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1
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Szudy-Szczyrek A, Mlak R, Pigoń-Zając D, Krupski W, Mazurek M, Tomczak A, Chromik K, Górska A, Koźlik P, Juda A, Kokoć A, Dubaj M, Sacha T, Niedoszytko M, Helbig G, Szczyrek M, Szumiło J, Małecka-Massalska T, Hus M. Role of sclerostin in mastocytosis bone disease. Sci Rep 2025; 15:161. [PMID: 39747949 PMCID: PMC11697018 DOI: 10.1038/s41598-024-83851-0] [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: 08/13/2024] [Accepted: 12/17/2024] [Indexed: 01/04/2025] Open
Abstract
Mastocytosis is a heterogeneous group of disorders, characterized by accumulation of clonal mast cells which can infiltrate several organs, most often spine (70%). The pathogenesis of mastocytosis bone disease is poorly understood. The main aim of the study was to investigate whether neoplastic mast cells may be the source of sclerostin and whether there is an association between sclerostin and selected bone remodeling markers with mastocytosis related bone disease. We assessed sclerostin, bioactive sclerostin, and SOST gene expression in HMC-1.2 human mast cell culture supernatants and plasma of SM patients (n = 39). We showed that human mast cells can secrete sclerostin, and after their stimulation with IL-6, there is a significant increase in SOST gene expression. We observed significantly higher levels of sclerostin in patients diagnosed with more advanced disease. We observed a statistically significant correlation between concentations of sclerostin and its bioactive form and the concentration of alkaline phosphatase (ALP), and between sclerostin and interleukin-6 (IL-6). We observed that significantly higher sclerostin concentrations are present in patients with increased sclerosis of the spongy bone. Sclerostin may serve as a marker of more advanced disease and bone disease in mastocytosis. Further studies are justified to evaluate its role in mastocytosis.
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Affiliation(s)
- Aneta Szudy-Szczyrek
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Staszica Street 11, 20-081, Poland
| | - Radosław Mlak
- Department of Laboratory Diagnostics, Medical University of Lublin, Lublin, Poland
| | | | - Witold Krupski
- Department of Medical Radiology, Medical University of Lublin, Lublin, Poland
| | - Marcin Mazurek
- Department of Human Physiology, Medical University of Lublin, Lublin, Poland
| | - Aleksandra Tomczak
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Staszica Street 11, 20-081, Poland
| | - Karolina Chromik
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia in Katowice, Katowice, Poland
| | - Aleksandra Górska
- Department of Pulmonology and Allergology, Medical University of Gdańsk, Gdańsk, Poland
| | - Paweł Koźlik
- Chair of Hematology, Jagiellonian University, Kraków, Poland
| | - Adrian Juda
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Staszica Street 11, 20-081, Poland
| | - Anna Kokoć
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Staszica Street 11, 20-081, Poland
| | - Maciej Dubaj
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Staszica Street 11, 20-081, Poland.
| | - Tomasz Sacha
- Chair of Hematology, Jagiellonian University, Kraków, Poland
| | - Marek Niedoszytko
- Department of Pulmonology and Allergology, Medical University of Gdańsk, Gdańsk, Poland
| | - Grzegorz Helbig
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia in Katowice, Katowice, Poland
| | - Michał Szczyrek
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Justyna Szumiło
- Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland
| | | | - Marek Hus
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Staszica Street 11, 20-081, Poland
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2
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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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3
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Yang HZ, Zhan Y, Liu Y, Guo M, Fan Y, Luo G, Zhao Y, Huang S, Sun T, Li SS, Ye Q, Jin X. NIR-stimulated rGO-HAMC hydrogel enhances fracture healing through regulating B-cell signaling. BIOMATERIALS ADVANCES 2025; 166:214080. [PMID: 39490190 DOI: 10.1016/j.bioadv.2024.214080] [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: 06/14/2024] [Revised: 10/01/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
Bone fractures are frequently encountered in clinical practice and pose significant challenges, due to the high incidence of delayed healing or non-union. Reduced graphene oxide (rGO) stands out for its unique sensitivity to a wide range of light wavelengths, especially in the near-infrared (NIR) spectrum. In this study, we developed an approach to promote fracture healing using an rGO-HAMC hydrogel activated by NIR stimulation. In vitro experiments demonstrated that NIR-stimulated rGO hydrogel significantly enhanced osteogenesis in bone marrow stromal cells (BMSCs). In an in vivo mouse fracture model, the rGO hydrogel was applied to the fracture site, and NIR light was delivered transdermally, showing promising results in accelerating bone regeneration. These results demonstrate that NIR-stimulated rGO hydrogel significantly accelerates fracture healing, as evidenced by increased bone volume and trabecular thickness. Additionally, transcriptomic analysis revealed that pathways related to B-cell activation are implicated in the enhanced healing effects mediated by NIR-stimulated rGO hydrogel. These findings highlight the potential of the NIR-stimulated rGO hydrogel as an innovative strategy for bone regeneration, offering promising new avenues for the treatment and management of bone fractures.
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Affiliation(s)
| | - Yifei Zhan
- School of Physics, Nankai University, Tianjin, China
| | - Yang Liu
- Department of Spinal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Miao Guo
- School of Medicine, Nankai University, Tianjin, China
| | - Yonggang Fan
- School of Medicine, Nankai University, Tianjin, China
| | - Gan Luo
- Tianjin Medical University, Tianjin, China
| | - Ying Zhao
- School of Medicine, Nankai University, Tianjin, China
| | | | - Tianwei Sun
- Department of Spinal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Shan-Shan Li
- School of Medicine, Nankai University, Tianjin, China.
| | - Qing Ye
- School of Physics, Nankai University, Tianjin, China.
| | - Xin Jin
- School of Medicine, Nankai University, Tianjin, China.
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4
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Terpos E, Ntanasis-Stathopoulos I, Gavriatopoulou M, Katodritou E, Hatjiharissi E, Malandrakis P, Verrou E, Golfinopoulos S, Migkou M, Manousou K, Delimpasi S, Symeonidis A, Kastritis E, Dimopoulos MA. Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide-exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA. Am J Hematol 2024; 99:396-407. [PMID: 38298023 DOI: 10.1002/ajh.27206] [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: 11/12/2023] [Revised: 12/16/2023] [Accepted: 12/19/2023] [Indexed: 02/02/2024]
Abstract
The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara-Ixa-dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide-based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow-up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second-line treatment with Dara-Ixa-dex in patients with RRMM pre-treated with a lenalidomide-based regimen resulted in rapid responses along with a favorable effect on bone metabolism.
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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
| | - Eirini Katodritou
- Department of Hematology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | - Evdoxia Hatjiharissi
- First Department of Internal Medicine, Division of Haematology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Panagiotis Malandrakis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Evgenia Verrou
- Department of Hematology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | - Magdalini Migkou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | | | - Sosana Delimpasi
- Department of Hematology and Bone Marrow Transplantation Unit, Evangelismos Hospital, Athens, Greece
| | - Argiris Symeonidis
- Hematology Division, Department of Internal Medicine, University of Patras Medical School, Patras, Greece
| | - Efstathios Kastritis
- 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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5
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Zhao D, Wu L, Hong M, Zheng S, Wu X, Ye H, Chen F, Zhang D, Liu X, Meng X, Chen X, Chen S, Zhu J, Li J. DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid Arthritis Patients. Inflammation 2024; 47:129-144. [PMID: 37688661 DOI: 10.1007/s10753-023-01898-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/07/2023] [Accepted: 08/26/2023] [Indexed: 09/11/2023]
Abstract
Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored. In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/β-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice. In vitro experiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of β-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/β-catenin pathway, aggravating the bone destruction in RA.
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Affiliation(s)
- Di Zhao
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Lisheng Wu
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Mukeng Hong
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Songyuan Zheng
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xianghui Wu
- Laboratory Animal Research Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haixin Ye
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Feilong Chen
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Dingding Zhang
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xinhang Liu
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiangyun Meng
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoyun Chen
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Shixian Chen
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Junqing Zhu
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Juan Li
- Department of Rheumatic & TCM Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
- Department of Traditional Chinese Internal Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
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Kim K, Su Y, Kucine AJ, Cheng K, Zhu D. Guided Bone Regeneration Using Barrier Membrane in Dental Applications. ACS Biomater Sci Eng 2023; 9:5457-5478. [PMID: 37650638 DOI: 10.1021/acsbiomaterials.3c00690] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Guided bone regeneration (GBR) is a widely used technique in preclinical and clinical studies due to its predictability. Its main purpose is to prevent the migration of soft tissue into the osseous wound space, while allowing osseous cells to migrate to the site. GBR is classified into two main categories: resorbable and non-resorbable membranes. Resorbable membranes do not require a second surgery but tend to have a short resorption period. Conversely, non-resorbable membranes maintain their mechanical strength and prevent collapse. However, they require removal and are susceptible to membrane exposure. GBR is often used with bone substitute graft materials to fill the defect space and protect the bone graft. The membrane can also undergo various modifications, such as surface modification and biological factor loading, to improve barrier functions and bone regeneration. In addition, bone regeneration is largely related to osteoimmunology, a new field that focuses on the interactions between bone and the immune system. Understanding these interactions can help in developing new treatments for bone diseases and injuries. Overall, GBR has the potential to be a powerful tool in promoting bone regeneration. Further research in this area could lead to advancements in the field of bone healing. This review will highlight resorbable and non-resorbable membranes with cellular responses during bone regeneration, provide insights into immunological response during bone remodeling, and discuss antibacterial features.
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Affiliation(s)
- Kakyung Kim
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
| | - Yingchao Su
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
| | - Allan J Kucine
- Department of Oral and Maxillofacial Surgery, Stony Brook University, Stony Brook, New York 11794, United States
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York City, New York 10027, United States
| | - Donghui Zhu
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York 11794, United States
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Huang B, Liu H, Chan S, Liu J, Gu J, Chen M, Kuang L, Li X, Zhang X, Li J. RUNX2 promotes the suppression of osteoblast function and enhancement of osteoclast activity by multiple myeloma cells. Med Oncol 2023; 40:115. [PMID: 36897488 PMCID: PMC10006269 DOI: 10.1007/s12032-023-01960-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/27/2023] [Indexed: 03/11/2023]
Abstract
RUNX2 is a transcription factor that participates in osteoblast differentiation and chondrocyte maturation and plays an important role in the invasion and metastasis of cancers. With the deepening of research, evidence has indicated the correlation between RUNX2 and bone destruction in cancers. However, the mechanisms underlying its role in multiple myeloma remain unclear. By observing the induction effects of conditioned medium from myeloma cells on preosteoblasts (MC3T3-E1) and preosteoclasts (RAW264.7) and constructing myeloma-bearing mice, we found that RUNX2 promotes bone destruction in multiple myeloma. In vitro, conditioned medium from RUNX2-overexpressing myeloma cells reduced osteoblast activity and increased osteoclast activity. In vivo, RUNX2 expression was positively correlated with bone loss in myeloma-bearing mice. These results suggest that therapeutic inhibition of RUNX2 may protect against bone destruction by maintaining the balance between osteoblast and osteoclast activity in multiple myeloma.
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Affiliation(s)
- Beihui Huang
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Huixin Liu
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Szehoi Chan
- Department of Pharmacology, School of Medicine, Molecular Cancer Research Center, Sun Yat-Sen University, No.66, Gongchang Road, Shenzhen, 518107, China
| | - Junru Liu
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Jingli Gu
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Meilan Chen
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Lifen Kuang
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Xiaozhe Li
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China
| | - Xingding Zhang
- Department of Pharmacology, School of Medicine, Molecular Cancer Research Center, Sun Yat-Sen University, No.66, Gongchang Road, Shenzhen, 518107, China.
| | - Juan Li
- Department of Hematopathology, The First Affiliated Hospital, Sun Yat-Sen University, No. 58, Zhongshan 2Nd Road, Guangzhou, 510080, China.
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8
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Boaretti D, Marques FC, Ledoux C, Singh A, Kendall JJ, Wehrle E, Kuhn GA, Bansod YD, Schulte FA, Müller R. Trabecular bone remodeling in the aging mouse: A micro-multiphysics agent-based in silico model using single-cell mechanomics. Front Bioeng Biotechnol 2023; 11:1091294. [PMID: 36937760 PMCID: PMC10017748 DOI: 10.3389/fbioe.2023.1091294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably, in silico models are regarded as powerful tools to further understand the signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA) in silico model of trabecular bone remodeling using longitudinal in vivo data from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A) mice, a mouse model of premature aging. Our in silico model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells' behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of five mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4 weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.
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Affiliation(s)
| | | | - Charles Ledoux
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Amit Singh
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | | | - Esther Wehrle
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
- AO Research Institute Davos, Davos Platz, Switzerland
| | - Gisela A. Kuhn
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | | | | | - Ralph Müller
- Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
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9
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Teramachi J, Miki H, Nakamura S, Hiasa M, Harada T, Abe M. Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents. J Bone Miner Metab 2023; 41:388-403. [PMID: 36856824 PMCID: PMC9975874 DOI: 10.1007/s00774-023-01403-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 01/20/2023] [Indexed: 03/02/2023]
Abstract
INTRODUCTION Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. APPROACH In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. CONCLUSIONS MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.
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Affiliation(s)
- Jumpei Teramachi
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
- Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Graduate School, 2-5-1 Shikata, Okayama, 700-8525, Japan.
| | - Hirokazu Miki
- Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan
| | - Shingen Nakamura
- Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Hiasa
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
- Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takeshi Harada
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Masahiro Abe
- Department of Hematology, Endocrinology and Metabolism, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
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10
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Immune microenvironment: novel perspectives on bone regeneration disorder in osteoradionecrosis of the jaws. Cell Tissue Res 2023; 392:413-430. [PMID: 36737519 DOI: 10.1007/s00441-023-03743-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023]
Abstract
Osteoradionecrosis of the jaws (ORNJ) is a severe complication that occurs after radiotherapy of head and neck malignancies. Clinically, conservative treatments and surgeries for ORNJ exhibited certain therapeutic effects, whereas the regenerative disorder of the post-radiation jaw remains a pending problem to be solved. In recent years, the recognition of the role of the immune microenvironment has led to a shift from an osteoblasts (OBs) or bone marrow mesenchymal stromal cells (BMSCs)-centered view of bone regeneration to the concept of a complicated microecosystem that supports bone regeneration. Current advances in osteoimmunology have uncovered novel targets within the immune microenvironment to help improve various regeneration therapies, notably therapies potentiating the interaction between BMSCs and immune cells. However, these researches lack a thorough understanding of the immune microenvironment and the interaction network of immune cells in the course of bone regeneration, especially for the post-operative defect of ORNJ. This review summarized the composition of the immune microenvironment during bone regeneration, how the immune microenvironment interacts with the skeletal system, and discussed existing and potential strategies aimed at targeting cellular and molecular immune microenvironment components.
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11
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Geusens P, Appelman-Dijkstra N, Lems W, van den Bergh J. Romosozumab for the treatment of postmenopausal women at high risk of fracture. Expert Opin Biol Ther 2023; 23:11-19. [PMID: 36440489 DOI: 10.1080/14712598.2022.2152320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Romosozumab is a monoclonal antibody that binds to sclerostin (an inhibitor of the Wingless-related integration site (Wnt) signaling pathway). It is a new osteoanabolic drug that simultaneously increases bone formation and decreases bone resorption. It has recently been approved by the US and EU authorities in postmenopausal women with at high risk of fractures. AREAS COVERED The literature on romosozumab in preclinical and in phase II and III clinical studies has been reviewed about the effect on bone, bone markers, and fracture reduction and its safety. EXPERT OPINION Compared to antiresorptive agents, its unique mechanism of action results in a quicker and greater increase in bone mineral density, it repairs and restores trabecular and cortical bone microarchitecture, and reduces fracture risk more rapidly and more effectively than alendronate, with persisting effects for at least two years after transition to antiresorptive agents. This finding has introduced the concept that, in patients at very high risk of fractures, the optimal sequence of treatment is to start with an osteoanabolic agent, followed by a potent AR drug. Recent national and international guidelines recommend the use of romosozumab as an initial treatment in patients at very high fracture risk without a history of stroke or myocardial infarction.
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Affiliation(s)
- Piet Geusens
- Department of Rheumatology, University Maastricht, Minderbroedersberg 4-6, 6211 LK Maastricht, Netherlands
| | - Natasha Appelman-Dijkstra
- Department of Internal Medicine-Endocrinology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, Netherlands
| | - Willem Lems
- Department of Rheumatology, Amsterdam University Medical Centre, De Boelelaan 1117 1081 HV Amsterdam, Netherlands
| | - Joop van den Bergh
- Department of Internal Medicine, VieCuri Medical Centre, Tegelseweg 210, 5912 BL Venlo, Netherlands
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12
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Agarwal G, Nador G, Varghese S, Getu H, Palmer C, Watson E, Pereira C, Sallemi G, Partington K, Patel N, Soundarajan R, Mills R, Brouwer R, Maritati M, Shah A, Peppercorn D, Oppermann U, Edwards CM, Rodgers CT, Javaid MK, Gooding S, Ramasamy K. Prospective Assessment of Tumour Burden and Bone Disease in Plasma Cell Dyscrasias Using DW-MRI and Exploratory Bone Biomarkers. Cancers (Basel) 2022; 15:cancers15010095. [PMID: 36612090 PMCID: PMC9817825 DOI: 10.3390/cancers15010095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/28/2022] [Accepted: 12/09/2022] [Indexed: 12/28/2022] Open
Abstract
Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density (r = 0.40-0.54). At baseline, serum BCMA correlated with serum paraprotein (r = 0.42) and serum DKK1 correlated with serum free light chains (r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility.
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Affiliation(s)
- Gaurav Agarwal
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Correspondence: (G.A.); (K.R.)
| | - Guido Nador
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
| | - Sherin Varghese
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Oxford Translational Myeloma Centre, Oxford OX3 7LD, UK
| | - Hiwot Getu
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
| | - Charlotte Palmer
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Edmund Watson
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Claudio Pereira
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Germana Sallemi
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Karen Partington
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Neel Patel
- Department of Radiology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Rajkumar Soundarajan
- Oxford Centre for Magnetic Resonance, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - Rebecca Mills
- Oxford Centre for Magnetic Resonance, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - Richard Brouwer
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Oxford Translational Myeloma Centre, Oxford OX3 7LD, UK
| | - Marina Maritati
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Aarti Shah
- Department of Radiology, Hampshire Hospitals NHS Foundation Trust, Hampshire SO22 5DG, UK
| | - Delia Peppercorn
- Department of Radiology, Hampshire Hospitals NHS Foundation Trust, Hampshire SO22 5DG, UK
| | - Udo Oppermann
- Oxford Translational Myeloma Centre, Oxford OX3 7LD, UK
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Claire M. Edwards
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
- Nuffield Department of Surgical Sciences (NDS), Oxford OX3 9DU, UK
| | | | - Muhammad Kassim Javaid
- Botnar Research Centre, The Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK
| | - Sarah Gooding
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Oxford Translational Myeloma Centre, Oxford OX3 7LD, UK
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Karthik Ramasamy
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
- Oxford Translational Myeloma Centre, Oxford OX3 7LD, UK
- Correspondence: (G.A.); (K.R.)
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13
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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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14
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Zhang F, Zhuang J. Pathophysiology and therapeutic advances in myeloma bone disease. Chronic Dis Transl Med 2022; 8:264-270. [PMID: 36420171 PMCID: PMC9676126 DOI: 10.1002/cdt3.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/19/2022] [Accepted: 05/26/2022] [Indexed: 11/11/2022] Open
Abstract
Bone disease is the most common complication in patients with multiple myeloma (MM), and it may lead to skeletal-related events (SREs) such as bone pain, pathological fractures, and spinal cord compression, which impair a patients' quality of life and survival. The pathogenesis of myeloma bone disease (MBD) involves disruption of bone reconstitution balance including excessive activation of osteoclasts, inhibition of osteoblasts, and participation of osteocytes and bone marrow stromal cells. Various factors, such as the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG), dickkopf-1 (DKK-1), sclerostin, and activin-A, are involved in the development of MBD. Bisphosphonates and the anti-RANKL antibody denosumab are currently the main treatment options for MBD, delaying the onset of SREs. Denosumab is preferred in patients with MM and renal dysfunction. Although effective drugs have been approved, antimyeloma therapy is the most important method for controlling bone disease.
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Affiliation(s)
- Fujing Zhang
- Department of HematologyPeking Union Medical College HospitalBeijingChina
- Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina
| | - Junling Zhuang
- Department of HematologyPeking Union Medical College HospitalBeijingChina
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15
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Morimoto E, Inagaki K, Komatsubara M, Terasaka T, Itoh Y, Fujisawa S, Sasaki E, Nishiyama Y, Hara T, Wada J. Effects of Wnt-β-catenin signaling and sclerostin on the phenotypes of rat pheochromocytoma PC12 cells. J Endocr Soc 2022; 6:bvac121. [PMID: 36042979 PMCID: PMC9419499 DOI: 10.1210/jendso/bvac121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Indexed: 11/19/2022] Open
Abstract
Abstract
Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), i.e. the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, up-regulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.
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Affiliation(s)
- Eisaku Morimoto
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Kenichi Inagaki
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Motoshi Komatsubara
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Tomohiro Terasaka
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Yoshihiko Itoh
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Satoshi Fujisawa
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Erika Sasaki
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Yuki Nishiyama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Takayuki Hara
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
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16
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Terpos E, Ntanasis-Stathopoulos I, Kastritis E, Hatjiharissi E, Katodritou E, Eleutherakis-Papaiakovou E, Verrou E, Gavriatopoulou M, Leonidakis A, Manousou K, Delimpasi S, Malandrakis P, Kyrtsonis MC, Papaioannou M, Symeonidis A, Dimopoulos MA. Daratumumab Improves Bone Turnover in Relapsed/Refractory Multiple Myeloma; Phase 2 Study “REBUILD”. Cancers (Basel) 2022; 14:cancers14112768. [PMID: 35681747 PMCID: PMC9179322 DOI: 10.3390/cancers14112768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Multiple myeloma (MM) is characterized by the presence of deregulated bone metabolism. Restoring bone turnover is essential for patients with MM. We prospectively evaluated the impact of the anti-CD38 monoclonal antibody daratumumab on markers of bone remodeling among patients with relapsed/refractory MM. Overall, daratumumab improved bone turnover by favoring bone formation. Abstract Biomarkers of bone turnover in serum are suggestive of bone dynamics during treatment in multiple myeloma (MM). We evaluated the role of daratumumab on bone remodeling among patients with relapsed/refractory MM in the prospective, open-label, phase 2 study REBUILD. Daratumumab was administered according to the approved indication. A total of 33 out of 57 enrolled patients completed 4 months of treatment. The median percent change from baseline to 4 months in C-terminal cross-linking telopeptide of type 1 collagen (CTX) (primary endpoint) was 3.9%, with 13 (39.4%) and 11 (33.3%) patients showing at least 20% and 30% reduction in CTX levels, respectively. The median percent decrease from baseline to 4 months in tartrate resistant acid phosphatase 5b (TRACP-5b) levels (co-primary endpoint) was 2.6%, with 10 (30.3%) and 6 (18.2%) patients showing at least 20% and 30% reduction in TRACP-5b levels, respectively. However, the changes in these markers of bone catabolism were not statistically significant. Furthermore, the levels of osteocalcin, bone-specific alkaline phosphatase and procollagen type-I N-pro-peptide (bone formation markers) increased from baseline to 4 months (secondary endpoints) by 18.4%, 92.6% and 10.2%, respectively. Furthermore, the median levels of dickkopf-1 and C-C motif ligand-3 showed a significant decrease at 4 months by 17.5% and 16.0%, respectively. In conclusion, daratumumab improved bone turnover by inducing bone formation and reducing osteoblast inhibition.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
- Correspondence: ; Tel.: +30-(213)-216-2846
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
| | - Evdoxia Hatjiharissi
- First Department of Internal Medicine, School of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (E.H.); (M.P.)
| | - Eirini Katodritou
- Department of Hematology, Theagenio Cancer Hospital, 54639 Thessaloniki, Greece; (E.K.); (E.V.)
| | - Evangelos Eleutherakis-Papaiakovou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
| | - Evgenia Verrou
- Department of Hematology, Theagenio Cancer Hospital, 54639 Thessaloniki, Greece; (E.K.); (E.V.)
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
| | | | - Kyriaki Manousou
- Health Data Specialists S.A., 11525 Athens, Greece; (A.L.); (K.M.)
| | - Sosana Delimpasi
- Bone Marrow Transplantation Unit and Department of Hematology, Evangelismos Hospital, 10676 Athens, Greece;
| | - Panagiotis Malandrakis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
| | - Marie-Christine Kyrtsonis
- First Department of Propedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Maria Papaioannou
- First Department of Internal Medicine, School of Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (E.H.); (M.P.)
| | - Argiris Symeonidis
- Hematology Division, Department of Internal Medicine, School of Medicine, University of Patras, 26334 Patras, Greece;
| | - Meletios-Athanasios Dimopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (I.N.-S.); (E.K.); (E.E.-P.); (M.G.); (P.M.); (M.-A.D.)
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Chiarito M, Piacente L, Chaoul N, Pontrelli P, D'Amato G, Grandone A, Russo G, Street ME, Wasniewska MG, Brunetti G, Faienza MF. Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome. J Endocrinol Invest 2022; 45:1255-1263. [PMID: 35237949 PMCID: PMC9098532 DOI: 10.1007/s40618-022-01760-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 02/07/2022] [Indexed: 12/22/2022]
Abstract
PURPOSE Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.
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Affiliation(s)
- M Chiarito
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University of Bari "A. Moro", Bari, Italy
| | - L Piacente
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University of Bari "A. Moro", Bari, Italy
| | - N Chaoul
- Department of Biomedical Sciences and Human Oncology, University of Bari "A. Moro", Bari, Italy
| | - P Pontrelli
- Department of Emergency and Organ Transplantation, Division of Nephrology, University of Bari "A. Moro", Bari, Italy
| | - G D'Amato
- Neonatal Intensive Care Unit, "Di Venere" Hospital, Bari, Italy
| | - A Grandone
- Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
| | - G Russo
- Department of Pediatrics, IRCCS San Raffaele Hospital, Milan, Italy
| | - M E Street
- Department of Mother and Child, Azienda USL-IRCCS Di Reggio Emilia, Reggio Emilia, Italy
| | - M G Wasniewska
- Pediatric Unit, Department of Human Pathology in Adulthood and Childhood, University of Messina, Messina, Italy
| | - G Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University "A. Moro" of Bari, Bari, Italy
| | - M F Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Unit, University of Bari "A. Moro", Bari, Italy.
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18
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Allegra A, Casciaro M, Barone P, Musolino C, Gangemi S. Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma. Cancers (Basel) 2022; 14:cancers14112597. [PMID: 35681577 PMCID: PMC9179362 DOI: 10.3390/cancers14112597] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/12/2022] [Accepted: 05/23/2022] [Indexed: 12/20/2022] Open
Abstract
In multiple myeloma, cells of the bone marrow microenvironment have a relevant responsibility in promoting the growth, survival, and drug resistance of multiple myeloma plasma cells. In addition to the well-recognized role of genetic lesions, microenvironmental cells also present deregulated epigenetic systems. However, the effect of epigenetic changes in reshaping the tumour microenvironment is still not well identified. An assortment of epigenetic regulators, comprising histone methyltransferases, histone acetyltransferases, and lysine demethylases, are altered in bone marrow microenvironmental cells in multiple myeloma subjects participating in disease progression and prognosis. Aberrant epigenetics affect numerous processes correlated with the tumour microenvironment, such as angiogenesis, bone homeostasis, and extracellular matrix remodelling. This review focuses on the interplay between epigenetic alterations of the tumour milieu and neoplastic cells, trying to decipher the crosstalk between these cells. We also evaluate the possibility of intervening specifically in modified signalling or counterbalancing epigenetic mechanisms.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (P.B.); (C.M.)
- Correspondence:
| | - Marco Casciaro
- Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy; (M.C.); (S.G.)
| | - Paola Barone
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (P.B.); (C.M.)
| | - Caterina Musolino
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy; (P.B.); (C.M.)
| | - Sebastiano Gangemi
- Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, School of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy; (M.C.); (S.G.)
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19
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Iwamoto R, Koide M, Udagawa N, Kobayashi Y. Positive and Negative Regulators of Sclerostin Expression. Int J Mol Sci 2022; 23:ijms23094895. [PMID: 35563281 PMCID: PMC9102037 DOI: 10.3390/ijms23094895] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/27/2022] [Accepted: 04/27/2022] [Indexed: 02/04/2023] Open
Abstract
Sclerostin is secreted from osteocytes, binds to the Wnt co-receptor Lrp5/6, and affects the interaction between Wnt ligands and Lrp5/6, which inhibits Wnt/β-catenin signals and suppresses bone formation. Sclerostin plays an important role in the preservation of bone mass by functioning as a negative regulator of bone formation. A sclerostin deficiency causes sclerosteosis, which is characterized by an excess bone mass with enhanced bone formation in humans and mice. The expression of sclerostin is positively and negatively regulated by many factors, which also govern bone metabolism. Positive and negative regulators of sclerostin expression and their effects are introduced and discussed herein based on recent and previous findings, including our research.
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Affiliation(s)
- Rina Iwamoto
- Division of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hiro-oka, Shiojiri 399-0781, Nagano, Japan; (R.I.); (M.K.)
| | - Masanori Koide
- Division of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hiro-oka, Shiojiri 399-0781, Nagano, Japan; (R.I.); (M.K.)
| | - Nobuyuki Udagawa
- Department of Biochemistry, Matsumoto Dental University, 1780 Gobara Hiro-oka, Shiojiri 399-0781, Nagano, Japan;
| | - Yasuhiro Kobayashi
- Division of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, 1780 Gobara Hiro-oka, Shiojiri 399-0781, Nagano, Japan; (R.I.); (M.K.)
- Correspondence: ; Tel.: +81-263-51-2238
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20
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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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21
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Pathogenesis and treatment of multiple myeloma bone disease. JAPANESE DENTAL SCIENCE REVIEW 2021; 57:164-173. [PMID: 34611468 PMCID: PMC8477206 DOI: 10.1016/j.jdsr.2021.08.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 02/02/2023] Open
Abstract
Multiple myeloma (Plasma cell myeloma), a malignancy of the plasma cells, exhibits tumor expansion preferentially in the bone marrow and the development of bone-destructive lesions. Multiple myeloma is still an incurable disease with changes in the bone marrow microenvironment in favor of the survival and proliferation of multiple myeloma cells and bone destruction. In this review, we described the recent findings on the regulators involved in the development of myeloma bone diseases, and succinctly summarize currently available therapeutic options and the development of novel bone modifying agents for myeloma treatment.
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22
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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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23
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Andrews RE, Brown JE, Lawson MA, Chantry AD. Myeloma Bone Disease: The Osteoblast in the Spotlight. J Clin Med 2021; 10:jcm10173973. [PMID: 34501423 PMCID: PMC8432062 DOI: 10.3390/jcm10173973] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 12/17/2022] Open
Abstract
Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.
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Affiliation(s)
- Rebecca E. Andrews
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
- Correspondence:
| | - Janet E. Brown
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
| | - Michelle A. Lawson
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
| | - Andrew D. Chantry
- Department of Oncology and Metabolism, The Medical School, The University of Sheffield, Sheffield S10 2RX, UK; (J.E.B.); (M.A.L.); (A.D.C.)
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
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24
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Lu H, Pundole X, Lee HC. The role of bone-modifying agents in myeloma bone disease. JBMR Plus 2021; 5:e10518. [PMID: 34368608 PMCID: PMC8328802 DOI: 10.1002/jbm4.10518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/13/2021] [Accepted: 05/19/2021] [Indexed: 01/23/2023] Open
Abstract
Bone disease is common in patients with multiple myeloma (MM), which manifests as bone pain and skeletal-related events (SREs) such as pathological fractures and spinal cord compression. Myeloma bone disease (MBD) can adversely affect the quality of life of patients and have negative effects on morbidity and mortality. The pathogenesis of MBD is complex, and several factors are involved in the dysregulation of bone metabolism and uncoupling of bone remodeling, which result in net bone loss and devastating SREs. Broadly speaking, elevated osteoclast activity, suppressed osteoblast activity, and an aberrant marrow microenvironment play a role in MBD. Interaction of MM cells with the main bone cell osteocytes also promote further bone destruction. This review focuses on the role of bone-modifying agents in the prevention and treatment of MBD. The mainstay of MBD prevention are antiresorptive agents, bisphosphonates and denosumab. However, these agents do not play a direct role in bone formation and repair of existing MBD. Newer agents with anabolic effects such as anti-sclerostin antibodies, parathyroid hormone, anti-Dickkopf-1 antibodies, and others have shown potential in repair of MBD lesions. With the development of several new agents, the treatment landscape of MBD is likely to evolve in the coming years. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Huifang Lu
- Department of General Internal Medicine Section of Rheumatology and Clinical Immunology Houston Texas USA
| | - Xerxes Pundole
- Department of Health Services Research The University of Texas MD Anderson Cancer Center Houston Texas USA.,Present address: Amgen Inc. Thousand Oaks CA USA
| | - Hans C Lee
- Department of Lymphoma/Myeloma The University of Texas MD Anderson Cancer Center Houston Texas USA
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25
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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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26
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Fan F, Podar K. The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology. Cancers (Basel) 2021; 13:2326. [PMID: 34066181 PMCID: PMC8151277 DOI: 10.3390/cancers13102326] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/02/2021] [Accepted: 05/06/2021] [Indexed: 12/19/2022] Open
Abstract
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.
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Affiliation(s)
- Fengjuan Fan
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China;
| | - Klaus Podar
- Department of Internal Medicine II, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria
- Molecular Oncology and Hematology Unit, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Strasse 30, 3500 Krems an der Donau, Austria
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27
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Giannakoulas N, Ntanasis-Stathopoulos I, Terpos E. The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma. Int J Mol Sci 2021; 22:ijms22094462. [PMID: 33923357 PMCID: PMC8123209 DOI: 10.3390/ijms22094462] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 12/16/2022] Open
Abstract
The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.
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Affiliation(s)
- Nikolaos Giannakoulas
- Department of Hematology of University Hospital of Larisa, Faculty of Medicine, University of Thessaly, 41110 Larisa, Greece;
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
| | - Evangelos Terpos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
- Correspondence:
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28
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Terpos E, Ntanasis-Stathopoulos I, Katodritou E, Kyrtsonis MC, Douka V, Spanoudakis E, Papatheodorou A, Eleutherakis-Papaiakovou E, Kanellias N, Gavriatopoulou M, Makras P, Kastritis E, Dimopoulos MA. Carfilzomib Improves Bone Metabolism in Patients with Advanced Relapsed/Refractory Multiple Myeloma: Results of the CarMMa Study. Cancers (Basel) 2021; 13:cancers13061257. [PMID: 33809268 PMCID: PMC7998249 DOI: 10.3390/cancers13061257] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/07/2021] [Accepted: 03/11/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Carfilzomib with dexamethasone is an important therapeutic option for patients with relapsed/refractory multiple myeloma. We sought to evaluate the effect of this regimen on the bone-related outcomes, which are associated with both quality of life and survival. Among 25 patients, less than one third experienced a new skeletal-related event during treatment, even in the absence of any bone-targeted agent. Interestingly, there was a significant decrease in serum biomarkers of bone resorption, which was at least partially due to the sRANKL/OPG ratio reduction. Furthermore, Kd produced an increase in markers of bone formation. Importantly, these changes were independent of myeloma response to treatment. Therefore, the combination of carfilzomib and dexamethasone improves bone metabolism and bone health in patients with advanced multiple myeloma. Abstract Carfilzomib with dexamethasone (Kd) is a well-established regimen for the treatment of relapsed/refractory multiple myeloma (RRMM). There is limited information for the effects of Kd on myeloma-related bone disease. This non-interventional study aimed to assess skeletal-related events (SREs) and bone metabolism in patients with RRMM receiving Kd, in the absence of any bone-targeted agent. Twenty-five patients were enrolled with a median of three prior lines of therapy; 72% of them had evidence of osteolytic bone disease at study entry. During Kd treatment, the rate of new SREs was 28%. Kd produced a clinically relevant (≥30%) decrease in C-telopeptide of collagen type-1 (p = 0.048) and of tartrate-resistant acid phosphatase-5b (p = 0.002) at 2 months. This reduction was at least partially due to the reduction in the osteoclast regulator RANKL/osteoprotegerin ratio, at 2 months (p = 0.026). Regarding bone formation, there was a clinically relevant increase in osteocalcin at 6 months (p = 0.03) and in procollagen type I N-propeptide at 8 months post-Kd initiation. Importantly, these bone metabolism changes were independent of myeloma response to treatment. In conclusion, Kd resulted in a low rate of SREs among RRMM patients, along with an early, sustained and clinically relevant decrease in bone resorption, which was accompanied by an increase in bone formation, independently of myeloma response and in the absence of any bone-targeted agent use.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
- Correspondence: ; Tel.: +30-2132162846
| | - Ioannis Ntanasis-Stathopoulos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Eirini Katodritou
- Department of Hematology, Theagenio Cancer Hospital, PS 54639 Thessaloniki, Greece;
| | - Marie-Christine Kyrtsonis
- First Department of Propedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece;
| | - Vassiliki Douka
- Department of Hematology and Bone Marrow Transplantation Unit, General Hospital “G.Papanikolaou”, PS 57010 Thessaloniki, Greece;
| | - Emmanouil Spanoudakis
- Department of Hematology, Faculty of Medicine, Democritus University of Thrace, PS 68131 Alexandroupolis, Greece;
| | - Athanasios Papatheodorou
- Department of Medical Research, 251 General Air-Force Hospital, PS 11525 Athens, Greece; (A.P.); (P.M.)
| | - Evangelos Eleutherakis-Papaiakovou
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Nikolaos Kanellias
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Polyzois Makras
- Department of Medical Research, 251 General Air-Force Hospital, PS 11525 Athens, Greece; (A.P.); (P.M.)
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, Alexandra General Hospital, School of Medicine, National and Kapodistrian University of Athens, PS 11528 Athens, Greece; (I.N.-S.); (E.E.-P.); (N.K.); (M.G.); (E.K.); (M.A.D.)
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Multiple Myeloma Bone Disease: Implication of MicroRNAs in Its Molecular Background. Int J Mol Sci 2021; 22:ijms22052375. [PMID: 33673480 PMCID: PMC7956742 DOI: 10.3390/ijms22052375] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 02/23/2021] [Accepted: 02/26/2021] [Indexed: 12/16/2022] Open
Abstract
Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD.
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Moser-Katz T, Joseph NS, Dhodapkar MV, Lee KP, Boise LH. Game of Bones: How Myeloma Manipulates Its Microenvironment. Front Oncol 2021; 10:625199. [PMID: 33634031 PMCID: PMC7900622 DOI: 10.3389/fonc.2020.625199] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma is a clonal disease of long-lived plasma cells and is the second most common hematological cancer behind Non-Hodgkin's Lymphoma. Malignant transformation of plasma cells imparts the ability to proliferate, causing harmful lesions in patients. In advanced stages myeloma cells become independent of their bone marrow microenvironment and form extramedullary disease. Plasma cells depend on a rich array of signals from neighboring cells within the bone marrow for survival which myeloma cells exploit for growth and proliferation. Recent evidence suggests, however, that both the myeloma cells and the microenvironment have undergone alterations as early as during precursor stages of the disease. There are no current therapies routinely used for treating myeloma in early stages, and while recent therapeutic efforts have improved patients' median survival, most will eventually relapse. This is due to mutations in myeloma cells that not only allow them to utilize its bone marrow niche but also facilitate autocrine pro-survival signaling loops for further progression. This review will discuss the stages of myeloma cell progression and how myeloma cells progress within and outside of the bone marrow microenvironment.
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Affiliation(s)
- Tyler Moser-Katz
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Nisha S. Joseph
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Madhav V. Dhodapkar
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
| | - Kelvin P. Lee
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, United States
| | - Lawrence H. Boise
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
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31
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Farrell M, Fairfield H, Costa S, D'Amico A, Falank C, Brooks DJ, Reagan MR. Sclerostin-Neutralizing Antibody Treatment Rescues Negative Effects of Rosiglitazone on Mouse Bone Parameters. J Bone Miner Res 2021; 36:158-169. [PMID: 32845528 PMCID: PMC8080259 DOI: 10.1002/jbmr.4170] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 08/14/2020] [Accepted: 08/19/2020] [Indexed: 12/12/2022]
Abstract
Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). in vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT's role in cancer. Overactivation of peroxisome-proliferator-activated receptor-γ (PPARγ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (eg, rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody [Scl-Ab]), which has been shown to inhibit adipogenesis, using DXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about one-half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± Scl-Ab for 4 weeks, and then rosiglitazone was discontinued and Scl-Ab or vehicle were continued for 6 weeks. Scl-Ab significantly increased bone parameters (eg, BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. Scl-Ab also overcame many negative effects of rosiglitazone (eg, effects on trabecular bone parameters, increased mineralization lag time [MLT], and decreased bone formation rate [BFR]). Interestingly, Scl-Ab significantly decreased rosiglitazone-induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone-induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT's role in tumor models. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Mariah Farrell
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.,Biology Department, University of Southern Maine, Portland, ME, USA
| | - Heather Fairfield
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.,Tufts University School of Medicine, Boston, MA, USA
| | - Samantha Costa
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.,Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA
| | - Anastasia D'Amico
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.,Biology Department, University of Southern Maine, Portland, ME, USA
| | - Carolyne Falank
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA
| | - Daniel J Brooks
- Center for Skeletal Research, Massachusetts General Hospital, Boston, MA, USA
| | - Michaela R Reagan
- Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.,Biology Department, University of Southern Maine, Portland, ME, USA.,Tufts University School of Medicine, Boston, MA, USA.,Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA
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Rummler M, Ziouti F, Bouchard AL, Brandl A, Duda GN, Bogen B, Beilhack A, Lynch ME, Jundt F, Willie BM. Mechanical loading prevents bone destruction and exerts anti-tumor effects in the MOPC315.BM.Luc model of myeloma bone disease. Acta Biomater 2021; 119:247-258. [PMID: 33130307 DOI: 10.1016/j.actbio.2020.10.041] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 10/05/2020] [Accepted: 10/27/2020] [Indexed: 02/08/2023]
Abstract
Bone continually adapts to changing external loading conditions via (re)modeling (modeling and remodeling) processes. While physical activity is known to beneficially enhance bone mass in healthy individuals, little is known in how physical stimuli affect osteolytic bone destruction in patients suffering from multiple myeloma bone disease. Multiple myeloma (MM) is caused by malignant plasma cells in the bone marrow, shifting the balance in bone remodeling towards massive resorption. We hypothesized that in vivo tibial mechanical loading has anabolic effects in mice with locally injected MOPC315.BM.Luc cells. Conventional microCT analysis revealed enhanced cortical bone mass and microstructure in loaded compared to nonloaded mice. State-of-the-art time-lapse microCT based image analysis demonstrated bone (re)modeling processes at the endosteal and periosteal surfaces as the underlying causes of increased bone mass. Loading prevented the progression and development of osteolytic destruction. Physical stimuli also diminished local MM cell growth and dissemination evidenced by quantification of MM cell-specific immunoglobulin A levels in the serum of mice and by bioluminescence analysis. These data indicate that mechanical loading not only rescues the bone phenotype, but also exerts cell-extrinsic anti-myeloma effects in the MOPC315.BM.Luc model. In conclusion, the use of physical stimuli should be further investigated as an anabolic treatment for osteolytic bone destruction in patients with MM.
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Yang N, Liu Y. The Role of the Immune Microenvironment in Bone Regeneration. Int J Med Sci 2021; 18:3697-3707. [PMID: 34790042 PMCID: PMC8579305 DOI: 10.7150/ijms.61080] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/03/2021] [Indexed: 01/08/2023] Open
Abstract
Bone is an active tissue, being constantly renewed in healthy individuals with participation of the immune system to a large extent. Any imbalance between the processes of bone formation and bone resorption is linked to various inflammatory bone diseases. The immune system plays an important role in tissue formation and bone resorption. Recently, many studies have demonstrated complex interactions between the immune and skeletal systems. Both of immune cells and cytokines contribute to the regulation of bone homeostasis, and bone cells, including osteoblasts, osteoclasts, osteocytes, also influence the cellular functions of immune cells. These crosstalk mechanisms between the bone and immune system finally emerged, forming a new field of research called osteoimmunology. Therefore, the immune microenvironment is crucial in determining the speed and outcome of bone healing, repair, and regeneration. In this review, we summarise the role of the immune microenvironment in bone regeneration from the aspects of immune cells and immune cytokines. The elucidation of immune mechanisms involved in the process of bone regeneration would provide new therapeutic targets for improving the curative effects of bone injury treatment.
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Affiliation(s)
- Ning Yang
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Yao Liu
- Department of Pediatric Dentistry, School and Hospital of Stomatology, China Medical University, Shenyang, China.,Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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Raimondi L, De Luca A, Giavaresi G, Raimondo S, Gallo A, Taiana E, Alessandro R, Rossi M, Neri A, Viglietto G, Amodio N. Non-Coding RNAs in Multiple Myeloma Bone Disease Pathophysiology. Noncoding RNA 2020; 6:ncrna6030037. [PMID: 32916806 PMCID: PMC7549375 DOI: 10.3390/ncrna6030037] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 08/27/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022] Open
Abstract
Bone remodeling is uncoupled in the multiple myeloma (MM) bone marrow niche, resulting in enhanced osteoclastogenesis responsible of MM-related bone disease (MMBD). Several studies have disclosed the mechanisms underlying increased osteoclast formation and activity triggered by the various cellular components of the MM bone marrow microenvironment, leading to the identification of novel targets for therapeutic intervention. In this regard, recent attention has been given to non-coding RNA (ncRNA) molecules, that finely tune gene expression programs involved in bone homeostasis both in physiological and pathological settings. In this review, we will analyze major signaling pathways involved in MMBD pathophysiology, and report emerging evidence of their regulation by different classes of ncRNAs.
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Affiliation(s)
- Lavinia Raimondi
- IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche–SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy; (A.D.L.); (G.G.)
- Correspondence: (L.R.); (N.A.); Tel.: +39-091-6236011 (L.R.); +39-0961-3694159 (N.A.)
| | - Angela De Luca
- IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche–SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy; (A.D.L.); (G.G.)
| | - Gianluca Giavaresi
- IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche–SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy; (A.D.L.); (G.G.)
| | - Stefania Raimondo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (S.R.); (R.A.)
| | - Alessia Gallo
- IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Research Department, 90127 Palermo, Italy;
| | - Elisa Taiana
- Department of Oncology and Hemato-oncology, University of Milan, 20122 Milan, Italy; (E.T.); (A.N.)
- Hematology, Fondazione Cà Granda IRCCS Policlinico, 20122 Milan, Italy
| | - Riccardo Alessandro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; (S.R.); (R.A.)
- Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italy
| | - Marco Rossi
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.R.); (G.V.)
| | - Antonino Neri
- Department of Oncology and Hemato-oncology, University of Milan, 20122 Milan, Italy; (E.T.); (A.N.)
- Hematology, Fondazione Cà Granda IRCCS Policlinico, 20122 Milan, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.R.); (G.V.)
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; (M.R.); (G.V.)
- Correspondence: (L.R.); (N.A.); Tel.: +39-091-6236011 (L.R.); +39-0961-3694159 (N.A.)
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Pathak JL, Bravenboer N, Klein-Nulend J. The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases. Front Endocrinol (Lausanne) 2020; 11:405. [PMID: 32733380 PMCID: PMC7360678 DOI: 10.3389/fendo.2020.00405] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/20/2020] [Indexed: 01/18/2023] Open
Abstract
Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.
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Affiliation(s)
- Janak L. Pathak
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam University Medical Centers, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jenneke Klein-Nulend
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, Amsterdam Movement Sciences, University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- *Correspondence: Jenneke Klein-Nulend
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Benetti F, Briso ALF, de Araújo Lopes JM, Carminatti M, Conti LC, Gallinari MO, Ervolino E, Cintra LTA. In vivo analysis of the presence of heme oxygenase-1, transcription factor Jun-D and CD90+/CD73+/CD105+/CD45- cells in the pulp of bleached teeth. Int Endod J 2019; 52:1723-1737. [PMID: 31322737 DOI: 10.1111/iej.13190] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 07/16/2019] [Indexed: 12/27/2022]
Abstract
AIM To investigate hydrogen peroxide (H2 O2 )-induced responsiveness in pulp cells using heme oxygenase-1 (HO-1) immunolabelling, Jun-D immunolabelling to study the effects of H2 O2 on odontoblastic differentiation and CD90+/CD73+/CD105+/CD45- cell counting for in vivo identification of mesenchymal stem cells in the pulp. METHODOLOGY The maxillary molars of 50 rats were treated with a bleaching gel (35% H2 O2 , 1 × 30 min) or placebo gel (control groups). At 2, 3, 7, 15 and 30 days after the treatment (n = 10), inflammation in pulp tissue was analysed by haematoxylin-eosin staining, HO-1- and Jun-D-immunolabelled cells were counted in each third of the pulp chamber, and the number of CD90+/CD73+/CD105+/CD45- cells was quantified by immunofluorescence. The results were assessed using the Paired t-test or Wilcoxon signed-rank test (P < 0.05). RESULTS Significant H2 O2 -induced inflammation was noted at 2 and 3 days (P < 0.05), with tertiary dentine formation occurring from 7 days. The bleached specimens had greater HO-1 immunolabelling in the middle and cervical thirds of the coronal pulp at 2 and 3 days, in all thirds at 7 days, and in the occlusal third at 15 days (P < 0.05), and significant nuclear Jun-D immunolabelling in the cervical third at 2 and 3 days and in the occlusal and middle thirds at 7 days (P < 0.05). Bleached and control groups had low numbers of CD90+/CD73+/CD105+/CD45- cells in the pulp at all periods (P > 0.05). CONCLUSIONS Pulp cells responded to oxidative stress by expressing HO-1 during the post-bleaching inflammation phase until the beginning of the repair phase. Jun-D expression occurred during the reduction of inflammation and the beginning of tertiary dentine production. The presence of oxidative stress did not influence the number of CD90+/CD73+/CD105+/CD45- cells identified in vivo in the dental pulp.
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Affiliation(s)
- F Benetti
- Department of Endodontics, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil.,Department of Restorative Dentistry, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - A L F Briso
- Department of Restorative Dentistry, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
| | - J M de Araújo Lopes
- Department of Endodontics, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
| | - M Carminatti
- Department of Endodontics, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
| | - L C Conti
- Department of Endodontics, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
| | - M O Gallinari
- Department of Restorative Dentistry, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
| | - E Ervolino
- Department of Basic Science, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
| | - L T A Cintra
- Department of Endodontics, School of Dentistry, São Paulo State University (UNESP), Araçatuba, SP, Brazil
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Kleber M, Ntanasis-Stathopoulos I, Dimopoulos MA, Terpos E. Monoclonal antibodies against RANKL and sclerostin for myeloma-related bone disease: can they change the standard of care? Expert Rev Hematol 2019; 12:651-663. [PMID: 31268745 DOI: 10.1080/17474086.2019.1640115] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: Over 80% of the patients with multiple myeloma (MM) develop myeloma bone disease (MBD) during the disease course. The clinical consequences include serious skeletal-related events (SRE) that impact survival and quality of life. Bisphosphonates are the mainstay in the treatment of MBD. Currently, new therapeutic strategies are being introduced and broaden the therapeutic options in MBD. Areas covered: The purpose of this review is to summarize the current clinical management of MBD and present novel data regarding monoclonal antibodies against the receptor activator of NF-kappa B ligand (RANKL) and sclerostin that may change the clinical practice. Expert opinion: Our better understanding of the pathophysiology of MBD has identified several factors as potential therapeutic targets. Recent data have shown that the RANKL inhibitor denosumab constitutes a new promising option. The non-inferiority compared with bisphosphonates in terms of SRE prevention, the potential survival benefit, the convenience of subcutaneous administration, and the favorable toxicity profile makes denosumab a valuable alternative for physicians in the current treatment of MBD. Anti-sclerostin antibodies are currently under clinical development. Further investigations are needed to address open questions in the field including the value of anabolic agents combined with anti-resorptive and anti-MM drugs in MBD.
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Affiliation(s)
- Martina Kleber
- a Division of Hematology, Department of Medicine, University Hospital Basel , Basel , Switzerland.,b Division of Internal Medicine, Department of Medicine, University Hospital Basel , Basel , Switzerland
| | - Ioannis Ntanasis-Stathopoulos
- c Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens , Athens , Greece
| | - Meletios A Dimopoulos
- c Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens , Athens , Greece
| | - Evangelos Terpos
- c Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens , Athens , Greece
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Abstract
STUDY DESIGN In vitro experimental study. OBJECTIVE To investigate the impact of increased osteoblastic activity on the proliferation and survival of multiple myeloma (MM) plasma cells in vitro SUMMARY OF BACKGROUND DATA.: MM is one of representative hematologic malignancies that cause skeletal-related events (SREs) and dysregulation of bone remodeling is known as a key pathomechanism of disease progression and skeletal-related events. However, decreased proliferation of MM at fracture sites is frequently noted in clinical situations regardless of systemic disease activity. METHODS Co-culture under various conditions was used to investigate effects of increased osteoblastic activity on survival and proliferation of MM plasma cells. MM plasma cells were cultured in culture media (control) and co-cultured with human mesenchymal stem cells (hMSCs, group I), osteoblasts (OBs) induced from hMSCs (group II) or bone morphogenic protein-2 (BMP-2, group III). Proliferation measured as extracellular signal-regulated kinase (ERK) and immunoglobulin G (Ig G) expression and apoptosis measured as fluorescence-activated cell sorting (FACS) with annexin V method, caspase-3, and stat-3 expression were assessed for cultured MM plasma cells, along with expression of sclerostin. RESULTS After 72 hours of co-culture, group II and III showed decreased ERK expression compared with controls. Lower Ig G expression was also noted for groups II and III compared with controls. Group I did not show significantly decreased Ig G and ERK expression compared with controls. Expressions of caspase-3 in groups II and III were higher than controls. Co-culture with hMSCs showed decreased caspase-3 expression compared with control. FACS with annexin V showed higher apoptosis in groups II and III. Sclerostin expression was also decreased in osteoblastic conditions compared with the control and hMSCs co-culture condition. CONCLUSION Collectively, our data suggest that increased osteoblastic conditions may provide not only prevention of SREs but also anti-tumor effects on MM cells in the bone marrow environment. LEVEL OF EVIDENCE N/A.
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Atkinson EG, Delgado‐Calle J. The Emerging Role of Osteocytes in Cancer in Bone. JBMR Plus 2019; 3:e10186. [PMID: 30918922 PMCID: PMC6419608 DOI: 10.1002/jbm4.10186] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/29/2019] [Accepted: 02/06/2019] [Indexed: 12/13/2022] Open
Abstract
Advances in the last decade have established the osteocyte, the most abundant cell in bone, as a dynamic and multifunctional cell capable of controlling bone homeostasis by regulating the function of both osteoblasts and osteoclasts. In addition, accumulating evidence demonstrates that osteocyte function is altered in several skeletal disorders, and targeting osteocytes and their derived factors improves skeletal health. Despite the remarkable progress in our understanding of osteocyte biology, there has been a paucity of information regarding the role of osteocytes in the progression of cancer in bone. Exciting, recent discoveries suggest that tumor cells communicate with osteocytes to generate a microenvironment that supports the growth and survival of cancer cells and stimulates bone destruction. This review features these novel findings and discussions regarding the impact of chemotherapy on osteocyte function and the potential of targeting osteocytes for the treatment of cancer in bone. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Emily G Atkinson
- Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisINUSA
| | - Jesús Delgado‐Calle
- Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisINUSA
- Department of MedicineDivision of Hematology/OncologyIndiana University School of MedicineIndianapolisINUSA
- Indiana Center for Musculoskeletal HealthIndiana University School of MedicineIndianapolisINUSA
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van Andel H, Kocemba KA, Spaargaren M, Pals ST. Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options. Leukemia 2019; 33:1063-1075. [PMID: 30770859 PMCID: PMC6756057 DOI: 10.1038/s41375-019-0404-1] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 01/06/2023]
Abstract
Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.
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Affiliation(s)
- Harmen van Andel
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands
| | - Kinga A Kocemba
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands
| | - Marcel Spaargaren
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.,Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands
| | - Steven T Pals
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. .,Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
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41
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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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Holdsworth G, Roberts SJ, Ke HZ. Novel actions of sclerostin on bone. J Mol Endocrinol 2019; 62:R167-R185. [PMID: 30532996 DOI: 10.1530/jme-18-0176] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/17/2018] [Indexed: 12/11/2022]
Abstract
The discovery that two rare autosomal recessive high bone mass conditions were caused by the loss of sclerostin expression prompted studies into its role in bone homeostasis. In this article, we aim to bring together the wealth of information relating to sclerostin in bone though discussion of rare human disorders in which sclerostin is reduced or absent, sclerostin manipulation via genetic approaches and treatment with antibodies that neutralise sclerostin in animal models and in human. Together, these findings demonstrate the importance of sclerostin as a regulator of bone homeostasis and provide valuable insights into its biological mechanism of action. We summarise the current state of knowledge in the field, including the current understanding of the direct effects of sclerostin on the canonical WNT signalling pathway and the actions of sclerostin as an inhibitor of bone formation. We review the effects of sclerostin, and its inhibition, on bone at the cellular and tissue level and discuss new findings that suggest that sclerostin may also regulate adipose tissue. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of sclerostin.
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Affiliation(s)
| | | | - Hua Zhu Ke
- Bone Therapeutic Area, UCB Pharma, Slough, United Kingdom
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43
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Abramson HN. Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update. Int J Mol Sci 2018; 19:E3924. [PMID: 30544512 PMCID: PMC6321340 DOI: 10.3390/ijms19123924] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/22/2018] [Accepted: 12/05/2018] [Indexed: 12/14/2022] Open
Abstract
The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development.
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Affiliation(s)
- Hanley N Abramson
- Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA.
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Toscani D, Bolzoni M, Ferretti M, Palumbo C, Giuliani N. Role of Osteocytes in Myeloma Bone Disease: Anti-sclerostin Antibody as New Therapeutic Strategy. Front Immunol 2018; 9:2467. [PMID: 30410490 PMCID: PMC6209728 DOI: 10.3389/fimmu.2018.02467] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 10/05/2018] [Indexed: 11/16/2022] Open
Abstract
Osteocytes are terminally differentiated cells of the osteoblast lineage. They are involved in the regulation of bone remodeling by increasing osteoclast formation or decreasing bone formation by the secretion of the osteoblast inhibitor sclerostin. Monoclonal antibody anti-sclerostin, Romosozumab, has been developed and tested in clinical trials in patients with osteoporosis. In the last years, the role of osteocytes in the development of osteolytic bone lesions that occurs in multiple myeloma, have been underlined. Myeloma cells increase osteocyte death through the up-regulation of both apoptosis and autophagy that, in turn, triggers osteoclast formation, and activity. When compared to healthy controls, myeloma patients with bone disease have higher osteocyte cell death, but the treatment with proteasome inhibitor bortezomib has been shown to maintain osteocyte viability. In preclinical mouse models of multiple myeloma, treatment with blocking anti-sclerostin antibody increased osteoblast numbers and bone formation rate reducing osteolytic bone lesions. Moreover, the combination of anti-sclerostin antibody and the osteoclast inhibitor zoledronic acid increased bone mass and fracture resistance synergistically. However, anti-sclerostin antibody did not affect tumor burden in vivo or the efficacy of anti-myeloma drugs in vitro. Nevertheless, the combination therapy of anti-sclerostin antibody and the proteasome inhibitor carfilzomib, displayed potent anti-myeloma activity as well as positive effects on bone disease in vivo. In conclusion, all these data suggest that osteocytes are involved in myeloma bone disease and may be considered a novel target for the use of antibody-mediated anti-sclerostin therapy also in multiple myeloma patients.
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Affiliation(s)
- Denise Toscani
- Department Medicine and Surgery, University of Parma, Parma, Italy
| | - Marina Bolzoni
- Department Medicine and Surgery, University of Parma, Parma, Italy
| | - Marzia Ferretti
- Department of Biomedical, Metabolic and Neural Sciences, Human Morphology Section, University of Modena and Reggio Emilia, Modena, Italy
| | - Carla Palumbo
- Department of Biomedical, Metabolic and Neural Sciences, Human Morphology Section, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicola Giuliani
- Department Medicine and Surgery, University of Parma, Parma, Italy
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Abstract
Multiple myeloma (MM) is the second-most-common hematologic malignancy and the most frequent cancer to involve bone. MM bone disease (MMBD) has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact survival of MM patients. MMBD results from excessive osteoclastic bone resorption and persistent suppressed osteoblastic bone formation, causing lytic lesions that do not heal, even when patients are in complete and prolonged remission. This review discusses the cellular and molecular mechanisms that regulate the uncoupling of bone remodeling in MM, the effects of MMBD on tumor growth, and potential therapeutic approaches that may prevent severe bone loss and repair damaged bone in MM patients.
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Affiliation(s)
- Silvia Marino
- Department of Medicine, Division Hematology Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - G David Roodman
- Department of Medicine, Division Hematology Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202
- Roudebush VA Medical Center, Indianapolis, Indiana 46202
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Terpos E, Christoulas D, Gavriatopoulou M. Biology and treatment of myeloma related bone disease. Metabolism 2018; 80:80-90. [PMID: 29175022 DOI: 10.1016/j.metabol.2017.11.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 11/16/2017] [Accepted: 11/18/2017] [Indexed: 02/08/2023]
Abstract
Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM), resulting in skeleton-related events (SREs) such as severe bone pain, pathologic fractures, vertebral collapse, hypercalcemia, and spinal cord compression that cause significant morbidity and mortality. It is due to an increased activity of osteoclasts coupled to the suppressed bone formation by osteoblasts. Novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition have recently been described, including the receptor activator of nuclear factor-kB ligand/osteoprotegerin pathway, activin-A and the wingless-type signaling inhibitors, dickkopf-1 (DKK-1) and sclerostin. These molecules interfere with tumor growth and survival, providing possible targets for the development of novel drugs for the management of lytic disease in myeloma but also for the treatment of MM itself. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease although several novel agents such as denosumab and sotatercept appear promising. This review focuses on recent advances in MBD pathophysiology and treatment, in addition to the established therapeutic guidelines.
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Affiliation(s)
- Evangelos Terpos
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece.
| | - Dimitrios Christoulas
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
| | - Maria Gavriatopoulou
- Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
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Sousa S, Clézardin P. Bone-Targeted Therapies in Cancer-Induced Bone Disease. Calcif Tissue Int 2018; 102:227-250. [PMID: 29079995 DOI: 10.1007/s00223-017-0353-5] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 10/19/2017] [Indexed: 01/14/2023]
Abstract
Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve disease-free, overall survival and quality of life of cancer patients with bone metastases. Depending of the cancer-type, bone metastases mainly involve the modulation of osteoclast and/or osteoblast activity by tumour cells. To inhibit metastatic bone disease effectively, it is imperative to understand its underlying mechanisms and identify the target cells for therapy. If the aim is to prevent bone metastasis, it is essential to target not only bone metastatic features in the tumour cells, but also tumour-nurturing bone microenvironment properties. The currently available bone-targeted agents mainly affect osteoclasts, inhibiting bone resorption (e.g. bisphosphonates, denosumab). Some agents targeting osteoblasts begin to emerge which target osteoblasts (e.g. romosozumab), activating bone formation. Moreover, certain drugs initially thought to target only osteoclasts are now known to have a dual action (activating osteoblasts and inhibiting osteoclasts, e.g. proteasome inhibitors). This review will focus on the evolution of bone-targeted therapies for the treatment of cancer-induced bone disease, summarizing preclinical and clinical findings obtained with anti-resorptive and bone anabolic therapies.
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Affiliation(s)
- Sofia Sousa
- National Institute of Health and Medical Research (INSERM), UMR 1033, 69372, Lyon, France.
- Faculty of Medicine Laennec, University of Lyon-1, 69372, Villeurbanne, France.
| | - Philippe Clézardin
- National Institute of Health and Medical Research (INSERM), UMR 1033, 69372, Lyon, France
- Faculty of Medicine Laennec, University of Lyon-1, 69372, Villeurbanne, France
- European Cancer and Bone Metastasis Laboratory, Department of Bone Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK
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48
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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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49
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Adamik J, Silbermann R, Marino S, Sun Q, Anderson JL, Zhou D, Xie XQ, Roodman GD, Galson DL. XRK3F2 Inhibition of p62-ZZ Domain Signaling Rescues Myeloma-Induced GFI1-Driven Epigenetic Repression of the Runx2 Gene in Pre-osteoblasts to Overcome Differentiation Suppression. Front Endocrinol (Lausanne) 2018; 9:344. [PMID: 30008697 PMCID: PMC6033965 DOI: 10.3389/fendo.2018.00344] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 06/07/2018] [Indexed: 01/05/2023] Open
Abstract
Multiple myeloma bone disease (MMBD) is characterized by non-healing lytic bone lesions that persist even after a patient has achieved a hematologic remission. We previously reported that p62 (sequestosome-1) in bone marrow stromal cells (BMSC) is critical for the formation of MM-induced signaling complexes that mediate OB suppression. Importantly, XRK3F2, an inhibitor of the p62-ZZ domain, blunted MM-induced Runx2 suppression in vitro, and induced new bone formation and remodeling in the presence of tumor in vivo. Additionally, we reported that MM cells induce the formation of repressive chromatin on the Runx2 gene in BMSC via direct binding of the transcriptional repressor GFI1, which recruits the histone modifiers, histone deacetylase 1 (HDAC1) and Enhancer of zeste homolog 2 (EZH2). In this study we investigated the mechanism by which blocking p62-ZZ domain-dependent signaling prevents MM-induced suppression of Runx2 in BMSC. XRK3F2 prevented MM-induced upregulation of Gfi1 and repression of the Runx2 gene when present in MM-preOB co-cultures. We also show that p62-ZZ-domain blocking by XRK3F2 also prevented MM conditioned media and TNF plus IL7-mediated Gfi1 mRNA upregulation and the concomitant Runx2 repression, indicating that XRK3F2's prevention of p62-ZZ domain signaling within preOB is involved in the response. Chromatin immunoprecipitation (ChIP) analyses revealed that XRK3F2 decreased MM-induced GFI1 occupancy at the Runx2-P1 promoter and prevented recruitment of HDAC1, thus preserving the transcriptionally permissive chromatin mark H3K9ac on Runx2 and allowing osteogenic differentiation. Furthermore, treatment of MM-exposed preOB with XRK3F2 after MM removal decreased GFI1 enrichment at Runx2-P1 and rescued MM-induced suppression of Runx2 mRNA and its downstream osteogenic gene targets together with increased osteogenic differentiation. Further, primary BMSC (hBMSC) from MM patients (MM-hBMSC) had little ability to increase H3K9ac on the Runx2 promoter in osteogenic conditions when compared to hBMSC from healthy donors (HD). XRK3F2 treatment enriched Runx2 gene H3K9ac levels in MM-hBMSC to the level observed in HD-hBMSC, but did not alter HD-hBMSC H3K9ac. Importantly, XRK3F2 treatment of long-term MM-hBMSC cultures rescued osteogenic differentiation and mineralization. Our data show that blocking p62-ZZ domain-dependent signaling with XRK3F2 can reverse epigenetic-based mechanisms of MM-induced Runx2 suppression and promote osteogenic differentiation.
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Affiliation(s)
- Juraj Adamik
- Division of Hematology/Oncology, Department of Medicine, UPMC Hillman Cancer Center, The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Rebecca Silbermann
- Division of Hematology-Oncology, Department of Medicine, Indiana University, Indianapolis, IN, United States
- Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States
| | - Silvia Marino
- Division of Hematology-Oncology, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Quanhong Sun
- Division of Hematology/Oncology, Department of Medicine, UPMC Hillman Cancer Center, The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Judith L. Anderson
- Division of Hematology-Oncology, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Dan Zhou
- Division of Hematology-Oncology, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Xiang-Qun Xie
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States
| | - G. David Roodman
- Division of Hematology-Oncology, Department of Medicine, Indiana University, Indianapolis, IN, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
| | - Deborah L. Galson
- Division of Hematology/Oncology, Department of Medicine, UPMC Hillman Cancer Center, The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- *Correspondence: Deborah L. Galson ;
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50
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Abstract
PURPOSE OF REVIEW This review provides a summary of the current knowledge on Sost/sclerostin in cancers targeting the bone, discusses novel observations regarding its potential as a therapeutic approach to treat cancer-induced bone loss, and proposes future research needed to fully understand the potential of therapeutic approaches that modulate sclerostin function. RECENT FINDINGS Accumulating evidence shows that sclerostin expression is dysregulated in a number of cancers that target the bone. Further, new findings demonstrate that pharmacological inhibition of sclerostin in preclinical models of multiple myeloma results in a robust prevention of bone loss and preservation of bone strength, without apparent effects on tumor growth. These data raise the possibility of targeting sclerostin for the treatment of cancer patients with bone metastasis. Sclerostin is emerging as a valuable target to prevent the bone destruction that accompanies the growth of cancer cells in the bone. Further studies will focus on combining anti-sclerostin therapy with tumor-targeted agents to achieve both beneficial skeletal outcomes and inhibition of tumor progression.
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Affiliation(s)
- Michelle M McDonald
- The Garvan Institute of Medical Research, Sydney, Australia
- St. Vincent's School of Medicine, University of New South Wales, Sydney, Australia
| | - Jesus Delgado-Calle
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA.
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