic progress. Recent genetic analyses have opened the possibility of enhancing risk stratification approaches and of using different risk and biologic strata as part of clinical trials. The Myeloma Genome Project is a collaborative project that has compiled the largest set of cases with sequencing and have outcome data that are available for stratification purposes. Mutation-targeted treatment of the Ras pathway has been shown to be active in MM, but is compromised by the presence of the subclonal genetic variation typical of myeloma. Going forward, risk and biologically stratified therapy for MM looks to be a promising way of maintaining therapeutic progress, as does precision immunotherapy directed by the cellular context of the bone marrow.
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Affiliation(s)
- Gareth J Morgan
- From the Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; Institute of Cancer Research, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
| | - John R Jones
- From the Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; Institute of Cancer Research, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
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The role of Eph/ephrin molecules in stromal–hematopoietic interactions. Int J Hematol 2016; 103:145-54. [PMID: 26475284 DOI: 10.1007/s12185-015-1886-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 10/05/2015] [Indexed: 12/12/2022]
Abstract
Bone marrow mesenchymal stromal/stem cells(BMSC) are fundamental regulatory elements of the hematopoietic stem cell niche; however, the molecular signals that mediate BMSC support of hematopoiesis are poorly understood. Recent studies indicate that BMSC and hematopoietic stem/progenitors cells differentially express the Eph cell surface tyrosine kinase receptors, and their ephrinligands. Eph/ephrin interactions are thought to mediate cross-talk between BMSC and different hematopoietic cell populations to influence cell development, migration and function. This review summarizes Eph/ephrin interactions in the regulation of BMSC communication with hematopoietic stem/progenitor cells and discusses Eph/ephrintargeted therapeutic strategies that are currently being pursued or various hematotological malignancies.
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Kwak H, Salvucci O, Weigert R, Martinez-Torrecuadrada JL, Henkemeyer M, Poulos MG, Butler JM, Tosato G. Sinusoidal ephrin receptor EPHB4 controls hematopoietic progenitor cell mobilization from bone marrow. J Clin Invest 2016; 126:4554-4568. [PMID: 27820703 PMCID: PMC5127687 DOI: 10.1172/jci87848] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 09/29/2016] [Indexed: 12/27/2022] Open
Abstract
Hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow. Stress signals from cancer and other conditions promote HSPC mobilization into circulation and subsequent homing to tissue microenvironments. HSPC infiltration into tissue microenvironments can influence disease progression; notably, in cancer, HSPCs encourage tumor growth. Here we have uncovered a mutually exclusive distribution of EPHB4 receptors in bone marrow sinusoids and ephrin B2 ligands in hematopoietic cells. We determined that signaling interactions between EPHB4 and ephrin B2 control HSPC mobilization from the bone marrow. In mice, blockade of the EPHB4/ephrin B2 signaling pathway reduced mobilization of HSPCs and other myeloid cells to the circulation. EPHB4/ephrin B2 blockade also reduced HSPC infiltration into tumors as well as tumor progression in murine models of melanoma and mammary cancer. These results identify EPHB4/ephrin B2 signaling as critical to HSPC mobilization from bone marrow and provide a potential strategy for reducing cancer progression by targeting the bone marrow.
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Affiliation(s)
- Hyeongil Kwak
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Ombretta Salvucci
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
| | - Roberto Weigert
- National Institute of Dental and Craniofacial Research (NIDCR) and Laboratory of Cellular and Molecular Biology, NCI, NIH, Bethesda, Maryland, USA
| | | | - Mark Henkemeyer
- Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Michael G. Poulos
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Jason M. Butler
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, and
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Zhu SY, Wang PL, Liao CS, Yang YQ, Yuan CY, Wang S, Dissanayaka WL, Heng BC, Zhang CF. Transgenic expression of ephrinB2 in periodontal ligament stem cells (PDLSCs) modulates osteogenic differentiation via signaling crosstalk between ephrinB2 and EphB4 in PDLSCs and between PDLSCs and pre-osteoblasts within co-culture. J Periodontal Res 2016; 52:562-573. [DOI: 10.1111/jre.12424] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2016] [Indexed: 12/23/2022]
Affiliation(s)
- S. Y. Zhu
- Endodontology; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
- HKU Shenzhen Institute of Research and Innovation; Hong Kon China
- Dental Implant Center; Xuzhou Stomatological Hospital; Xuzhou China
| | - P. L. Wang
- Dental Implant Center; Xuzhou Stomatological Hospital; Xuzhou China
| | - C. S. Liao
- Orthodontics; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
| | - Y. Q. Yang
- Orthodontics; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
| | - C. Y. Yuan
- Endodontology; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
| | - S. Wang
- Endodontology; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
| | - W. L. Dissanayaka
- Endodontology; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
| | - B. C. Heng
- Endodontology; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
| | - C. F. Zhang
- Endodontology; Faculty of Dentistry; The University of Hong Kong; Pokfulam Hong Kong China
- HKU Shenzhen Institute of Research and Innovation; Hong Kon China
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Xi H, An R, Li L, Wang G, Tao Y, Gao L. Myeloma bone disease: Progress in pathogenesis. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2016; 122:149-155. [PMID: 27496181 DOI: 10.1016/j.pbiomolbio.2016.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 07/31/2016] [Accepted: 08/02/2016] [Indexed: 12/12/2022]
Abstract
Myeloma bone disease (MBD) is one of the most serious complications of multiple myeloma (MM) and the most severe cause of MM morbidity. Dysregulation of osteoblast and osteoclast cells plays key roles in MBD. In the bone marrow microenvironment, myeloma cells, osteoblasts, osteoclasts and bone marrow stromal cells can secrete multiple cytokines, categorized as osteoclast cell activating factors (OAFs) and osteoblast cell inactivating factors, which have been discovered to participate in bone metabolism and contribute to the pathogenesis of MBD. Several signaling pathways related to these cytokines were also revealed in the MBD pathogenesis. To better understand the pathogenesis of MBD and therefore the potential therapeutic targets of this disease, we will summarize recent study progress in the factors and underlying signaling pathways involved in the occurrence and development of MBD.
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Affiliation(s)
- Hao Xi
- Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Ran An
- Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lu Li
- Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Gang Wang
- Department of Physiology, Second Military Medical University, Shanghai, China
| | - Yi Tao
- Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Lu Gao
- Department of Physiology, Second Military Medical University, Shanghai, China.
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Li L, Duan Z, Yu J, Dang HX. NFATc1 regulates cell proliferation, migration, and invasion of ovarian cancer SKOV3 cells in vitro and in vivo. Oncol Rep 2016; 36:918-28. [PMID: 27350254 DOI: 10.3892/or.2016.4904] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 02/20/2016] [Indexed: 11/06/2022] Open
Abstract
NFATc1 (nuclear factor of activated T‑cells c1) is associated with malignancy in several cancer models. However, the expression and function of NFATc1 in ovarian cancer remain elusive. In the present study, we investigated the role of NFATc1 in human epithelial ovarian cancer (EOC) using human ovarian adenocarcinoma SKOV3 cells and patient characteristics. NFATc1 expression was silenced by siRNA in the SKOV3 ovarian cancer cell line and in human ovarian cancer nude mouse xenografts. Real‑time PCR, western blotting, immunohistochemical staining, MTT, flow cytometry, transwell, erasion trace and mouse assays were used to detect NFATc1 expression, cell proliferation, apoptosis, cell invasion and migration, tumor growth and angiogenesis. Survival analysis was performed to assess the correlation between NFATc1 expression and survival. NFATc1 was overexpressed in the SKOV3 ovarian cancer cell line and in human serous/mucinous ovarian cancer tissues. The silencing of NFATc1 expression by siRNA reduced cell proliferation and migration and promoted apoptosis in vitro and decreased the ovarian cancer cell tumorigenesis in vivo in nude mice. NFATc1 overexpression in high‑grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival and of early relapse (P<0.01) in a univariate analysis. Our present data provide evidence that NFATc1 is overexpressed in human serous/mucinous ovarian cancer and is associated with a poor prognosis. NFATc1 silencing regulates the cell cycle, apoptosis, invasion and migration. NFATc1 thus has the potential to be a therapeutic target and to be used in EOC diagnosis and prognosis.
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Affiliation(s)
- Long Li
- Department of Physical Examination, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zhaoning Duan
- Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jihui Yu
- Department of Physical Examination, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hong-Xing Dang
- Department of PICU, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders; Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing 400016, P.R. China
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Hashimoto T, Tsuneki M, Foster TR, Santana JM, Bai H, Wang M, Hu H, Hanisch JJ, Dardik A. Membrane-mediated regulation of vascular identity. BIRTH DEFECTS RESEARCH. PART C, EMBRYO TODAY : REVIEWS 2016; 108:65-84. [PMID: 26992081 PMCID: PMC5310768 DOI: 10.1002/bdrc.21123] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 02/22/2016] [Indexed: 02/06/2023]
Abstract
Vascular diseases span diverse pathology, but frequently arise from aberrant signaling attributed to specific membrane-associated molecules, particularly the Eph-ephrin family. Originally recognized as markers of embryonic vessel identity, Eph receptors and their membrane-associated ligands, ephrins, are now known to have a range of vital functions in vascular physiology. Interactions of Ephs with ephrins at cell-to-cell interfaces promote a variety of cellular responses such as repulsion, adhesion, attraction, and migration, and frequently occur during organ development, including vessel formation. Elaborate coordination of Eph- and ephrin-related signaling among different cell populations is required for proper formation of the embryonic vessel network. There is growing evidence supporting the idea that Eph and ephrin proteins also have postnatal interactions with a number of other membrane-associated signal transduction pathways, coordinating translation of environmental signals into cells. This article provides an overview of membrane-bound signaling mechanisms that define vascular identity in both the embryo and the adult, focusing on Eph- and ephrin-related signaling. We also discuss the role and clinical significance of this signaling system in normal organ development, neoplasms, and vascular pathologies.
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Affiliation(s)
- Takuya Hashimoto
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, Connecticut
- Department of Vascular Surgery, The University of Tokyo, Tokyo, Japan
| | - Masayuki Tsuneki
- Division of Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Trenton R. Foster
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
| | - Jeans M. Santana
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
| | - Hualong Bai
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
- Department of Vascular Surgery, The 1st Affiliated Hospital of Zhengzhou University, Henan, China
| | - Mo Wang
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
| | - Haidi Hu
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
| | - Jesse J. Hanisch
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
| | - Alan Dardik
- The Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, Connecticut
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, Connecticut
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Teramachi J, Nagata Y, Mohammad K, Inagaki Y, Ohata Y, Guise T, Michou L, Brown JP, Windle JJ, Kurihara N, Roodman GD. Measles virus nucleocapsid protein increases osteoblast differentiation in Paget's disease. J Clin Invest 2016; 126:1012-22. [PMID: 26878170 DOI: 10.1172/jci82012] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 12/18/2015] [Indexed: 02/02/2023] Open
Abstract
Paget's disease (PD) is characterized by focal and dramatic bone resorption and formation. Treatments that target osteoclasts (OCLs) block both pagetic bone resorption and formation; therefore, PD offers key insights into mechanisms that couple bone resorption and formation. Here, we evaluated OCLs from 3 patients with PD and determined that measles virus nucleocapsid protein (MVNP) was expressed in 70% of these OCLs. Moreover, transgenic mice with OCL-specific expression of MVNP (MVNP mice) developed PD-like bone lesions that required MVNP-dependent induction of high IL-6 expression levels in OCLs. In contrast, mice harboring a knockin of p62P394L (p62-KI mice), which is the most frequent PD-associated mutation, exhibited increased bone resorption, but not formation. Evaluation of OCLs from MVNP, p62-KI, and WT mice revealed increased IGF1 expression in MVNP-expressing OCLs that resulted from the high IL-6 expression levels in these cells. IL-6, in turn, increased the expression of coupling factors, specifically ephrinB2 on OCLs and EphB4 on osteoblasts (OBs). IGF1 enhanced ephrinB2 expression on OCLs and OB differentiation. Importantly, ephrinB2 and IGF1 levels were increased in MVNP-expressing OCLs from patients with PD and MVNP-transduced human OCLs compared with levels detected in controls. Further, anti-IGF1 or anti-IGF1R blocked Runx2 and osteocalcin upregulation in OBs cocultured with MVNP-expressing OCLs. These results suggest that in PD, MVNP upregulates IL-6 and IGF1 in OCLs to increase ephrinB2-EphB4 coupling and bone formation.
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Wu M, Ai W, Chen L, Zhao S, Liu E. Bradykinin receptors and EphB2/EphrinB2 pathway in response to high glucose-induced osteoblast dysfunction and hyperglycemia-induced bone deterioration in mice. Int J Mol Med 2016; 37:565-74. [PMID: 26782642 PMCID: PMC4771119 DOI: 10.3892/ijmm.2016.2457] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 12/30/2015] [Indexed: 01/06/2023] Open
Abstract
This study was carried out in order to investigate bone dysfunction and the involvement of bradykinin receptors and the Eph/Ephrin signaling pathway in osteoblasts and in mice with diabetes-related osteoporosis in response to exposure to high glucose. Osteogenic transdifferentiation was inhibited when the osteoblasts were exposed to high glucose, and the expression levels of bone formation-related genes [Runx2 and alkaline phosphatase (ALP)] were decreased, while those of bone resorption-related genes [matrix metalloproteinase (MMP)9 and carbonic anhydrase II (CAII)] were increased. Moreover, the mRNA and protein expression levels of bradykinin receptor B1 (BK1R)/bradykinin receptor B2 (BK2R) and EphB2/EphrinB2 were significantly decreased in the osteoblasts following exposure to high glucose. Intriguingly, the interaction between BK2R and EphB2/EphrinB2 was confirmed, and BK2R loss-of-function significantly decreased the mRNA and protein expression levels of EphB2/EphrinB4. In vivo, hyperglycemia induced the disequilibrium of calcium homeostasis through the inhibition of bone formation and the acceleration of bone resorption, which was manifested by the reduction of trabecular bone mass of the primary and secondary spongiosa, as well as by the increase in the number of mature osteoclasts throughout the proximal tibial metaphysis in mice with diabetes-related osteoporosis. Furthermore, the mRNA and protein expression levels of BK1R/BK2R and EphB2/EphrinB2 in the tibias of the mice with diabetes-related osteoporosis were significantly decreased. These results demonstrate that bradykinin receptors and the EphB4/EphrinB2 pathway mediate the development of complications in mice with diabetes-related osteoporosis and suggest that the inactivation of bradykinin receptors and the EphB4/EphrinB2 pathway enhance the severity of complications in mice with diabetes-related osteoporosis.
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Affiliation(s)
- Min Wu
- Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China
| | - Wenting Ai
- Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Lin Chen
- Department of Pathology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Sihai Zhao
- Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China
| | - Enqi Liu
- Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, P.R. China
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Zhang F, Zhang Z, Sun D, Dong S, Xu J, Dai F. Periostin: A Downstream Mediator of EphB4-Induced Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cells Int 2016; 2016:7241829. [PMID: 26788070 PMCID: PMC4695675 DOI: 10.1155/2016/7241829] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 08/05/2015] [Accepted: 08/24/2015] [Indexed: 01/06/2023] Open
Abstract
Erythropoietin-producing hepatocyte B4 (EphB4) has been reported to be a key molecular switch in the regulation of bone homeostasis, but the underlying mechanism remains poorly understood. In this study, we investigated the role of EphB4 in regulating the expression of periostin (POSTN) within bone marrow-derived mesenchymal stem cells (MSCs) and assessed its effect and molecular mechanism of osteogenic induction in vitro. Treatment with ephrinB2-FC significantly increased the expression of POSTN in MSCs, and the inhibition of EphB4 could abrogate this effect. In addition, osteogenic markers were upregulated especially in MSCs overexpressing EphB4. To elucidate the underlying mechanism of cross talk between EphB4 and the Wnt pathway, we detected the change in protein expression of phosphorylated-glycogen synthase kinase 3β-serine 9 (p-GSK-3β-Ser9) and β-catenin, as well as the osteogenic markers Runx2 and COL1. The results showed that GSK-3β activation and osteogenic marker expression levels were downregulated by ephrinB2-FC treatment, but these effects were inhibited by blocking integrin αvβ3 in MSCs. Our findings demonstrate that EphB4 can promote osteogenic differentiation of MSCs via upregulation of POSTN expression. It not only helps to reveal the interaction mechanism between EphB4 and Wnt pathway but also brings a better understanding of EphB4/ephrinB2 signaling in bone homeostasis.
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Affiliation(s)
- Fei Zhang
- National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University, Chongqing 400038, China
- Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Zehua Zhang
- National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University, Chongqing 400038, China
- Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Dong Sun
- National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University, Chongqing 400038, China
- Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Shiwu Dong
- National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University, Chongqing 400038, China
- Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China
| | - Jianzhong Xu
- National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University, Chongqing 400038, China
- Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
- *Jianzhong Xu: and
| | - Fei Dai
- National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University, Chongqing 400038, China
- Department of Orthopaedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
- *Fei Dai:
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Suvannasankha A, Chirgwin JM. Role of bone-anabolic agents in the treatment of breast cancer bone metastases. Breast Cancer Res 2015; 16:484. [PMID: 25757219 PMCID: PMC4429670 DOI: 10.1186/s13058-014-0484-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2025] Open
Abstract
Skeletal metastases are an incurable complication afflicting the majority of patients who die from advanced breast cancer. They are most often osteolytic, characterized by net bone destruction and suppressed new bone formation. Life expectancy from first diagnosis of breast cancer bone metastases is several years, during which time skeletal-related events - including pain, fracture, hypercalcemia, and spinal cord compression - significantly degrade quality of life. The bone marrow niche can also confer hormonal and chemo-resistance. Most treatments for skeletal metastases target bone-destroying osteoclasts and are palliative. Recent results from the Breast cancer trials of Oral Everolimus-2 trial suggest that agents such as the mammalian target of rapamycin inhibitor everolimus may have efficacy against breast cancer bone metastases in part via stimulating osteoblasts as well as by inhibiting tumor growth. Selective estrogen receptor modulators similarly inhibit growth of estrogen receptor-positive breast cancers while having positive effects on the skeleton. This review discusses the future role of bone-anabolic agents for the specific treatment of osteolytic breast cancer metastases. Agents with both anti-tumor and bone-anabolic actions have been tested in the setting of multiple myeloma, a hematological malignancy that causes severe osteolytic bone loss and suppression of osteoblastic new bone formation. Stimulation of osteoblast activity inhibits multiple myeloma growth - a strategy that might decrease breast cancer burden in osteolytic bone metastases. Proteasome inhibitors (bortezomib and carfilzomib) inhibit the growth of myeloma directly and are anabolic for bone. Drugs with limited anti-tumor activity but which are anabolic for bone include intermittent parathyroid hormone and antibodies that neutralize the WNT inhibitors DKK1 and sclerostin, as well as the activin A blocker sotatercept and the osteoporosis drug strontium ranelate. Transforming growth factor-beta inhibitors have little tumor antiproliferative activity but block breast cancer production of osteolytic factors and are also anabolic for bone. Some of these treatments are already in clinical trials. This review provides an overview of agents with bone-anabolic properties, which may have utility in the treatment of breast cancer metastatic to the skeleton.
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Chen S, Ye X, Yu X, Xu Q, Pan K, Lu S, Yang P. Co-culture with periodontal ligament stem cells enhanced osteoblastic differentiation of MC3T3-E1 cells and osteoclastic differentiation of RAW264.7 cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:14596-14607. [PMID: 26823783 PMCID: PMC4713569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/19/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVES Periodontal ligament stem cells (PDLSCs) are characterized by having multipotential differentiation and immunoregulatory properties, which are the main mechanisms of PDLSCs-mediated periodontal regeneration. Periodontal or bone regeneration requires coordination of osteoblast and osteoclast, however, very little is known about the interactions between PDLSCs and osteoblast-like cells or osteoclast precursors. In this study, the indirect co-culture approach was introduced to preliminarily elucidate the effects of PDLSCs on differentiation of osteoblast-like cells and osteoclast precursors in vitro. MATERIALS AND METHODS Human PDLSCs were obtained from premolars extracted and their stemness was identified in terms of their colony-forming ability, proliferative capacity, cell surface epitopes and multi-lineage differentiation potentials. A noncontact co-culture system of PDLSCs and preosteoblastic cell line MC3T3-E1 or osteoclast precursor cell line RAW264.7 was established, and osteoblastic differentiation of MC3T3-E1 and osteoclastic differentiation of RAW264.7 were evaluated. RESULTS PDLSCs exhibited features of mesenchymal stem cells. Further investigation through indirect co-culture system showed that PDLSCs enhanced ALP activity, expressions of ALP, Runx2, BSP, OPN mRNA and BSP, OPN proteins and mineralization matrix deposition in MC3T3-E1. Meanwhile, they improved maturation of osteoclasts and expressions of TRAP, CSTK, TRAF6 mRNA and TRAP, TRAF6 proteins in RAW264.7. CONCLUSIONS PDLSCs stimulates osteoblastic differentiation of osteoblast precursors and osteoclastic differentiation of osteoclast precursors, at least partially, in a paracrine fasion.
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Affiliation(s)
- Shulan Chen
- School of Stomatology, Shandong UniversityJinan 250012, Shandong, China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong UniversityJinan 250012, Shandong, China
- Department of Stomatology, Qingdao Municipal HospitalQingdao 266011, Shandong, China
| | - Xin Ye
- School of Stomatology, Shandong UniversityJinan 250012, Shandong, China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong UniversityJinan 250012, Shandong, China
| | - Xinbo Yu
- Department of Periodontology, Affiliated Hospital of Qingdao UniversityQingdao 266011, Shandong, China
| | - Quanchen Xu
- Department of Periodontology, Affiliated Hospital of Qingdao UniversityQingdao 266011, Shandong, China
| | - Keqing Pan
- Department of Periodontology, Affiliated Hospital of Qingdao UniversityQingdao 266011, Shandong, China
| | - Shulai Lu
- Department of Stomatology, Qingdao Municipal HospitalQingdao 266011, Shandong, China
| | - Pishan Yang
- School of Stomatology, Shandong UniversityJinan 250012, Shandong, China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong UniversityJinan 250012, Shandong, China
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He S, Lu Y, Liu X, Huang X, Keller ET, Qian CN, Zhang J. Wnt3a: functions and implications in cancer. CHINESE JOURNAL OF CANCER 2015; 34:554-62. [PMID: 26369691 PMCID: PMC4593336 DOI: 10.1186/s40880-015-0052-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 08/18/2015] [Indexed: 12/30/2022]
Abstract
Wnt3a, one of Wnt family members, plays key roles in regulating pleiotropic cellular functions, including self-renewal, proliferation, differentiation, and motility. Accumulating evidence has suggested that Wnt3a promotes or suppresses tumor progression via the canonical Wnt signaling pathway depending on cancer type. In addition, the roles of Wnt3a signaling can be inhibited by multiple proteins or chemicals. Herein, we summarize the latest findings on Wnt3a as an important therapeutic target in cancer.
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Affiliation(s)
- Sha He
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, Guangxi, 530021, P.R. China. .,Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, P.R. China.
| | - Yi Lu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, Guangxi, 530021, P.R. China. .,Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, P.R. China.
| | - Xia Liu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, Guangxi, 530021, P.R. China. .,Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, P.R. China.
| | - Xin Huang
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, Guangxi, 530021, P.R. China. .,Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, P.R. China.
| | - Evan T Keller
- Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Chao-Nan Qian
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 51006, P.R. China.
| | - Jian Zhang
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, Guangxi, 530021, P.R. China. .,Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, P.R. China. .,Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
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Zhang F, Zhang Z, Sun D, Dong S, Xu J, Dai F. EphB4 Promotes Osteogenesis of CTLA4-Modified Bone Marrow-Derived Mesenchymal Stem Cells Through Cross Talk with Wnt Pathway in Xenotransplantation. Tissue Eng Part A 2015; 21:2404-16. [PMID: 26132739 DOI: 10.1089/ten.tea.2015.0012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Cytotoxic T lymphocyte-associated antigen 4-Ig (CTLA4-Ig)-modified bone marrow-derived mesenchymal stem cells (MSCs-CTLA4) have excellent osteogenic function in xenografts, but their mechanism of action remains to be elucidated. As bidirectional signaling between erythropoietin-producing hepatocyte receptors B4 (EphB4) and ephrinB2 is vital for bone remodeling, this study aimed to fully characterize the role of MSCs-CTLA4 in promoting bone regeneration in xenotransplantation through EphB4/ephrinB2 and their cross talk with the Wnt/beta-catenin pathway. METHODS MSCs-CTLA4 were investigated for their osteogenic capacity through xenotransplantation in vivo. MSCs-CTLA4 were treated with ephrinB2-FC or FC under conditions of osteogenic induction and cultured with or without immune activation conditions established by phytohemagglutinin and peripheral blood mononuclear cells in vitro. Osteogenesis markers and the Wnt pathway-related molecules such as EphB4, runt-related transcription factor 2 (Runx2), collagen 1 (COL1), osteocalcin (OCN), alkaline phosphatase (ALP), calcium nodus, β-catenin, phospho-glycogen synthase kinase 3-beta (p-GSK-3β)-Ser9, and glycogen synthase kinase 3-beta (GSK-3β) were detected. RESULTS MSCs-CTLA4-based xenografts show better osteogenic capacity compared with MSC-based xenografts. EphB4 expression was reduced in MSCs compared with MSCs-CTLA4 under immune activation conditions. In ephrinB2-FC-treated cells, levels of osteogenesis markers were increased compared with FC-treated cells. The activity of GSK-3 was inhibited and the expression of β-catenin in MSCs was increased by ephrinB2-FC treatment. CONCLUSIONS CTLA4 modification maintains EphB4 expression in MSCs under immune activation conditions, and EphB4 cross talk with the Wnt pathway promotes osteogenic differentiation of MSCs-CTLA4.
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Affiliation(s)
- Fei Zhang
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University , Chongqing, People's Republic of China .,2 Department of Orthopaedics, Southwest Hospital, Third Military Medical University , Chongqing, People's Republic of China
| | - Zehua Zhang
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University , Chongqing, People's Republic of China .,2 Department of Orthopaedics, Southwest Hospital, Third Military Medical University , Chongqing, People's Republic of China
| | - Dong Sun
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University , Chongqing, People's Republic of China .,2 Department of Orthopaedics, Southwest Hospital, Third Military Medical University , Chongqing, People's Republic of China
| | - Shiwu Dong
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University , Chongqing, People's Republic of China .,3 Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University , Chongqing, People's Republic of China
| | - Jianzhong Xu
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University , Chongqing, People's Republic of China .,2 Department of Orthopaedics, Southwest Hospital, Third Military Medical University , Chongqing, People's Republic of China
| | - Fei Dai
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Third Military Medical University , Chongqing, People's Republic of China .,2 Department of Orthopaedics, Southwest Hospital, Third Military Medical University , Chongqing, People's Republic of China
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Garcia-Gomez A, De Las Rivas J, Ocio EM, Díaz-Rodríguez E, Montero JC, Martín M, Blanco JF, Sanchez-Guijo FM, Pandiella A, San Miguel JF, Garayoa M. Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease. Oncotarget 2015; 5:8284-305. [PMID: 25268740 PMCID: PMC4226683 DOI: 10.18632/oncotarget.2058] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.
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Affiliation(s)
- Antonio Garcia-Gomez
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain. Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
| | - Javier De Las Rivas
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
| | - Enrique M Ocio
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain. Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Elena Díaz-Rodríguez
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
| | - Juan C Montero
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
| | - Montserrat Martín
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain. Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
| | - Juan F Blanco
- Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Fermín M Sanchez-Guijo
- Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
| | - Atanasio Pandiella
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain. Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
| | - Jesús F San Miguel
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain. Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
| | - Mercedes Garayoa
- Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain. Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain. Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
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