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Rummler M, Ziouti F, Snyder L, Zimmermann EA, Lynch M, Donnelly E, Wagermaier W, Jundt F, Willie BM. Bone mechanical properties were altered in a mouse model of multiple myeloma bone disease. BIOMATERIALS ADVANCES 2025; 166:214047. [PMID: 39303656 DOI: 10.1016/j.bioadv.2024.214047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 07/29/2024] [Accepted: 09/13/2024] [Indexed: 09/22/2024]
Abstract
Multiple myeloma bone disease (MMBD) is characterized by the growth of malignant plasma cells in bone marrow, leading to an imbalance in bone (re)modeling favoring excessive resorption. Loss of bone mass and altered microstructure characterize MMBD in humans and preclinical animal models, although, no study to date has examined bone composition or material properties. We hypothesized that MMBD alters bone composition, mineral crystal properties and mechanical properties in the MOPC315.BM.Luc model after intra-tibial injection of myeloma cells and three weeks of daily in vivo tibial loading. Decreased cortical bone elastic modulus and hardness measured by nanoindentation of tibiae were observed in MM-injected mice compared to PBS-injected mice, whereas cortical bone composition, mineral crystal properties measured by Fourier-transform infrared imaging or small angle X-ray scattering, respectively remained unchanged. However, MM-injected mice had thinner cancellous bone mineral particles compared to PBS-injected mice. Mechanical loading did not lead to altered cortical bone composition, mineral structure, or mechanical properties in the context of MM. Unexpectedly, we observed the intra-tibial injection itself altered the material composition of bone, manifested by increased matrix mineralization and crystal size of the hydroxyapatite crystals in the bone matrix. In conclusion, our data suggest that mechanical stimuli can be used as an adjuvant bone anabolic therapy in patients with MMBD to rebuild bone with unaltered composition and mineral structure to reduce subsequent fracture risk.
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Affiliation(s)
- Maximilian Rummler
- Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada; Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada; Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
| | - Fani Ziouti
- Department of Internal Medicine II, Hematology and Oncology, University Hospital of Würzburg, Würzburg, Germany
| | - Leah Snyder
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, USA
| | - Elizabeth A Zimmermann
- Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada; Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada
| | - Maureen Lynch
- University of Colorado, Department of Mechanical Engineering, Boulder, CO, USA
| | - Eve Donnelly
- Department of Materials Science and Engineering, Cornell University, Ithaca, NY, USA
| | - Wolfgang Wagermaier
- Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
| | - Franziska Jundt
- Department of Internal Medicine II, Hematology and Oncology, University Hospital of Würzburg, Würzburg, Germany; Comprehensive Cancer Center Mainfranken, Würzburg, Germany
| | - Bettina M Willie
- Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada; Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada.
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2
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Yuan Y, Guo M, Gu C, Yang Y. The role of Wnt/β-catenin signaling pathway in the pathogenesis and treatment of multiple myeloma (review). Am J Transl Res 2021; 13:9932-9949. [PMID: 34650674 PMCID: PMC8507016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/07/2021] [Indexed: 06/13/2023]
Abstract
Multiple myeloma (MM) is a refractory hematological malignancy characterized by aberrant accumulation of plasma cells. Patients with MM are susceptible to becoming resistant to chemotherapy, eventually leading to relapse. Progression of MM is largely dependent on the bone marrow microenvironment. Stromal cells in the bone marrow microenvironment secrete Wnt ligands to activate Wnt signaling in MM, which is mediated through the transcription regulator β-catenin. In addition, Wnt/β-catenin pathway encourages osteoblast differentiation and bone formation, dysregulation of which is responsible for proliferation and drug resistance of MM cells. As a result, direct inhibition or silencing of β-catenin or associated genes in the Wnt/β-catenin pathway has been proposed to be an effective therapeutic anti-MM strategy. However, the underlying regulatory mechanism of the Wnt/β-catenin pathway in MM remains to be fully elucidated. Herein, we summarized research advances on the specific genes and molecular biology process of Wnt/β-catenin pathway involved in tumorigenesis of MM, as well as the interaction with bone marrow microenvironment. Additionally, comprehensive summaries of drugs or small molecule inhibitors acting on Wnt/β-catenin pathway and targeting MM were introduced. This review intends to provide an overview of theoretical supports for novel Wnt/β-catenin pathway based treatment strategies in MM.
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Affiliation(s)
- Yuxia Yuan
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing 210022, Jiangsu, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
| | - Mengjie Guo
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
| | - Chunyan Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing 210022, Jiangsu, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
| | - Ye Yang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing 210022, Jiangsu, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese MedicineNanjing 210023, Jiangsu, China
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3
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Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory. Cancers (Basel) 2020; 12:cancers12082158. [PMID: 32759688 PMCID: PMC7463431 DOI: 10.3390/cancers12082158] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/31/2020] [Accepted: 08/02/2020] [Indexed: 12/21/2022] Open
Abstract
The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at the origin/facilitate the emergence of MM. We propose the tissue disruption-induced cell stochasticity (TiDiS) theory for MM oncogenesis that integrates disruption of the microenvironment, differentiation, and genetic alterations. It starts with the observation that the bone marrow endosteal niche controls differentiation. As decrease in cellular stochasticity occurs thanks to cellular interactions in differentiating cells, the initiating role of bone disruption would be in the increase of cellular stochasticity. Thus, in the context of polyclonal activation of B cells, memory B cells and plasmablasts would compete for localizing in endosteal niches with the risk that some cells cannot fully differentiate if they cannot reside in the niche because of a disrupted microenvironment. Therefore, they would remain in an unstable state with residual proliferation, with the risk that subclones may transform into malignant cells. Finally, diagnostic and therapeutic perspectives are provided.
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4
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Awasthi H, Mani D, Singh D, Gupta A. The underlying pathophysiology and therapeutic approaches for osteoporosis. Med Res Rev 2018; 38:2024-2057. [DOI: 10.1002/med.21504] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/28/2018] [Accepted: 04/04/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Harshika Awasthi
- Herbal Medicinal Products Department; CSIR-Central Institute of Medicinal and Aromatic Plants; Lucknow India
| | - Dayanandan Mani
- Herbal Medicinal Products Department; CSIR-Central Institute of Medicinal and Aromatic Plants; Lucknow India
| | - Divya Singh
- Division of Endocrinology; CSIR-Central Drug Research Institute; Lucknow India
| | - Atul Gupta
- Medicinal Chemistry Department; CSIR-Central Institute of Medicinal and Aromatic Plants; Lucknow India
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5
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Management of Children With β-Thalassemia Intermedia: Overview, Recent Advances, and Treatment Challenges. J Pediatr Hematol Oncol 2018; 40:253-268. [PMID: 29629992 DOI: 10.1097/mph.0000000000001148] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Our knowledge of the various clinical morbidities that thalassemia intermedia (TI) patients endure has substantially increased over the past decade. It is mandatory to grasp a solid understanding of disease-specific complications in order to tailor management. The optimal course of management for TI patients has been hard to identify, and several controversies remain with regard to the best treatment plan. Although advances in TI are moving at a fast pace, many complications remain with no treatment guidelines. Studies that expand our understanding of the mechanisms and risk factors, as well as clinical trials evaluating the roles of available treatments, will help establish management guidelines that improve patient care. Novel therapeutic modalities are now emerging. This article focuses on the management of children with β-TI. We present various clinical morbidities and their association with the underlying disease pathophysiology and risk factors. All therapeutic options, recent advances, and treatment challenges were reviewed.
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6
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McDonald MM, Fairfield H, Falank C, Reagan MR. Adipose, Bone, and Myeloma: Contributions from the Microenvironment. Calcif Tissue Int 2017; 100:433-448. [PMID: 27343063 PMCID: PMC5396178 DOI: 10.1007/s00223-016-0162-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Accepted: 06/06/2016] [Indexed: 12/24/2022]
Abstract
Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.
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Affiliation(s)
- Michelle M McDonald
- Garvan Institute of Medical Research, 384 Victoria Street, Sydney, NSW, 2010, Australia.
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, NSW, 2010, Australia.
| | - Heather Fairfield
- Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Carolyne Falank
- Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA
| | - Michaela R Reagan
- Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA.
- School of Medicine, Tufts University, Boston, MA, USA.
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7
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Eda H, Santo L, Wein MN, Hu DZ, Cirstea DD, Nemani N, Tai YT, Raines SE, Kuhstoss SA, Munshi NC, Kronenberg HM, Raje NS. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease. J Bone Miner Res 2016; 31:1225-34. [PMID: 26763740 PMCID: PMC5002355 DOI: 10.1002/jbmr.2789] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 01/07/2016] [Accepted: 01/08/2016] [Indexed: 01/09/2023]
Abstract
Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease and provides the rationale for studying scl-Ab combined with proteasome inhibitors in MM. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Homare Eda
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Loredana Santo
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Marc N. Wein
- Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Dorothy Z. Hu
- Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Diana D. Cirstea
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Neeharika Nemani
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Yu-Tzu Tai
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Sarah E. Raines
- Regenerative Biology, Lilly Research Laboratories, Indianapolis, IN, USA
| | | | - Nikhil C. Munshi
- LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Noopur S. Raje
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
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8
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Abstract
Bone involvement represented by osteolytic bone disease (OBD) or osteopenia is one of the pathognomonic and defining characteristics of multiple myeloma (MM). Nearly 90 % of patients with MM develop osteolytic bone lesions, frequently complicated by skeletal-related events (SRE) such as severe bone pain, pathological fractures, vertebral collapse, hypercalcemia, and spinal cord compression. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. OBD is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Inhibition of osteolysis and stimulation of OB differentiation leads to reduced tumor growth in vivo. Therefore, novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM. Several novel agents in addition to bisphosphonates are currently under investigation for their positive effect on bone remodeling via OC inhibition or OB stimulation. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from MM OBD but also capitalizing on the resultant antitumor activity.
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Affiliation(s)
- Homare Eda
- Multiple Myeloma Program, Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Loredana Santo
- Multiple Myeloma Program, Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - G David Roodman
- Multiple Myeloma Program, Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Noopur Raje
- Multiple Myeloma Program, Medical Oncology, Massachusetts General Hospital, Boston, MA, USA.
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9
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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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10
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Hinge M, Delaisse JM, Plesner T, Clasen-Linde E, Salomo M, Andersen TL. High-dose therapy improves the bone remodelling compartment canopy coverage and bone formation in multiple myeloma. Br J Haematol 2015. [PMID: 26212720 DOI: 10.1111/bjh.13584] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti-myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti-myeloma treatment.
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Affiliation(s)
- Maja Hinge
- Department of Clinical Cell Biology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark.,Department of Internal Medicine, Section of Haematology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark
| | - Jean-Marie Delaisse
- Department of Clinical Cell Biology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark
| | - Torben Plesner
- Department of Internal Medicine, Section of Haematology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark
| | | | - Morten Salomo
- Department of Haematology, Rigshospitalet, Copenhagen, Denmark
| | - Thomas Levin Andersen
- Department of Clinical Cell Biology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark
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11
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Bataille R. The multiple myeloma bone eco-system and its relation to oncogenesis. Morphologie 2015; 99:31-7. [PMID: 26005000 DOI: 10.1016/j.morpho.2015.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 03/27/2015] [Indexed: 11/15/2022]
Abstract
Pure lytic bone lesions are the hallmark of myeloma (MM). MM is the only hematological malignancy associated with lytic bone lesions and the mechanisms of bone destruction are well documented both at the cellular and molecular levels. An uncoupling bone process characterizes MM, with stimulation of bone resorption and inhibition of bone formation. The capacity of MM cells to directly or indirectly inhibit bone formation is specific of MM, although many carcinomas have the capacity to stimulate bone resorption, directly or indirectly in a similar way to MM. Few MM do not develop bone lesions, while true sclerotic MM remain exceptional. Inhibition of bone formation is the major event explaining the transition from MGUS to overt MM. It is now well documented that bone cells regulate MM cell growth, osteoclast stimulating MM cell growth and osteoblasts inhibiting it. Progression of MM from MGUS is characterized by the selection of MM clones able to inhibit osteoblasts, favoring tumor growth. These data underline the interest of new treatments able to regenerate bone.
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Affiliation(s)
- R Bataille
- Institut de cancérologie de l'Ouest, université d'Angers, 2, rue Moll, 49933 Angers cedex 9, France; CRCNA UMR Inserm 892, IRS UN, 44000 Nantes, France.
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12
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Nemani N, Santo L, Eda H, Cirstea D, Mishima Y, Patel C, O'Donnell E, Yee A, Raje N. Role of decorin in multiple myeloma (MM) bone marrow microenvironment. J Bone Miner Res 2015; 30:465-70. [PMID: 25407518 DOI: 10.1002/jbmr.2371] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Revised: 09/18/2014] [Accepted: 09/20/2014] [Indexed: 11/12/2022]
Abstract
Decorin is a small, leucine-rich proteoglycan found in the extracellular matrix of various connective tissues with potential effective tumor suppressive properties. Recent data suggest low levels of decorin in multiple myeloma (MM) patients compared to healthy volunteers, as well as in patients with osteolytic bone lesions compared to non-osteolytic lesions. In the present report, we investigated the role of decorin in the MM microenvironment or niche. Our data suggests that decorin is produced by osteoblasts (OBs) but not by MM cells. Furthermore, MM cells decrease OB-induced decorin secretion and this effect is mediated by CCL3. Importantly, neutralizing CCL3 from MM cells restores decorin levels in OBs as does proteasome inhibitors such as carfilzomib. These findings indicate that decorin may indirectly act as an antagonist to MM cell survival and that the interplay between MM and decorin may be an important target to explore in manipulating the tumor niche to inhibit tumorigenesis.
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Affiliation(s)
- Neeharika Nemani
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
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13
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Papamerkouriou YM, Kenanidis E, Gamie Z, Papavasiliou K, Kostakos T, Potoupnis M, Sarris I, Tsiridis E, Kyrkos J. Treatment of multiple myeloma bone disease: experimental and clinical data. Expert Opin Biol Ther 2014; 15:213-30. [DOI: 10.1517/14712598.2015.978853] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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14
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Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model. Blood 2014; 124:3250-9. [PMID: 25205118 DOI: 10.1182/blood-2014-02-558007] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required. Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillary-like assembly of endothelial cells and cell adhesion-mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)- and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone-useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation.
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15
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Kassen D, Moore S, Percy L, Herledan G, Bounds D, Rodriguez-Justo M, Croucher P, Yong K. The bone marrow stromal compartment in multiple myeloma patients retains capability for osteogenic differentiation in vitro: defining the stromal defect in myeloma. Br J Haematol 2014; 167:194-206. [PMID: 25079197 DOI: 10.1111/bjh.13020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 05/20/2014] [Indexed: 12/20/2022]
Abstract
Defects in bone repair contribute to multiple myeloma (MM) bone disease. It is unknown whether this reflects failure of osteogenic differentiation from mesenchymal stromal cells (MSC), inherent stromal defects or mature cell dysfunction. We quantified the number of fibroblast colony-forming units (CFU-f) and osteoblast colony-forming units (CFU-ob) in freshly isolated bone marrow (BM) from healthy individuals (N = 10) and MM patients (N = 54). CFU-f and CFU-ob were present in MM BM, at comparable frequency to normal subjects, irrespective of disease stage, and the presence of bone disease. Adherent cultures from MM BM are able to differentiate into osteoblasts, as indicated by the early upregulation of RUNX2, SP7, AXIN2 and DLX5, and the production of alkaline phosphatase and calcium. Coculture with MM cells failed to prevent osteogenic differentiation of adult human MSC. On the other hand, MM cells induced cell cycle progression in resting MSC in a cell contact dependent manner. This effect was confirmed using both primary CD138+ cells and MM cell lines, and was not seen with B or T cell lines. Our data confirm the presence of osteoblast progenitors and the preservation of osteogenic function in MM, however dysregulation of cell cycle control may contribute to the loss of normal bone homeostasis that ultimately results in osteolytic bone loss.
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Affiliation(s)
- Deepika Kassen
- Department of Haematology, University College London, London, UK
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Garcia-Gomez A, Sanchez-Guijo F, del Cañizo MC, San Miguel JF, Garayoa M. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics. World J Stem Cells 2014; 6:322-343. [PMID: 25126382 PMCID: PMC4131274 DOI: 10.4252/wjsc.v6.i3.322] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/24/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.
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A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity. Leukemia 2014; 28:1892-901. [PMID: 24518207 DOI: 10.1038/leu.2014.69] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 01/13/2014] [Accepted: 02/06/2014] [Indexed: 11/08/2022]
Abstract
Bruton's tyrosine kinase (Btk) modulates B-cell development and activation and has an important role in antibody production. Interestingly, Btk may also affect human osteoclast (OC) function; however, the mechanism was unknown. Here we studied a potent and specific Btk inhibitor, CC-292, in multiple myeloma (MM). In this report, we demonstrate that, although CC-292 increased OC differentiation, it inhibited OC function via inhibition of c-Src, Pyk2 and cortactin, all involved in OC-sealing zone formation. As CC-292 did not show potent in vitro anti-MM activity, we next evaluated it in combination with the proteasome inhibitor, carfilzomib. We first studied the effect of carfilzomib on OC. Carfilzomib did not have an impact on OC-sealing zone formation but significantly inhibited OC differentiation. CC-292 combined with carfilzomib inhibited both sealing zone formation and OC differentiation, resulting in more profound inhibition of OC function than carfilzomib alone. Moreover, the combination treatment in an in vivo MM mouse model inhibited tumor burden compared with CC-292 alone; it also increased bone volume compared with carfilzomib alone. These results suggest that CC-292 combined with carfilzomib augments the inhibitory effects against OC within the bone microenvironment and has promising therapeutic potential for the treatment of MM and related bone disease.
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Garcia-Gomez A, Quwaider D, Canavese M, Ocio EM, Tian Z, Blanco JF, Berger AJ, Ortiz-de-Solorzano C, Hernández-Iglesias T, Martens ACM, Groen RWJ, Mateo-Urdiales J, Fraile S, Galarraga M, Chauhan D, San Miguel JF, Raje N, Garayoa M. Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease. Clin Cancer Res 2014; 20:1542-54. [PMID: 24486586 DOI: 10.1158/1078-0432.ccr-13-1657] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. EXPERIMENTAL DESIGN The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. RESULTS Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-κB ligand)-induced NF-κB activation, F-actin ring disruption, and diminished expression of αVβ3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/β-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). CONCLUSION Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma.
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Affiliation(s)
- Antonio Garcia-Gomez
- Authors' Affiliations: Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC); Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León; Hospital Universitario de Salamanca-IBSAL, Salamanca; Laboratorio de Imagen del Cáncer, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain; MGH Cancer Center, Massachusetts General Hospital; Dana-Farber Cancer Institute, Harvard Medical School, Boston; Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA; and Departments of Cell Biology and Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
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[Occipito-cervical fixation in plasmocytoma. Method modification. Technical report]. Neurol Neurochir Pol 2012; 46:403-6. [PMID: 23023441 DOI: 10.5114/ninp.2012.30274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Intraoperative modification of use and stabilization of the Axon system (Synthes) for occipito-cervical fusion in a patient treated oncologically due to plasmocytoma is presented. Pathological fracture, range of the process and damage of anterior cervical fusion necessitated the use of occipito-cervical stabilization. Different anatomical conditions within the occipital bone in the form of its thinning was observed. Fixing with screws was impossible due to the bone structure. In consequence, modification of stabilization with an ad hoc elaborated technique (burr holes in the occipital bone and stabilization with titanium wire) was implemented. Modifications and specific indications related to the clinical course of plasmocytoma are discussed.
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Sottnik JL, Hall CL, Zhang J, Keller ET. Wnt and Wnt inhibitors in bone metastasis. BONEKEY REPORTS 2012; 1:101. [PMID: 23951488 DOI: 10.1038/bonekey.2012.101] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 04/24/2012] [Indexed: 02/06/2023]
Abstract
Bone metastasis is a clinically devastating development of progressive cancers including prostate carcinoma, breast carcinoma and multiple myeloma. Bone metastases are typically painful, lead to adverse skeletal-related events, such as fracture, and are highly resistant to therapy. A major contribution to the ability of cancers to successfully establish bone metastases is their ability to exploit mechanisms of normal bone remodeling. Wnts are a large family of morphogenic proteins that are critical for bone development and contribute to maintaining bone mass in the mature organism. Wnt function is balanced by the presence of a variety of endogenous inhibitors, such as the dickkopf family members, secreted frizzled related proteins and sclerostin. Together, these factors contribute to normal bone homeostasis, allowing for dynamic changes in bone to withstand alterations in physical forces and physiological needs. In this review, we describe the role that Wnts and their inhibitors have in normal bone biology and cancer-related bone pathology. An overview of Wnt signaling pathways is discussed and key bone microenvironment cellular players, as they pertain to Wnt biology, are examined. Finally, we describe clinical trials of several Wnt inhibitor antagonists for patients with tumor-related bone disease. As few options currently exist for the treatment of bone-metastatic disease, Wnt proteins and their inhibitors offer promise for the development of novel therapeutics.
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Affiliation(s)
- Joseph L Sottnik
- Department of Urology, University of Michigan , Ann Arbor, MI, USA
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