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Yue H, Ye H, Ruan R, Du H, Li C. Identification of ActivinβA and Gonadotropin Regulation of the Activin System in the Ovary of Chinese Sturgeon Acipenser sinensis. Animals (Basel) 2024; 14:2314. [PMID: 39199851 PMCID: PMC11350771 DOI: 10.3390/ani14162314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Activin is a dimeric growth factor with diverse biological activities in vertebrates. This study aimed to investigate the regulatory role of the activin signaling pathway in the ovary of the endangered, cultured sturgeon species Acipenser sinensis. One activinβA subunit was identified, with a full-length complementary DNA (cDNA) sequence of 1572 base pairs. Multiple sequence alignment suggested that ActivinβA shared high sequence identities with its counterparts in four other sturgeon species. Phylogenetic analysis indicated the conserved evolution of ActivinβA among vertebrates from mammals to fish species. Transcripts of activinβA were distributed ubiquitously in the liver, kidney, intestine, ovary, midbrain, hypothalamus, and pituitary, with the highest transcription found in the pituitary. In Chinese sturgeon ovarian cells, in vitro human recombinant Activin A incubation stimulated the activin system-related gene transcriptions of activinβA, follistatin, its receptors -activinRIIA and activinRIIB, and drosophila mothers against decapentaplegic proteins (smads) smad2, smad3, and smad4. Ovary development-related mRNA levels of cyp19a1a and aromatase receptors of erα and erβ were enhanced by Activin A or human chorionic gonadotropin (hCG) incubation. Furthermore, 15 IU/mL hCG treatment increased the transcription levels of activinβA, follistatin, activinRIIA, and smad2. This suggested that the activin system was functional for the regulation of ovary development in Chinese sturgeon, possibly under the regulation of gonadotropin, by recruiting activinβA, follistatin, activinRIIA, and smad2. These results were helpful for the molecular exploration of activin signaling in fish species, as well as the ovarian maturation regulation of A. sinensis.
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Affiliation(s)
| | | | | | | | - Chuangju Li
- Key Laboratory of Freshwater Biodiversity Conservation, Ministry of Agriculture and Rural Affairs of China, Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China; (H.Y.)
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2
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Mou K, Chan SMH, Vlahos R. Musculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials. Pharmacol Ther 2024; 257:108635. [PMID: 38508342 DOI: 10.1016/j.pharmthera.2024.108635] [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: 11/06/2023] [Revised: 02/13/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a multifaceted respiratory disorder characterized by progressive airflow limitation and systemic implications. It has become increasingly apparent that COPD exerts its influence far beyond the respiratory system, extending its impact to various organ systems. Among these, the musculoskeletal system emerges as a central player in both the pathogenesis and management of COPD and its associated comorbidities. Muscle dysfunction and osteoporosis are prevalent musculoskeletal disorders in COPD patients, leading to a substantial decline in exercise capacity and overall health. These manifestations are influenced by systemic inflammation, oxidative stress, and hormonal imbalances, all hallmarks of COPD. Recent research has uncovered an intricate interplay between COPD and musculoskeletal comorbidities, suggesting that muscle and bone tissues may cross-communicate through the release of signalling molecules, known as "myokines" and "osteokines". We explored this dynamic relationship, with a particular focus on the role of the immune system in mediating the cross-communication between muscle and bone in COPD. Moreover, we delved into existing and emerging therapeutic strategies for managing musculoskeletal disorders in COPD. It underscores the development of personalized treatment approaches that target both the respiratory and musculoskeletal aspects of COPD, offering the promise of improved well-being and quality of life for individuals grappling with this complex condition. This comprehensive review underscores the significance of recognizing the profound impact of COPD on the musculoskeletal system and its comorbidities. By unravelling the intricate connections between these systems and exploring innovative treatment avenues, we can aspire to enhance the overall care and outcomes for COPD patients, ultimately offering hope for improved health and well-being.
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Affiliation(s)
- Kevin Mou
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Stanley M H Chan
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia
| | - Ross Vlahos
- Centre for Respiratory Science and Health, School of Health & Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
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3
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Williams MJ, Halabi CM, Patel HM, Joseph Z, McCommis K, Weinheimer C, Kovacs A, Lima F, Finck B, Malluche H, Hruska KA. In chronic kidney disease altered cardiac metabolism precedes cardiac hypertrophy. Am J Physiol Renal Physiol 2024; 326:F751-F767. [PMID: 38385175 PMCID: PMC11386984 DOI: 10.1152/ajprenal.00416.2023] [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: 12/22/2023] [Revised: 02/15/2024] [Accepted: 02/15/2024] [Indexed: 02/23/2024] Open
Abstract
Conduit arterial disease in chronic kidney disease (CKD) is an important cause of cardiac complications. Cardiac function in CKD has not been studied in the absence of arterial disease. In an Alport syndrome model bred not to have conduit arterial disease, mice at 225 days of life (dol) had CKD equivalent to humans with CKD stage 4-5. Parathyroid hormone (PTH) and FGF23 levels were one log order elevated, circulating sclerostin was elevated, and renal activin A was strongly induced. Aortic Ca levels were not increased, and vascular smooth muscle cell (VSMC) transdifferentiation was absent. The CKD mice were not hypertensive, and cardiac hypertrophy was absent. Freshly excised cardiac tissue respirometry (Oroboros) showed that ADP-stimulated O2 flux was diminished from 52 to 22 pmol/mg (P = 0.022). RNA-Seq of cardiac tissue from CKD mice revealed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. To examine the effect of activin A signaling, some Alport mice were treated with a monoclonal Ab to activin A or an isotype-matched IgG beginning at 75 days of life until euthanasia. Treatment with the activin A antibody (Ab) did not affect cardiac oxidative phosphorylation. However, the activin A antibody was active in the skeleton, disrupting the effect of CKD to stimulate osteoclast number, eroded surfaces, and the stimulation of osteoclast-driven remodeling. The data reported here show that cardiac mitochondrial respiration is impaired in CKD in the absence of conduit arterial disease. This is the first report of the direct effect of CKD on cardiac respiration.NEW & NOTEWORTHY Heart disease is an important morbidity of chronic kidney disease (CKD). Hypertension, vascular stiffness, and vascular calcification all contribute to cardiac pathophysiology. However, cardiac function in CKD devoid of vascular disease has not been studied. Here, in an animal model of human CKD without conduit arterial disease, we analyze cardiac respiration and discover that CKD directly impairs cardiac mitochondrial function by decreasing oxidative phosphorylation. Protection of cardiac oxidative phosphorylation may be a therapeutic target in CKD.
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Affiliation(s)
- Matthew J Williams
- Renal Division, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Carmen M Halabi
- Renal Division, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Hiral M Patel
- Renal Division, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Zachary Joseph
- Renal Division, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Kyle McCommis
- Geriatrics and Nutritional Science Division, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Carla Weinheimer
- Cardiology Division, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Attila Kovacs
- Cardiology Division, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Florence Lima
- Renal Division, Department of Medicine, University of Kentucky, Lexington, Kentucky, United States
| | - Brian Finck
- Geriatrics and Nutritional Science Division, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
| | - Hartmut Malluche
- Renal Division, Department of Medicine, University of Kentucky, Lexington, Kentucky, United States
| | - Keith A Hruska
- Renal Division, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, United States
- Renal Division, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
- Department of Cell Biology, Washington University in St. Louis, St. Louis, Missouri, United States
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4
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Riccardi F, Tangredi C, Dal Bo M, Toffoli G. Targeted therapy for multiple myeloma: an overview on CD138-based strategies. Front Oncol 2024; 14:1370854. [PMID: 38655136 PMCID: PMC11035824 DOI: 10.3389/fonc.2024.1370854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 03/28/2024] [Indexed: 04/26/2024] Open
Abstract
Multiple myeloma (MM) is an incurable hematological disease characterized by the uncontrolled growth of plasma cells primarily in the bone marrow. Although its treatment consists of the administration of combined therapy regimens mainly based on immunomodulators and proteosome inhibitors, MM remains incurable, and most patients suffer from relapsed/refractory disease with poor prognosis and survival. The robust results achieved by immunotherapy targeting MM-associated antigens CD38 and CD319 (also known as SLAMF7) have drawn attention to the development of new immune-based strategies and different innovative compounds in the treatment of MM, including new monoclonal antibodies, antibody-drug conjugates, recombinant proteins, synthetic peptides, and adaptive cellular therapies. In this context, Syndecan1 (CD138 or SDC1), a transmembrane heparan sulfate proteoglycan that is upregulated in malignant plasma cells, has gained increasing attention in the panorama of MM target antigens, since its key role in MM tumorigenesis, progression and aggressiveness has been largely reported. Here, our aim is to provide an overview of the most important aspects of MM disease and to investigate the molecular functions of CD138 in physiologic and malignant cell states. In addition, we will shed light on the CD138-based therapeutic approaches currently being tested in preclinical and/or clinical phases in MM and discuss their properties, mechanisms of action and clinical applications.
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Affiliation(s)
- Federico Riccardi
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
| | - Carmela Tangredi
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
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Elsheikh AA, Shalaby AM, Alabiad MA, Abd-Almotaleb NA, Alorini M, Alnasser SM, Elhasadi I, El-Nagdy SA. Trigonelline Chloride Ameliorated Triphenyltin-Induced Testicular Autophagy, Inflammation, and Apoptosis: Role of Recovery. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2024; 30:133-150. [PMID: 38156731 DOI: 10.1093/micmic/ozad137] [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: 08/23/2023] [Revised: 11/17/2023] [Accepted: 11/24/2023] [Indexed: 01/03/2024]
Abstract
Triphenyltin chloride (TPT-Cl) is an organometallic organotin. This study aimed to investigate the role of trigonelline (TG) along with the impact of TPT withdrawal on the testicular toxicity induced by TPT-Cl. Thirty-six adult male albino rats were divided into control, TG (40 mg/kg/day), TPT-Cl (0.5 mg/kg/day), TG + TPT-Cl, and recovery groups. Animals were daily gavaged for 12 weeks. Both TG and TPT-Cl withdrawal improved TPT-Cl-induced testicular toxicity features involving testis and relative testis weight reduction, luteinizing hormone, follicular stimulating hormone, and sex hormone-binding globulin elevation, reduction of inhibin B, free testosterone levels, and sperm count reduction with increased abnormal sperm forms. Moreover, both TG and TPT-Cl withdrawal reduced inflammatory activin A, follistatin, tumor necrosis factor α, interleukin-1β, and proapoptotic Bax and elevated antiapoptotic Bcl2 in testicular tissues mediated by TPT-Cl. TG and TPT-Cl withdrawal restored the excessive autophagy triggered by TPT-Cl via elevation of mTOR, AKT, PI3K, and P62/SQSTM1 and reduction of AMPK, ULK1, Beclin1, and LC3 mRNA gene expressions and regained the deteriorated testicular structure. In conclusion, TG and TPT-Cl withdrawal had an ameliorative role in partially reversing TPT-Cl-induced testicular toxicity. However, the findings indicated that the use of TG as an adjunctive factor is more favorable than TPT-Cl withdrawal, suggesting the capability of the testis for partial self-improvement.
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Affiliation(s)
- Arwa A Elsheikh
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Amany Mohamed Shalaby
- Histology and Cell Biology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
| | - Mohamed Ali Alabiad
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Noha Ali Abd-Almotaleb
- Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mohammed Alorini
- Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah 51911, Saudi Arabia
| | - Sulaiman Mohammed Alnasser
- Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Buraydah 51911, Saudi Arabia
| | - Ibtesam Elhasadi
- Department of Pathology, Faculty of Medicine, University of Benghazi, Benghazi, Libya
| | - Samah A El-Nagdy
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
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Almuradova E, Cicin I. Cancer-related hypercalcemia and potential treatments. Front Endocrinol (Lausanne) 2023; 14:1039490. [PMID: 37033238 PMCID: PMC10073684 DOI: 10.3389/fendo.2023.1039490] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 03/13/2023] [Indexed: 04/11/2023] Open
Abstract
Cancer-related hypercalcemia is a common finding typically seen in patients with advanced cancer and occurs in about 20 to 30 percent of cases. The most common cause of hypercalcemia in hospitalized patients is hypercalcemia due to malignancy.This clinical problem is seen in patients with both solid tumors and patients with hematologic malignancies. Hypercalcemia is associated with a poor prognosis in oncology patients. This pathologic condition can occur due to many different mechanisms but is usually caused by abnormal calcium use resulting from bone resorption, intestinal absorption, or renal excretion. Hypercalcemia may present with a wide range of symptoms ranging from gastrointestinal system symptoms to neurologic symptoms. Timely diagnosis and initiation of treatment by the physician significantly reduce the risk of complications. Treatment aims to decrease serum calcium by increasing calciuresis, decreasing bone resorption, and decreasing intestinal calcium absorption. The mainstays of treatment are IV hydration, bisphosphonates and calcitonin, denosumab, and in some patients, prednisone, and cinacalcet. Patients with underlying advanced kidney disease and refractory severe hypercalcemia should be evaluated for hemodialysis. Every physician dealing with oncology patients should know the fastest and most effective management of hypercalcemia. We aimed to contribute in this sense.
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Affiliation(s)
| | - Irfan Cicin
- Medical Oncology Department, Faculty of Medicine, Trakya University, Trakya, Türkiye
- *Correspondence: Irfan Cicin,
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7
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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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8
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Waltereit-Kracke V, Wehmeyer C, Beckmann D, Werbenko E, Reinhardt J, Geers F, Dienstbier M, Fennen M, Intemann J, Paruzel P, Korb-Pap A, Pap T, Dankbar B. Deletion of activin A in mesenchymal but not myeloid cells ameliorates disease severity in experimental arthritis. Ann Rheum Dis 2022; 81:1106-1118. [PMID: 35418478 PMCID: PMC9279851 DOI: 10.1136/annrheumdis-2021-221409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 04/06/2022] [Indexed: 12/03/2022]
Abstract
OBJECTIVE The aim of this study was to assess the extent and the mechanism by which activin A contributes to progressive joint destruction in experimental arthritis and which activin A-expressing cell type is important for disease progression. METHODS Levels of activin A in synovial tissues were evaluated by immunohistochemistry, cell-specific expression and secretion by PCR and ELISA, respectively. Osteoclast (OC) formation was assessed by tartrat-resistant acid phosphatase (TRAP) staining and activity by resorption assay. Quantitative assessment of joint inflammation and bone destruction was performed by histological and micro-CT analysis. Immunoblotting was applied for evaluation of signalling pathways. RESULTS In this study, we demonstrate that fibroblast-like synoviocytes (FLS) are the main producers of activin A in arthritic joints. Most significantly, we show for the first time that deficiency of activin A in arthritic FLS (ActβAd/d ColVI-Cre) but not in myeloid cells (ActβAd/d LysM-Cre) reduces OC development in vitro, indicating that activin A promotes osteoclastogenesis in a paracrine manner. Mechanistically, activin A enhanced OC formation and activity by promoting the interaction of activated Smad2 with NFATc1, the key transcription factor of osteoclastogenesis. Consistently, ActβAd/d LysM-Cre hTNFtg mice did not show reduced disease severity, whereas deficiency of activin A in ColVI-Cre-expressing cells such as FLS highly diminished joint destruction reflected by less inflammation and less bone destruction. CONCLUSIONS The results highly suggest that FLS-derived activin A plays a crucial paracrine role in inflammatory joint destruction and may be a promising target for treating inflammatory disorders associated with OC formation and bone destruction like rheumatoid arthritis.
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Affiliation(s)
- Vanessa Waltereit-Kracke
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Corinna Wehmeyer
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Denise Beckmann
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Eugenie Werbenko
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Julia Reinhardt
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Fabienne Geers
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Mike Dienstbier
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Michelle Fennen
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Johanna Intemann
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Peter Paruzel
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Adelheid Korb-Pap
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Thomas Pap
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
| | - Berno Dankbar
- Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Nordrhein-Westfalen, Germany
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9
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Schwestermann J, Besse A, Driessen C, Besse L. Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors. Front Oncol 2022; 12:899272. [PMID: 35692781 PMCID: PMC9178120 DOI: 10.3389/fonc.2022.899272] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Virtually all patients with multiple myeloma become unresponsive to treatment with proteasome inhibitors over time. Relapsed/refractory multiple myeloma is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations, diverse proteomic and metabolic alterations, and profound changes of the bone marrow microenvironment. However, the molecular mechanisms that drive resistance to proteasome inhibitors within the context of the bone marrow microenvironment remain elusive. In this review article, we summarize the latest knowledge about the complex interaction of malignant plasma cells with its surrounding microenvironment. We discuss the pivotal role of metabolic reprograming of malignant plasma cells within the tumor microenvironment with a subsequent focus on metabolic rewiring in plasma cells upon treatment with proteasome inhibitors, driving multiple ways of adaptation to the treatment. At the same time, mutual interaction of plasma cells with the surrounding tumor microenvironment drives multiple metabolic alterations in the bone marrow. This provides a tumor-promoting environment, but at the same time may offer novel therapeutic options for the treatment of relapsed/refractory myeloma patients.
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Affiliation(s)
| | | | | | - Lenka Besse
- Laboratory of Experimental Oncology, Clinics for Medical Hematology and Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
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10
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Puolakkainen T, Rummukainen P, Pihala-Nieminen V, Ritvos O, Savontaus E, Kiviranta R. Treatment with Soluble Activin Type IIB Receptor Ameliorates Ovariectomy-Induced Bone Loss and Fat Gain in Mice. Calcif Tissue Int 2022; 110:504-517. [PMID: 35024891 PMCID: PMC8927044 DOI: 10.1007/s00223-021-00934-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 11/25/2021] [Indexed: 11/23/2022]
Abstract
INTRODUCTION In postmenopausal osteoporosis, hormonal changes lead to increased bone turnover and metabolic alterations including increased fat mass and insulin resistance. Activin type IIB receptors bind several growth factors of the TGF-β superfamily and have been demonstrated to increase muscle and bone mass. We hypothesized that ActRIIB-Fc treatment could improve bone and muscle mass, inhibit fat accumulation, and restore metabolic alterations in an ovariectomy (OVX) model of postmenopausal osteoporosis. MATERIALS AND METHODS Female C57Bl/6 N mice were subjected to SHAM or OVX procedures and received intraperitoneal injections of either PBS or ActRIIB-Fc (5 mg/kg) once weekly for 7 weeks. Glucose and insulin tolerance tests (GTT and ITT, respectively) were performed at 7 and 8 weeks, respectively. Bone samples were analyzed with micro-computed tomography imaging, histomorphometry, and quantitative RT-PCR. RESULTS Bone mass decreased in OVX PBS mice compared to the SHAM PBS group but ActRIIB-Fc was able to prevent these changes as shown by µCT and histological analyses. This was due to decreased osteoclast numbers and function demonstrated by histomorphometric and qRT-PCR analyses. OVX induced adipocyte hypertrophy that was rescued by ActRIIB-Fc, which also decreased systemic adipose tissue accumulation. OVX itself did not affect glucose levels in GTT but ActRIIB-Fc treatment resulted in impaired glucose clearance in both SHAM and OVX groups. OVX induced mild insulin resistance in ITT but ActRIIB-Fc treatment did not affect this. CONCLUSION Our results reinforce the potency of ActRIIB-Fc as a bone-enhancing agent but also bring new insight into the metabolic effects of ActRIIB-Fc in normal and OVX mice.
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Affiliation(s)
- Tero Puolakkainen
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Petri Rummukainen
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Vappu Pihala-Nieminen
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Olli Ritvos
- Department of Physiology, University of Helsinki, Helsinki, Finland
| | - Eriika Savontaus
- Clinical Pharmacology, Turku University Hospital, Turku, Finland
- Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Riku Kiviranta
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.
- Department of Endocrinology, Division of Medicine, University of Turku and Turku University Hospital, Turku, Finland.
- Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
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11
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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: 17] [Impact Index Per Article: 5.7] [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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12
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Esposito P, Verzola D, Picciotto D, Cipriani L, Viazzi F, Garibotto G. Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification. Cells 2021; 10:2070. [PMID: 34440838 PMCID: PMC8393536 DOI: 10.3390/cells10082070] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023] Open
Abstract
A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.
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Affiliation(s)
- Pasquale Esposito
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
- IRCCS Ospedale Policlinico San Martino, Clinica Nefrologica, Dialisi, Trapianto, 16132 Genova, Italy;
| | - Daniela Verzola
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
| | - Daniela Picciotto
- IRCCS Ospedale Policlinico San Martino, Clinica Nefrologica, Dialisi, Trapianto, 16132 Genova, Italy;
| | - Leda Cipriani
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
| | - Francesca Viazzi
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
- IRCCS Ospedale Policlinico San Martino, Clinica Nefrologica, Dialisi, Trapianto, 16132 Genova, Italy;
| | - Giacomo Garibotto
- Department of Internal Medicine, University of Genova, 16132 Genova, Italy; (P.E.); (D.V.); (L.C.); (F.V.)
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13
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Chan ASM, McGregor NE, Poulton IJ, Hardee JP, Cho EHJ, Martin TJ, Gregorevic P, Sims NA, Lynch GS. Bone Geometry Is Altered by Follistatin-Induced Muscle Growth in Young Adult Male Mice. JBMR Plus 2021; 5:e10477. [PMID: 33869993 PMCID: PMC8046154 DOI: 10.1002/jbm4.10477] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/04/2021] [Indexed: 12/13/2022] Open
Abstract
The development of the musculoskeletal system and its maintenance depends on the reciprocal relationship between muscle and bone. The size of skeletal muscles and the forces generated during muscle contraction are potent sources of mechanical stress on the developing skeleton, and they shape bone structure during growth. This is particularly evident in hypermuscular global myostatin (Mstn)‐null mice, where larger muscles during development increase bone mass and alter bone shape. However, whether muscle hypertrophy can similarly influence the shape of bones after the embryonic and prepubertal period is unknown. To address this issue, bone structure was assessed after inducing muscle hypertrophy in the lower hindlimbs of young‐adult C57BL/6J male mice by administering intramuscular injections of recombinant adeno‐associated viral vectors expressing follistatin (FST), a potent antagonist of Mstn. Two FST isoforms were used: the full‐length 315 amino acid isoform (FST‐315) and a truncated 288 amino acid isoform (FST‐288). In both FST‐treated cohorts, muscle hypertrophy was observed, and the anterior crest of the tibia, adjacent to the tibialis anterior muscle, was lengthened. Hypertrophy of the muscles surrounding the tibia caused the adjacent cortical shell to recede inward toward the central axis: an event driven by bone resorption adjacent to the hypertrophic muscle. The findings reveal that inducing muscle hypertrophy in mice can confer changes in bone shape in early adulthood. © 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)
- Audrey S M Chan
- Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences University of Melbourne Melbourne 3010 Australia
| | | | - Ingrid J Poulton
- St. Vincent's Institute of Medical Research Fitzroy 3065 Australia
| | - Justin P Hardee
- Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences University of Melbourne Melbourne 3010 Australia
| | - Ellie H-J Cho
- Biological Optical Microscopy Platform University of Melbourne Melbourne Australia
| | - T John Martin
- St. Vincent's Institute of Medical Research Fitzroy 3065 Australia.,Department of Medicine, St. Vincent's Hospital University of Melbourne Fitzroy 3065 Australia
| | - Paul Gregorevic
- Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences University of Melbourne Melbourne 3010 Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research Fitzroy 3065 Australia.,Department of Medicine, St. Vincent's Hospital University of Melbourne Fitzroy 3065 Australia
| | - Gordon S Lynch
- Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences University of Melbourne Melbourne 3010 Australia
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14
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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: 30] [Impact Index Per Article: 7.5] [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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15
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Mace ML, Olgaard K, Lewin E. New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis. Int J Mol Sci 2020; 21:E8810. [PMID: 33233840 PMCID: PMC7699902 DOI: 10.3390/ijms21228810] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/16/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
The bone-derived hormone fibroblast growth factor 23 (FGF23) acts in concert with parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol in the regulation of calcium (Ca) and phosphate (P) homeostasis. More factors are being identified to regulate FGF23 levels and the endocrine loops between the three hormones. The present review summarizes the complex regulation of FGF23 and the disturbed FGF23/Klotho system in chronic kidney disease (CKD). In addition to the reduced ability of the injured kidney to regulate plasma levels of FGF23, several CKD-related factors have been shown to stimulate FGF23 production. The high circulating FGF23 levels have detrimental effects on erythropoiesis, the cardio-vascular system and the immune system, all contributing to the disturbed system biology in CKD. Moreover, new factors secreted by the injured kidney and the uremic calcified vasculature play a role in the mineral and bone disorder in CKD and create a vicious pathological crosstalk.
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Affiliation(s)
- Maria L. Mace
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (K.O.); (E.L.)
| | - Klaus Olgaard
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (K.O.); (E.L.)
| | - Ewa Lewin
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (K.O.); (E.L.)
- Department of Nephrology, Herlev Hospital, University of Copenhagen, 2730 Herlev, Denmark
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16
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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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17
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Kuranobu T, Mokuda S, Oi K, Tokunaga T, Yukawa K, Kohno H, Yoshida Y, Hirata S, Sugiyama E. Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis. Pathobiology 2020; 87:198-207. [PMID: 32126552 DOI: 10.1159/000506260] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/29/2020] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Activin A is known to be highly expressed in rheumatoid synovium. In the present study, we investigated the effect of inflammatory cytokines on activin A production and its role in rheumatoid inflammation using freshly prepared rheumatoid synovial cells (fresh-RSC). METHODS Fresh-RSC from patients with rheumatoid arthritis were obtained and stimulated with multiple cytokines for activin A production. Gene expression levels of activin A and inflammatory cytokines were determined by quantitative PCR (qPCR) analysis. An enzyme-linked immunosorbent assay (ELISA) was used to measure activin A and CXCL10 in culture supernatants. The osteoclasts generated from human peripheral monocytes by RANKL stimulation were identified by tartrate-resistant acid phosphatase staining and bone resorption assay using Osteo plate. The expression levels of NFATc1 and cathepsin K, critical intracellular proteins for osteoclastogenesis, were determined by Western blotting. RESULTS Activin A production in fresh-RSC was markedly enhanced by the synergistic effect of TGF-β1 with inflammatory cytokines, including TNFα, IL-1β, and IL-6. Activin A inhibited TNFα-induced CXCL10, an important chemoattractant for pathogen-activated T cells and monocytes of osteoclast precursors, but it did not affect the expression of inflammatory cytokines and chemokines. In addition, activin A directly inhibited the expression of NFATc1 and cathepsin K, as well as osteoclast formation in human samples. CONCLUSION Our data indicated that TGF-β1 is involved in the expression of activin A at inflamed joints. Activin A mainly exerts an anti-inflammatory action, which prevents joint damage via the regulation of CXCL10 and osteoclastogenesis.
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Affiliation(s)
- Tatsuomi Kuranobu
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Sho Mokuda
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Katsuhiro Oi
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Tadahiro Tokunaga
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazutoshi Yukawa
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Hiroki Kohno
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yusuke Yoshida
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shintaro Hirata
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan
| | - Eiji Sugiyama
- Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan,
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18
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Zhou YL, Li B, Xu YP, Wang LZ, Gu WB, Liu ZP, Dong WR, Shu MA. The Activin-like ligand Dawdle regulates innate immune responses through modulating NF-κB signaling in mud crab Scylla paramamosain. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2019; 101:103450. [PMID: 31306697 DOI: 10.1016/j.dci.2019.103450] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 06/10/2023]
Abstract
Activins, members of transforming growth factor β (TGF-β) superfamily, are pleiotropic cytokines with critical roles in mediating cell proliferation, differentiation, homeostasis, apoptosis and immune response. However, the structural characteristics and specific functions of Activins remain largely unknown in invertebrates. In the present study, an Activin-like ligand Dawdle (Daw) was firstly identified and characterized from mud crab Scylla paramamosain. The obtained cDNA sequence of SpDaw was 2, 196 bp long with a 1, 149 bp open reading fame, which encoded a putative protein of 382 amino acids. The putative SpDaw protein contained a signal peptide, a TGF-β propeptide region and a TGF-β domain. Real-time PCR analysis demonstrated that SpDaw was predominantly expressed at early embryonic development stage and premolt stages, implying its participation in development and growth. Furthermore, SpDaw responded to both Vibro alginolyticus and Poly (I:C) challenges, suggesting the involvement of SpDaw in innate immune responses. Knockdown of SpDaw in vivo dramatically increased the expressions of NF-κB signaling genes and anti-lipopolysaccharide factor (ALF) genes, and the bacteria clearance efficiency was also markedly enhanced in SpDaw-silenced crabs. Moreover, the in vitro experiment further demonstrated that recombinant SpDaw protein could block the increased transcription of IKKs, NF-κBs and ALFs induced by pathogen challenges. Taken together, these results indicated that SpDaw not only participated in development and growth processes but also played an immune-regulatory role in crabs' innate immunity, which may pave the way for a better understanding of TGF-β superfamily members in crustacean species.
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Affiliation(s)
- Yi-Lian Zhou
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Bo Li
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ya-Ping Xu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Lan-Zhi Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wen-Bin Gu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ze-Peng Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wei-Ren Dong
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Miao-An Shu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, China.
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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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Diller M, Frommer K, Dankbar B, Tarner I, Hülser ML, Tsiklauri L, Hasseli R, Sauerbier M, Pap T, Rehart S, Müller-Ladner U, Neumann E. The activin-follistatin anti-inflammatory cycle is deregulated in synovial fibroblasts. Arthritis Res Ther 2019; 21:144. [PMID: 31182152 PMCID: PMC6558802 DOI: 10.1186/s13075-019-1926-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/26/2019] [Indexed: 12/25/2022] Open
Abstract
Background Activin A and follistatin exhibit immunomodulatory functions, thus affecting autoinflammatory processes as found in rheumatoid arthritis (RA). The impact of both proteins on the behavior of synovial fibroblasts (SF) in RA as well as in osteoarthritis (OA) is unknown. Methods Immunohistochemical analyses of synovial tissue for expression of activin A and follistatin were performed. The influence of RASF overexpressing activin A on cartilage invasion in a SCID mouse model was examined. RASF and OASF were stimulated with either IL-1β or TNFα in combination with or solely with activin A, activin AB, or follistatin. Protein secretion was measured by ELISA and mRNA expression by RT-PCR. Smad signaling was confirmed by western blot. Results In human RA synovial tissue, the number of activin A-positive cells as well as its extracellular presence was higher than in the OA synovium. Single cells within the tissue expressed follistatin in RA and OA synovial tissue. In the SCID mouse model, activin A overexpression reduced RASF invasion. In human RASF, activin A was induced by IL-1β and TNFα. Activin A slightly increased IL-6 release by unstimulated RASF, but decreased protein and mRNA levels of follistatin. Conclusion The observed decrease of cartilage invasion by RASF overexpressing activin A in the SCID mouse model appears to be mediated by an interaction between activin/follistatin and other local cells indirectly affecting RASF because activin A displayed certain pro-inflammatory effects on RASF. Activin A even inhibits production and release of follistatin in RASF and therefore prevents itself from being blocked by its inhibitory binding protein follistatin in the local inflammatory joint environment. Electronic supplementary material The online version of this article (10.1186/s13075-019-1926-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Magnus Diller
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Klaus Frommer
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Berno Dankbar
- Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Ingo Tarner
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Marie-Lisa Hülser
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Lali Tsiklauri
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Rebecca Hasseli
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Michael Sauerbier
- Department of Plastic, Hand and Reconstructive Surgery, BGU Frankfurt, Frankfurt, Germany
| | - Thomas Pap
- Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany
| | - Stefan Rehart
- Department of Orthopaedics and Trauma Surgery, Agaplesion Markus Hospital, Frankfurt, Germany
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany
| | - Elena Neumann
- Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Campus Kerckhoff, Bad Nauheim, Benekestr: 2-8, 61231, Bad Nauheim, Germany.
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Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F, Reis FM. Activin A in Mammalian Physiology. Physiol Rev 2019; 99:739-780. [DOI: 10.1152/physrev.00002.2018] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
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Affiliation(s)
- Enrrico Bloise
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Pasquapina Ciarmela
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Cynthia Dela Cruz
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Stefano Luisi
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Felice Petraglia
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
| | - Fernando M. Reis
- Department of Morphology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona, Italy; Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Department of Molecular and Developmental Medicine, Obstetrics and Gynecological Clinic, University of Siena, Siena, Italy; and Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and
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22
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Almehmadi A, Ohyama Y, Kaku M, Alamoudi A, Husein D, Katafuchi M, Mishina Y, Mochida Y. VWC2 Increases Bone Formation Through Inhibiting Activin Signaling. Calcif Tissue Int 2018; 103:663-674. [PMID: 30074079 PMCID: PMC6549224 DOI: 10.1007/s00223-018-0462-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 07/30/2018] [Indexed: 12/27/2022]
Abstract
By a bioinformatics approach, we have identified a novel cysteine knot protein member, VWC2 (von Willebrand factor C domain containing 2) previously known as Brorin. Since Brorin has been proposed to function as a bone morphogenetic protein (BMP) antagonist, we investigated the binding of Brorin/VWC2 to several BMPs; however, none of the BMPs tested were bound to VWC2. Instead, the βA subunit of activin was found as a binding partner among transforming growth factor (TGF)-β superfamily members. Here, we show that Vwc2 gene expression is temporally upregulated early in osteoblast differentiation, VWC2 protein is present in bone matrix, and localized at osteoblasts/osteocytes. Activin A-induced Smad2 phosphorylation was inhibited in the presence of exogenous VWC2 in MC3T3-E1 osteoblast cell line and primary osteoblasts. The effect of VWC2 on ex vivo cranial bone organ cultures treated with activin A was investigated, and bone morphometric parameters decreased by activin A were restored with VWC2. When we further investigated the biological mechanism how VWC2 inhibited the effects of activin A on bone formation, we found that the effects of activin A on osteoblast cell growth, differentiation, and mineralization were reversed by VWC2. Taken together, a novel secretory protein, VWC2 promotes bone formation by inhibiting Activin-Smad2 signaling pathway.
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Affiliation(s)
- Ahmad Almehmadi
- Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, USA
- Department of Periodontology and Oral Biology, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Yoshio Ohyama
- Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, USA
- Departoment of Maxillofacial Surgery, Tokyo Medical and Dental University Graduate School, Tokyo, Japan
| | - Masaru Kaku
- Division of Bio-Prosthodontics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Ahmed Alamoudi
- Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, USA
- Department of Oral Biology, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Dina Husein
- Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, USA
| | - Michitsuna Katafuchi
- Department of Oral Rehabilitation, Section of Fixed Prosthodontics, Fukuoka Dental College, Fukuoka, Japan
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Yoshiyuki Mochida
- Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, USA.
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23
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Jeong Y, Daghlas SA, Yixia X, Hulbert MA, Pfeiffer FM, Dallas MR, Omosule CL, Pearsall RS, Dallas SL, Phillips CL. Skeletal Response to Soluble Activin Receptor Type IIB in Mouse Models of Osteogenesis Imperfecta. J Bone Miner Res 2018; 33:1760-1772. [PMID: 29813187 PMCID: PMC6400483 DOI: 10.1002/jbmr.3473] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 05/20/2018] [Accepted: 05/29/2018] [Indexed: 01/21/2023]
Abstract
Osteogenesis imperfecta (OI) is a heritable connective tissue disorder primarily due to mutations in the type I collagen genes (COL1A1 and COL1A2), leading to compromised biomechanical integrity in type I collagen-containing tissues such as bone. Bone is inherently mechanosensitive and thus responds and adapts to external stimuli, such as muscle mass and contractile strength, to alter its mass and shape. Myostatin, a member of the TGF-β superfamily, signals through activin receptor type IIB to negatively regulate muscle fiber growth. Because of the positive impact of myostatin deficiency on bone mass, we utilized a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein in two molecularly distinct OI mouse models (G610C and oim) and evaluated their bone properties. Wild-type (WT), +/G610C, and oim/oim mice were treated from 2 to 4 months of age with either vehicle (Tris-buffered saline) or sActRIIB-mFc (10 mg/kg). Femurs of sActRIIB-mFc-treated mice exhibited increased trabecular bone volume regardless of genotype, whereas the cortical bone microarchitecture and biomechanical strength were only improved in WT and +/G610C mice. Dynamic histomorphometric analyses suggest the improved cortical bone geometry and biomechanical integrity reflect an anabolic effect due to increased mineral apposition and bone formation rates, whereas static histomorphometric analyses supported sActRIIB-mFc treatment also having an anti-catabolic impact with decreased osteoclast number per bone surface on trabecular bone regardless of sex and genotype. Together, our data suggest that sActRIIB-mFc may provide a new therapeutic direction to improve both bone and muscle properties in OI. © 2018 American Society for Bone and Mineral Research.
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Affiliation(s)
- Youngjae Jeong
- Department of Biochemistry, University of Missouri, Columbia, Missouri, 65211
| | - Salah A. Daghlas
- Department of Biochemistry, University of Missouri, Columbia, Missouri, 65211
| | - Xie Yixia
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri, 64108
| | - Molly A Hulbert
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri, 64108
| | - Ferris M. Pfeiffer
- Department of Orthopaedic Surgery and Bioengineering, University of Missouri, Columbia, MO, 65211
| | - Mark R. Dallas
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri, 64108
| | | | | | - Sarah L. Dallas
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, Missouri, 64108
| | - Charlotte L. Phillips
- Department of Biochemistry, University of Missouri, Columbia, Missouri, 65211
- Department of Child Health, University of Missouri, Columbia, Missouri, 65211
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Systemic Activation of Activin A Signaling Causes Chronic Kidney Disease-Mineral Bone Disorder. Int J Mol Sci 2018; 19:ijms19092490. [PMID: 30142896 PMCID: PMC6163495 DOI: 10.3390/ijms19092490] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 08/20/2018] [Accepted: 08/21/2018] [Indexed: 11/19/2022] Open
Abstract
The high cardiovascular mortality associated with chronic kidney disease (CKD) is caused in part by the CKD-mineral bone disorder (CKD-MBD) syndrome. The CKD-MBD consists of skeletal, vascular and cardiac pathology caused by metabolic derangements produced by kidney disease. The prevalence of osteopenia/osteoporosis resulting from the skeletal component of the CKD-MBD, renal osteodystrophy (ROD), in patients with CKD exceeds that of the general population and is a major public health concern. That CKD is associated with compromised bone health is widely accepted, yet the mechanisms underlying impaired bone metabolism in CKD are not fully understood. Therefore, clarification of the molecular mechanisms by which CKD produces ROD is of crucial significance. We have shown that activin A, a member of the transforming growth factor (TGF)-β super family, is an important positive regulator of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis with Smad-mediated signaling being crucial for inducing osteoclast development and function. Recently, we have demonstrated systemic activation of activin receptors and activin A levels in CKD mouse models, such as diabetic CKD and Alport (AL) syndrome. In these CKD mouse models, bone remodeling caused by increased osteoclast numbers and activated osteoclastic bone resorption was observed and treatment with an activin receptor ligand trap repaired CKD-induced-osteoclastic bone resorption and stimulated individual osteoblastic bone formation, irrespective of parathyroid hormone (PTH) elevation. These findings have opened a new field for exploring mechanisms of activin A-enhanced osteoclast formation and function in CKD. Activin A appears to be a strong candidate for CKD-induced high-turnover ROD. Therefore, the treatment with the decoy receptor for activin A might be a good candidate for treatment for CKD-induced osteopenia or osteoporosis, indicating that the new findings from in these studies will lead to the identification of novel therapeutic targets for CKD-related and osteopenia and osteoporosis in general. In this review, we describe the impact of CKD-induced Smad signaling in osteoclasts, osteoblasts and vascular cells in CKD.
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Abstract
PURPOSE OF REVIEW The development of therapeutics that target anabolic pathways involved in skeletogenesis is of great importance with regard to disease resulting in bone loss, or in cases of impaired bone repair. This review aims to summarize recent developments in this area. RECENT FINDINGS A greater understanding of how drugs that modulate signaling pathways involved in skeletogenesis exert their efficacy, and the molecular mechanisms resulting in bone formation has led to novel pharmacological bone repair strategies. Furthermore, crosstalk between pathways and molecules has suggested signaling synergies that may be exploited for enhanced tissue formation. The sequential pharmacological stimulation of the molecular cascades resulting in tissue repair is a promising strategy for the treatment of bone fractures. It is proposed that a therapeutic strategy which mimics the natural cascade of events observed during fracture repair may be achieved through temporal targeting of tissue repair pathways.
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Affiliation(s)
- Scott J Roberts
- Bone Therapeutic Area, UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.
| | - Hua Zhu Ke
- Bone Therapeutic Area, UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
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26
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Kajita T, Ariyoshi W, Okinaga T, Mitsugi S, Tominaga K, Nishihara T. Mechanisms involved in enhancement of osteoclast formation by activin-A. J Cell Biochem 2018; 119:6974-6985. [PMID: 29737562 DOI: 10.1002/jcb.26906] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 03/28/2018] [Indexed: 12/23/2022]
Abstract
Several growth factors in bone tissues are reported to be associated with osteoclastogenesis. Activin-A, a member of the transforming growth factor-β (TGF-β) family is known to be present in bone tissues and an important regulator in osteoclastogenesis with SMAD-mediated signaling being crucial for inducing osteoclast differentiation. In the present study, we examined the effect and underlying mechanisms of activin-A on osteoclast formation in vitro culture systems. Activin-A enhanced osteoclast formation in both mouse bone marrow cells and monocyte/macrophage cell line RAW 264.7 cells induced by receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) and/or macrophage stimulating factor (M-CSF). We also found that activin-A stimulated bone resorption and actin ring formation induced by RANKL and/or M-CSF. Furthermore, activin-A enhanced RANKL-induced expression of nuclear factor of activated T cell cytoplasmic 1 (NFATc1), a key regulator of osteoclastogenesis, thereby increasing osteoclastogenesis-related marker gene expression, including tartrate-resistant acid phosphatase, osteoclast stimulatory transmembrane protein, and cathepsin K. Blockage of receptor binding by follistatin, an activing-binding protein suppressed the activin-A-mediated stimulation of NFATc1. In addition, activin-A increased RANKL-induced c-fos expression without significantly affecting the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathway. Pre-treatment of the cells with a specific inhibitor of SMAD2/3 attenuated the activin-A-induced expression of NFATc1 and co-immunoprecipitation assay revealed that treatment with activin-A increased physical interaction of phosphorylated-c-fos and phosphorylated-SMAD2 protein induced by RANKL. These results suggest that activin-A enhances RANKL-induced osteoclast formation mediated by interaction of c-fos and smad2/3.
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Affiliation(s)
- Tomonari Kajita
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan.,Division of Oral and Maxillofacial Surgery, Department of Science and Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Wataru Ariyoshi
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Toshinori Okinaga
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Sho Mitsugi
- Division of Oral and Maxillofacial Surgery, Department of Science and Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Kazuhiro Tominaga
- Division of Oral and Maxillofacial Surgery, Department of Science and Physical Functions, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
| | - Tatsuji Nishihara
- Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Fukuoka, Japan
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27
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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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Hu J, Wang X, Tang YH, Shan YG, Zou Q, Wang ZQ, Huang CX. Activin A inhibition attenuates sympathetic neural remodeling following myocardial infarction in rats. Mol Med Rep 2018; 17:5074-5080. [PMID: 29393433 PMCID: PMC5865969 DOI: 10.3892/mmr.2018.8496] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 04/24/2017] [Indexed: 01/19/2023] Open
Abstract
Inflammation serves a critical role in driving sympathetic neural remodeling following myocardial infarction (MI), and activin A has been implicated as an important mediator of the inflammatory response post-MI. However, whether activin A impacts sympathetic neural remodeling post-MI remains unclear. In the present study, the authors assessed the effects of activin A on sympathetic neural remodeling in a rat model of MI. Rats were randomly divided into sham, MI, and MI + follistatin-300 (FS, activin A inhibitor) groups. Cardiac tissues from the peri-infarct zone were assessed for expression of sympathetic neural remodeling and inflammatory factors in rats 4 weeks post-MI by western blotting and immunohistochemical methods. Heart function was assessed by echocardiography. It is demonstrated that FS administration significantly reduced post-MI upregulation of activin A, nerve growth factor protein lever, and the density of nerve fibers with positive and protein expression of sympathetic neural remodeling markers in nerve fibers, which included growth associated protein 43 and tyrosine hydroxylase. In addition, inhibition of activin A reduced cardiac inflammation post-MI based on the reduction of i) interleukin-1 and tumor necrosis factor-α protein expression, ii) numbers and/or proportional area of infiltrating macrophages and myofibroblasts and iii) phosphorylated levels of p65 and IκBα. Furthermore, activin A inhibition lessened heart dysfunction post-MI. These results suggested that activin A inhibition reduced sympathetic neural remodeling post-MI in part through inhibition of the inflammatory response. The current study implicates activin A as a potential therapeutic target to circumvent sympathetic neural remodeling post-MI.
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Affiliation(s)
- Juan Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yan-Hong Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ying-Guang Shan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qiang Zou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhi-Qiang Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Cong-Xin Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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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: 223] [Impact Index Per Article: 31.9] [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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30
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Williams MJ, Sugatani T, Agapova OA, Fang Y, Gaut JP, Faugere MC, Malluche HH, Hruska KA. The activin receptor is stimulated in the skeleton, vasculature, heart, and kidney during chronic kidney disease. Kidney Int 2018; 93:147-158. [PMID: 28843411 PMCID: PMC6628245 DOI: 10.1016/j.kint.2017.06.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 06/02/2017] [Accepted: 06/08/2017] [Indexed: 01/09/2023]
Abstract
We examined activin receptor type IIA (ActRIIA) activation in chronic kidney disease (CKD) by signal analysis and inhibition in mice with Alport syndrome using the ActRIIA ligand trap RAP-011 initiated in 75-day-old Alport mice. At 200 days of age, there was severe CKD and associated Mineral and Bone Disorder (CKD-MBD), consisting of osteodystrophy, vascular calcification, cardiac hypertrophy, hyperphosphatemia, hyperparathyroidism, elevated FGF23, and reduced klotho. The CKD-induced bone resorption and osteoblast dysfunction was reversed, and bone formation was increased by RAP-011. ActRIIA inhibition prevented the formation of calcium apatite deposits in the aortic adventitia and tunica media and significantly decreased the mean aortic calcium concentration from 0.59 in untreated to 0.36 mg/g in treated Alport mice. Aortic ActRIIA stimulation in untreated mice increased p-Smad2 levels and the transcription of sm22α and αSMA. ActRIIA inhibition reversed aortic expression of the osteoblast transition markers Runx2 and osterix. Heart weight was significantly increased by 26% in untreated mice but remained normal during RAP-011 treatment. In 150-day-old mice, GFR was significantly reduced by 55%, but only by 30% in the RAP-011-treated group. In 200-day-old mice, the mean BUN was 100 mg/dl in untreated mice compared to 60 mg/dl in the treated group. In the kidneys of 200-day-old mice, ActRIIA and p-Smad2 were induced and MCP-1, fibronectin, and interstitial fibrosis were stimulated; all were attenuated by RAP-011 treatment. Hence, the activation of ActRIIA signaling during early CKD contributes to the CKD-MBD components of osteodystrophy and cardiovascular disease and to renal fibrosis. Thus, the inhibition of ActRIIA signaling is efficacious in improving and delaying CKD-MBD in this model of Alport syndrome.
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MESH Headings
- Actins/metabolism
- Activin Receptors, Type II/antagonists & inhibitors
- Activin Receptors, Type II/genetics
- Activin Receptors, Type II/metabolism
- Animals
- Blood Vessels/metabolism
- Blood Vessels/pathology
- Blood Vessels/physiopathology
- Bone Remodeling
- Bone Resorption/genetics
- Bone Resorption/metabolism
- Bone Resorption/physiopathology
- Bone Resorption/prevention & control
- Bone and Bones/metabolism
- Bone and Bones/pathology
- Bone and Bones/physiopathology
- Cardiomegaly/genetics
- Cardiomegaly/metabolism
- Cardiomegaly/physiopathology
- Cardiomegaly/prevention & control
- Chronic Kidney Disease-Mineral and Bone Disorder/genetics
- Chronic Kidney Disease-Mineral and Bone Disorder/metabolism
- Chronic Kidney Disease-Mineral and Bone Disorder/physiopathology
- Chronic Kidney Disease-Mineral and Bone Disorder/prevention & control
- Collagen Type IV/deficiency
- Collagen Type IV/genetics
- Core Binding Factor Alpha 1 Subunit/metabolism
- Disease Models, Animal
- Fibroblast Growth Factor-23
- Fibrosis
- Glomerular Filtration Rate
- Kidney/metabolism
- Kidney/pathology
- Kidney/physiopathology
- Mice, Knockout
- Microfilament Proteins/metabolism
- Muscle Proteins/metabolism
- Myocardium/metabolism
- Myocardium/pathology
- Nephritis, Hereditary/drug therapy
- Nephritis, Hereditary/genetics
- Nephritis, Hereditary/metabolism
- Nephritis, Hereditary/physiopathology
- Phosphorylation
- Recombinant Fusion Proteins/pharmacology
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/physiopathology
- Renal Insufficiency, Chronic/prevention & control
- Signal Transduction
- Smad2 Protein/metabolism
- Sp7 Transcription Factor/metabolism
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
- Vascular Calcification/physiopathology
- Vascular Calcification/prevention & control
- Vascular Remodeling
- Ventricular Remodeling
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Affiliation(s)
- Matthew J Williams
- Renal Division, Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Toshifumi Sugatani
- Renal Division, Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Olga A Agapova
- Renal Division, Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Yifu Fang
- Renal Division, Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Joseph P Gaut
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Marie-Claude Faugere
- Renal Division Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Hartmut H Malluche
- Renal Division Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Keith A Hruska
- Renal Division, Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA; Departments of Medicine and Cell Biology, Washington University School of Medicine, Saint Louis, Missouri, USA.
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miR-217 Is a Useful Diagnostic Biomarker and Regulates Human Podocyte Cells Apoptosis via Targeting TNFSF11 in Membranous Nephropathy. BIOMED RESEARCH INTERNATIONAL 2017; 2017:2168767. [PMID: 29214160 PMCID: PMC5682891 DOI: 10.1155/2017/2168767] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/24/2017] [Accepted: 10/01/2017] [Indexed: 12/13/2022]
Abstract
Background MicroRNAs have recently been verified as useful diagnostic biomarkers in various diseases. In this study, we investigated whether miR-217 is a useful diagnostic biomarker and the possible pathological mechanism of miR-217 in this disease. Methods Patients with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and diabetic nephropathy (DN) and control patients were enrolled in this study. The miR-217 inhibitor and mimics were transfected into human podocyte cells to investigate the pathological mechanism of miR-217 in this disease. Relevant indicators were detected and tested. Results Compared with control patients, miR-217 was significantly downregulated and TNFSF11 was significantly upregulated in MN. Then, miR-217 had obvious separation between patients with MN and control patients, with an AUC of 0.941, a cutoff value of <750.0 copies/ul, and sensitivity and specificity of 88.9% and 75.9%. In addition, the TNFSF11 was confirmed to be the target gene of miR-217. Finally, in in vitro experiments, the upregulation of miR-217 could decrease the expression of TNFSF11 and not induce human podocyte cells apoptosis; however, the downregulation of miR-217 could bring about an opposite change. Conclusions miR-217 is a useful diagnostic biomarker and is involved in human podocyte cells apoptosis via targeting TNFSF11 in membranous nephropathy.
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Terpos E, Christoulas D, Gavriatopoulou M, Dimopoulos MA. Mechanisms of bone destruction in multiple myeloma. Eur J Cancer Care (Engl) 2017; 26. [PMID: 28940410 DOI: 10.1111/ecc.12761] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/02/2017] [Indexed: 02/02/2023]
Abstract
Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of an increased activity of osteoclasts, which is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition. Among them, the most important include the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the macrophage inflammatory proteins and the activin-A that play a crucial role in osteoclast stimulation in myeloma, while the wingless-type (Wnt) signalling inhibitors (sclerostin and dickkopf-1) along with the growth factor independence-1 are considered the most important factors for the osteoblast dysfunction of myeloma patients. Finally, the role of osteocytes, which is the key cell for normal bone remodelling, has also revealed during the last years through their interaction with myeloma cells that leads to their apoptosis and the release of RANKL and sclerostin maintaining bone loss in these patients. This review focuses on the latest available data for the mechanisms of bone destruction in multiple myeloma.
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Affiliation(s)
- E Terpos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
| | - D Christoulas
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
| | - M Gavriatopoulou
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
| | - M A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
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Brunetti G, Faienza MF, Colaianni G, Grano M, Colucci S. Mechanisms of Altered Bone Remodeling in Multiple Myeloma. Clin Rev Bone Miner Metab 2017. [DOI: 10.1007/s12018-017-9236-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Seher A, Lagler C, Stühmer T, Müller-Richter UDA, Kübler AC, Sebald W, Müller TD, Nickel J. Utilizing BMP-2 muteins for treatment of multiple myeloma. PLoS One 2017; 12:e0174884. [PMID: 28489849 PMCID: PMC5425150 DOI: 10.1371/journal.pone.0174884] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/16/2017] [Indexed: 12/16/2022] Open
Abstract
Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.
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Affiliation(s)
- Axel Seher
- Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Charlotte Lagler
- Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Thorsten Stühmer
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | | | | | - Walter Sebald
- Department Physiological Chemistry II, Theodor-Boveri-Institute (Biocentre), University of Würzburg, Würzburg, Germany
| | - Thomas Dieter Müller
- Julius-von-Sachs-Institute, Department Molecular Plant Physiology and Biophysics, University of Würzburg, Würzburg, Germany
| | - Joachim Nickel
- Chair Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, Würzburg, Germany
- Fraunhofer IGB, Translational Centre Würzburg "Regenerative Therapies in Oncology and Musculoskeletal Diseases", Würzburg, Germany
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Gavriatopoulou M, Dimopoulos MA, Kastritis E, Terpos E. Emerging treatment approaches for myeloma-related bone disease. Expert Rev Hematol 2017; 10:217-228. [PMID: 28092987 DOI: 10.1080/17474086.2017.1283213] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Multiple myeloma is characterized by the presence of osteolytic lesions that leads to devastating skeletal-related events in the majority of patients. Myeloma bone disease is attributed to increased osteoclastic and suppressed osteoblastic activity. Areas covered: Bisphosphonates remain the main treatment option, however they have limitations on their own. Understanding the pathogenesis of myeloma bone disease may provide a roadmap for new therapeutic approaches. The pathway of RANKRANKLOPG pathway has revealed denosumab, a monoclonal antibody targeting RANKL as a novel emerging therapy for myeloma-related bone disease. Furthermore, the Wnt signaling inhibitors dicckopf-1 and sclerostin that are implicated in the pathogenesis of bone destruction of myeloma are now targeted by novel monoclonal antibodies. Activin-A is a TGF-beta superfamily member which increases osteoclast activity and inhibits osteoblast function in myeloma; sotatercept and other molecules targeting activin-A have entered into clinical development. Several other molecules and pathways that play an important role in the pathogenesis of bone destruction in myeloma, such as periostin, adiponectin, Notch and BTK signaling are also targeted in an attempt to develop novel therapies for myeloma-related bone disease. Expert commentary: We summarize the current advances in the biology of myeloma bone disease and the potential therapeutic targets.
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Affiliation(s)
- Maria Gavriatopoulou
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
| | - Meletios A Dimopoulos
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
| | - Efstathios Kastritis
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
| | - Evangelos Terpos
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
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P. Croxford K, L. Reader K, D. Nicholson H. The potential role of transforming growth factor beta family ligand interactions in prostate cancer. AIMS MOLECULAR SCIENCE 2017. [DOI: 10.3934/molsci.2017.1.41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Fennen M, Pap T, Dankbar B. Smad-dependent mechanisms of inflammatory bone destruction. Arthritis Res Ther 2016; 18:279. [PMID: 27906049 PMCID: PMC5134126 DOI: 10.1186/s13075-016-1187-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 11/18/2016] [Indexed: 12/20/2022] Open
Abstract
Homeostatic bone remodelling becomes disturbed in a variety of pathologic conditions that affect the skeleton, including inflammatory diseases. Rheumatoid arthritis is the prototype of an inflammatory arthritis characterised by chronic inflammation, progressive cartilage destruction and focal bone erosions and is a prime example for a disease with disturbed bone homeostasis. The inflammatory milieu favours the recruitment and activation of osteoclasts, which have been found to be the cells that are primarily responsible for bone erosions in many animal models of inflammatory arthritis. Among the inflammatory modulators, members of the transforming growth factor (TGF)-β super family are shown to be important regulators in osteoclastogenesis with Smad-mediated signalling being crucial for inducing osteoclast differentiation. These findings have opened a new field for exploring mechanisms of osteoclast differentiation under inflammatory conditions. Recent studies have shown that the TGF-β superfamily members TGF-β1, myostatin and activin A directly regulate osteoclast differentiation through mechanisms that depend on the RANKL–RANK interplay. These growth factors transduce their signals through type I and II receptor serine/threonine kinases, thereby activating the Smad pathway. In this review, we describe the impact of inflammation-induced Smad signalling in osteoclast development and subsequently bone erosion in rheumatoid arthritis.
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Affiliation(s)
- Michelle Fennen
- Institute of Experimental Musculoskeletal Medicine, Westfalian Wilhelms-University Münster, Münster, Germany
| | - Thomas Pap
- Institute of Experimental Musculoskeletal Medicine, Westfalian Wilhelms-University Münster, Münster, Germany
| | - Berno Dankbar
- Institute of Experimental Musculoskeletal Medicine, Westfalian Wilhelms-University Münster, Münster, Germany.
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Sugatani T, Agapova OA, Fang Y, Berman AG, Wallace JM, Malluche HH, Faugere MC, Smith W, Sung V, Hruska KA. Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease. Kidney Int 2016; 91:86-95. [PMID: 27666759 DOI: 10.1016/j.kint.2016.07.039] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 07/22/2016] [Accepted: 07/28/2016] [Indexed: 12/22/2022]
Abstract
Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr-/- high fat-fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr-/- high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin-A induced osteoclastogenesis.
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Affiliation(s)
- Toshifumi Sugatani
- Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA
| | - Olga A Agapova
- Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA
| | - Yifu Fang
- Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA
| | - Alycia G Berman
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA
| | - Joseph M Wallace
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA
| | - Hartmut H Malluche
- Division of Nephrology, Bone and Mineral Metabolism, Department of Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Marie-Claude Faugere
- Division of Nephrology, Bone and Mineral Metabolism, Department of Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - William Smith
- Early Clinical Development, Celgene Corp., Basking Ridge, New Jersey, USA
| | - Victoria Sung
- Translational Medicine, Celgene Corp., San Francisco, California, USA
| | - Keith A Hruska
- Department of Pediatrics and Medicine, Renal Division, Washington University, St. Louis, Missouri, USA.
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39
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Effects of myokines on bone. BONEKEY REPORTS 2016; 5:826. [PMID: 27579164 DOI: 10.1038/bonekey.2016.48] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 05/01/2016] [Indexed: 12/22/2022]
Abstract
The links between muscle and bone have been recently examined because of the increasing number of patients with osteoporosis and sarcopenia. Myokines are skeletal muscle-derived humoral cytokines and growth factors, which exert physiological and pathological functions in various distant organs, including the regulation of glucose, energy and bone metabolism. Myostatin is a crucial myokine, the expression of which is mainly limited to muscle tissues. The inhibition of myostatin signaling increases bone remodeling, bone mass and muscle mass, and it may provide a target for the treatment of both sarcopenia and osteoporosis. As myostatin is involved in osteoclast formation and bone destruction in rheumatoid arthritis, myostatin may be a target myokine for the treatment of accelerated bone resorption and joint destruction in rheumatoid arthritis. Numerous other myokines, including transforming growth factor-β, follistatin, insulin-like growth factor-I, fibroblast growth factor-2, osteoglycin, FAM5C, irisin, interleukin (IL)-6, leukemia inhibitory factor, IL-7, IL-15, monocyte chemoattractant protein-1, ciliary neurotrophic factor, osteonectin and matrix metalloproteinase 2, also affect bone cells in various manners. However, the effects of myokines on bone metabolism are largely unknown. Further research is expected to clarify the interaction between muscle and bone, which may lead to greater diagnosis and the development of the treatment for muscle and bone disorders, such as osteoporosis and sarcopenia.
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40
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MiR-195 participates in the placental disorder of preeclampsia via targeting activin receptor type-2B in trophoblastic cells. J Hypertens 2016; 34:1371-9. [DOI: 10.1097/hjh.0000000000000948] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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41
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Morais SA, du Preez HE, Akhtar MR, Cross S, Isenberg DA. Musculoskeletal complications of haematological disease. Rheumatology (Oxford) 2015; 55:968-81. [DOI: 10.1093/rheumatology/kev360] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Indexed: 01/19/2023] Open
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42
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KIM YOUNGIL, PARK SEUNGWON, KANG INJUNG, SHIN MINKYUNG, LEE MUHYOUNG. Activin suppresses LPS-induced Toll-like receptor, cytokine and inducible nitric oxide synthase expression in normal human melanocytes by inhibiting NF-κB and MAPK pathway activation. Int J Mol Med 2015; 36:1165-72. [DOI: 10.3892/ijmm.2015.2308] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Accepted: 07/31/2015] [Indexed: 11/06/2022] Open
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43
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Dankbar B, Fennen M, Brunert D, Hayer S, Frank S, Wehmeyer C, Beckmann D, Paruzel P, Bertrand J, Redlich K, Koers-Wunrau C, Stratis A, Korb-Pap A, Pap T. Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat Med 2015; 21:1085-90. [DOI: 10.1038/nm.3917] [Citation(s) in RCA: 149] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 07/06/2015] [Indexed: 02/07/2023]
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Rachner TD, Jakob F, Hofbauer LC. Cancer-targeted therapies and radiopharmaceuticals. BONEKEY REPORTS 2015; 4:707. [PMID: 26131359 DOI: 10.1038/bonekey.2015.76] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 04/16/2015] [Indexed: 12/26/2022]
Abstract
The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed.
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Affiliation(s)
- Tilman D Rachner
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III, Dresden University Medical Center , Dresden, Germany
| | - Franz Jakob
- Orthopedic Center for Musculoskeletal Research, University Hospital Wuerzburg , Wuerzburg, Germany
| | - Lorenz C Hofbauer
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III, Dresden University Medical Center , Dresden, Germany ; Center for Regenerative Therapies, Dresden Technical University , Dresden, Germany
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Fowler TW, Kamalakar A, Akel NS, Kurten RC, Suva LJ, Gaddy D. Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures. J Cell Sci 2015; 128:683-94. [PMID: 25609708 PMCID: PMC4327386 DOI: 10.1242/jcs.157834] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Accepted: 12/12/2014] [Indexed: 12/26/2022] Open
Abstract
The process of osteoclastic bone resorption is complex and regulated at multiple levels. The role of osteoclast (OCL) fusion and motility in bone resorption are unclear, with the movement of OCL on bone largely unexplored. RANKL (also known as TNFSF11) is a potent stimulator of murine osteoclastogenesis, and activin A (ActA) enhances that stimulation in whole bone marrow. ActA treatment does not induce osteoclastogenesis in stroma-free murine bone marrow macrophage cultures (BMM), but rather inhibits RANKL-induced osteoclastogenesis. We hypothesized that ActA and RANKL differentially regulate osteoclastogenesis by modulating OCL precursors and mature OCL migration. Time-lapse video microscopy measured ActA and RANKL effects on BMM and OCL motility and function. ActA completely inhibited RANKL-stimulated OCL motility, differentiation and bone resorption, through a mechanism mediated by ActA-dependent changes in SMAD2, AKT1 and inhibitor of nuclear factor κB (IκB) signaling. The potent and dominant inhibitory effect of ActA was associated with decreased OCL lifespan because ActA significantly increased activated caspase-3 in mature OCL and OCL precursors. Collectively, these data demonstrate a dual action for ActA on murine OCLs.
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Affiliation(s)
- Tristan W Fowler
- Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA
| | - Archana Kamalakar
- Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA
| | - Nisreen S Akel
- Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA
| | - Richard C Kurten
- Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA
| | - Larry J Suva
- Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA
| | - Dana Gaddy
- Departments of Physiology & Biophysics, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, College of Medicine, Little Rock, AR 72205 USA
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47
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Papamerkouriou YM, Kenanidis E, Gamie Z, Papavasiliou K, Kostakos T, Potoupnis M, Sarris I, Tsiridis E, Kyrkos J. Treatment of multiple myeloma bone disease: experimental and clinical data. Expert Opin Biol Ther 2014; 15:213-30. [DOI: 10.1517/14712598.2015.978853] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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48
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Webb SL, Edwards CM. Novel therapeutic targets in myeloma bone disease. Br J Pharmacol 2014; 171:3765-76. [PMID: 24750110 PMCID: PMC4128042 DOI: 10.1111/bph.12742] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/02/2014] [Accepted: 04/15/2014] [Indexed: 12/21/2022] Open
Abstract
Multiple myeloma is a neoplastic disorder of plasma cells characterized by clonal proliferation within the bone marrow. One of the major clinical features of multiple myeloma is the destructive osteolytic bone disease that occurs in the majority of patients. Myeloma bone disease is associated with increased osteoclast activity and suppression of osteoblastogenesis. Bisphosphonates have been the mainstay of treatment for many years; however, their use is limited by their inability to repair existing bone loss. Therefore, research into novel approaches for the treatment of myeloma bone disease is of the utmost importance. This review will discuss the current advances in our understanding of osteoclast stimulation and osteoblast suppression mechanisms in myeloma bone disease and the treatments that are under development to target this destructive and debilitating feature of myeloma.
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Affiliation(s)
- S L Webb
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Garcia-Gomez A, Sanchez-Guijo F, del Cañizo MC, San Miguel JF, Garayoa M. Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics. World J Stem Cells 2014; 6:322-343. [PMID: 25126382 PMCID: PMC4131274 DOI: 10.4252/wjsc.v6.i3.322] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 03/24/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple myeloma is a hematological malignancy in which clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic lesions due to increased osteoclast (OC) activity and suppressed osteoblast (OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells (MSCs) play a critical role in multiple myeloma pathophysiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of myeloma bone disease (MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients (pMSCs) and their healthy counterparts (dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibitory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and activity at various levels (i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncoupling ephrinB2-EphB4 signaling, and through augmented production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents (at preclinical or clinical stage) targeting those signaling pathways is commented.
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Montagnani A. Bone anabolics in osteoporosis: Actuality and perspectives. World J Orthop 2014; 5:247-54. [PMID: 25035827 PMCID: PMC4095017 DOI: 10.5312/wjo.v5.i3.247] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Revised: 05/19/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Vertebral and nonvertebral fractures prevention is the main goal for osteoporosis therapy by inhibiting bone resorption and/or stimulating bone formation. Antiresorptive drugs decrease the activation frequency, thereby determining a secondary decrease in bone formation rate and a low bone turnover. Bisphosphonates are today's mainstay among antiresorptive treatment of osteoporosis. Also, oral selective estrogen receptor modulators and recently denosumab have a negative effect on bone turnover. Agents active on bone formation are considered a better perspective in the treatment of severe osteoporosis. Recombinant-human parathyroid hormone (PTH) has showed to increase bone formation and significantly decrease vertebral fractures in severe patients, but with a modest effect on nonvertebral fractures. The study of Wnt signaling pathway, that induces prevalently an osteoblastic activity, opens large possibilities to antagonists of Wnt-inhibitors, such as sclerostin antibodies and dickkopf-1 antagonists, with potential effects not only on trabecular bone but also on cortical bone.
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