|
1
|
Gangat N, Tefferi A. Emerging Pathogenetic Mechanisms and New Drugs for Anemia in Myelofibrosis and Myelodysplastic Syndromes. Am J Hematol 2025; 100 Suppl 4:51-65. [PMID: 40056069 DOI: 10.1002/ajh.27659] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/20/2025] [Accepted: 02/27/2025] [Indexed: 05/13/2025]
Abstract
Anemia in myeloid neoplasms is multifaceted, with heterogeneous pathogenetic mechanisms that include ineffective erythropoiesis, hepcidin-induced iron-restricted erythropoiesis, and abnormal inflammatory cytokine production. Current management of anemia is challenged by limited approved drugs that specifically treat anemia in myelofibrosis (MF) and myelodysplastic syndrome (MDS). Newer therapies target the transforming growth factor beta (TGF-β)-bone morphogenic protein/sons of mothers against decapentaplegic (BMP-SMAD) signaling pathway, which plays a significant role in ineffective erythropoiesis (SMAD 2/3) and abnormal hepcidin production (SMAD 1/5/8). These include TGF-β ligand traps (luspatercept, elritercept), activin A receptor type 1 (ACVR1)/activin receptor-like kinase 2 (ALK2) inhibitors (momelotinib, zilurgisertib), and anti-hemojuvelin antibody-based therapies (DISC-0974). Luspatercept and momelotinib are approved for anemia related to lower-risk MDS and MF, respectively, and represent an important addition to the treatment armamentarium, along with imetelstat, a telomerase inhibitor, recently ratified for anemia in lower-risk MDS. A promising strategy to overcome the limitations of existing anemia-directed therapies includes the use of drug combinations with complementary mechanisms (luspatercept + erythropoiesis stimulating agents, luspatercept + momelotinib, DISC-0974 + momelotinib), and harnessing the erythropoietic potential of sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Future research should address the complex pathophysiology of anemia, standardize definitions for anemia with gender-specified cutoffs, implement uniform erythroid response criteria, and consider early therapeutic intervention in clinical trials for anemia-directed therapies.
Collapse
Affiliation(s)
- Naseema Gangat
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ayalew Tefferi
- Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA
| |
Collapse
|
|
2
|
Welc SS, Brotto M, White KE, Bonewald LF. Aging: A struggle for beneficial to overcome negative factors made by muscle and bone. Mech Ageing Dev 2025; 224:112039. [PMID: 39952614 PMCID: PMC11893237 DOI: 10.1016/j.mad.2025.112039] [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: 10/28/2024] [Revised: 12/15/2024] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.
Collapse
Affiliation(s)
- Steven S Welc
- Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
| | - Marco Brotto
- Bone-Muscle Research Center, College of Nursing & Health Innovation, University of Texas-Arlington, Arlington, TX 76019, USA.
| | - Kenneth E White
- Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Department of Molecular and Medical Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
| | - Lynda F Bonewald
- Department of Anatomy, Cell Biology, & Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA; Indiana Center for Musculoskeletal Health, School of Medicine, Indiana University, Indianapolis, IN 46202, USA.
| |
Collapse
|
|
3
|
Ongaro L, Zhou X, Wang Y, Schultz H, Zhou Z, Buddle ERS, Brûlé E, Lin YF, Schang G, Hagg A, Castonguay R, Liu Y, Su GH, Seidah NG, Ray KC, Karp SJ, Boehm U, Ruf-Zamojski F, Sealfon SC, Walton KL, Lee SJ, Bernard DJ. Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis. Science 2025; 387:329-336. [PMID: 39818879 DOI: 10.1126/science.adi4736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/18/2024] [Accepted: 10/31/2024] [Indexed: 01/19/2025]
Abstract
Myostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor-β family, the activins. Our results both challenge activin's eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility.
Collapse
Affiliation(s)
- Luisina Ongaro
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Xiang Zhou
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Ying Wang
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Hailey Schultz
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
| | - Ziyue Zhou
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Evan R S Buddle
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Emilie Brûlé
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
| | - Yeu-Farn Lin
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Gauthier Schang
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Adam Hagg
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | | | - Yewei Liu
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Gloria H Su
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM)-University of Montreal, Montreal, Quebec, Canada
| | - Kevin C Ray
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Seth J Karp
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ulrich Boehm
- Department of Pharmacology and Toxicology, University of Saarland School of Medicine, Homburg, Germany
| | - Frederique Ruf-Zamojski
- Cedars-Sinai Medical Center, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Los Angeles, CA, USA
| | - Stuart C Sealfon
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kelly L Walton
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Se-Jin Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Daniel J Bernard
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
| |
Collapse
|
|
4
|
Lachey J, Rovaldi C, Bobba S, Tur J, Natarajan H, Snyder B, Seehra J. Elritercept, a modified activin receptor IIA ligand trap, increased erythropoiesis and thrombopoiesis in a phase 1 trial. Blood Adv 2025; 9:193-201. [PMID: 39437803 PMCID: PMC11758838 DOI: 10.1182/bloodadvances.2024014172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/19/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024] Open
Abstract
ABSTRACT The transforming growth factor β (TGF-β) superfamily plays a crucial role in regulating biological processes of virtually every tissue and system in the body, including hemostasis and hematopoiesis. Elritercept (KER-050) is an investigational, modified activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands, including activin B, growth differentiation factor 8 (GDF-8), and GDF-11. The objectives of this phase 1 randomized, placebo-controlled study of elritercept were to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic markers of activin inhibition and hematopoiesis in healthy postmenopausal women (N = 48). This study comprised 2 parts: single ascending doses ranging from 0.05 to 4.5 mg/kg; and multiple (up to 2 doses) ascending doses of 0.75 mg/kg administered subcutaneously (SC) every 4 weeks. Elritercept was generally well tolerated at all dose levels, with no dose-limiting toxicities observed. There were no severe or serious adverse events or clinically significant changes in safety laboratory measures. Serum concentrations increased in a dose-proportional manner after single SC doses, with peak concentrations achieved in 4.5 to 6 days and a mean elimination half-life of 12 days. These parameters were comparable after multiple doses. Elritercept elicited rapid, sustained, and dose-dependent increases in reticulocytes, red blood cells, hemoglobin, and platelets without eliciting detrimental changes in white blood cells such as neutrophils and lymphocytes. The time course and duration of changes in these cell populations supported a differentiated pharmacologic profile that is consistent with the stimulation of both early- and late-stage hematologic pathways. The trial was registered at www.anzctr.org.au/ as #ACTRN12619000318189.
Collapse
Affiliation(s)
| | | | | | | | | | - Ben Snyder
- Nucleus Network, Melbourne, VIC, Australia
| | | |
Collapse
|
|
5
|
Stump B, Waxman AB. Pulmonary Arterial Hypertension and TGF-β Superfamily Signaling: Focus on Sotatercept. BioDrugs 2024; 38:743-753. [PMID: 39292393 DOI: 10.1007/s40259-024-00680-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 09/19/2024]
Abstract
Pulmonary arterial hypertension (PAH) is a rare and progressive disease that continues to remain highly morbid despite multiple advances in medical therapies. There remains a persistent and desperate need to identify novel methods of treating and, ideally, reversing the pathologic vasculopathy that results in PAH development and progression. Sotatercept is a first-in-class fusion protein that is believed to primarily inhibit activin signaling resulting in decreased cell proliferation and differentiation, though the exact mechanism remains uncertain. Here, we review the currently available PAH therapies, data highlighting the importance of transforming growth factor-β (TGF-β) superfamily signaling in the development of PAH, and the published and on-going clinical trials evaluating sotatercept in the treatment of PAH. We will also discuss preclinical data supporting the potential use of the fusion protein KER-012 in the inhibition of aberrant TGF-β superfamily signaling to ameliorate the obstructive vasculopathy of PAH.
Collapse
|
|
6
|
Preston IR, Lewis D, Gomberg-Maitland M. Using Sotatercept in the Care of Patients With Pulmonary Arterial Hypertension. Chest 2024; 166:604-611. [PMID: 39004216 DOI: 10.1016/j.chest.2024.06.3801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 07/16/2024] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary microvasculature leading to elevated precapillary pulmonary hypertension. Pulmonary vascular remodeling, a characteristic of PAH, is driven by dysfunctions in the signaling between the pulmonary smooth muscle and endothelial cells with abnormalities that affect cell proliferation and immune dysregulation. Sotatercept, an activin signaling inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of PAH based on two pivotal clinical trials. Evidence-based clinical trials have provided a framework to guide clinicians treating the disease; however, they are not tailored to the individual patient. Often, recommendations from these data are unclear or too general, due to remaining gaps in knowledge. In this edition of "How I Do It," we provide a case-based discussion of common clinical decisions regarding diagnostic testing, choice of first-line agents, escalation of therapy, potential timing of sotatercept, safety awareness, practical use, potential management changes, and the future use of sotatercept in other pulmonary hypertension cohorts.
Collapse
Affiliation(s)
- Ioana R Preston
- Pulmonary Critical Care and Sleep Division, Tufts University School of Medicine, Boston, MA.
| | - Denise Lewis
- Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Mardi Gomberg-Maitland
- Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC
| |
Collapse
|
|
7
|
Bozzini C, Busti F, Marchi G, Vianello A, Cerchione C, Martinelli G, Girelli D. Anemia in patients receiving anticancer treatments: focus on novel therapeutic approaches. Front Oncol 2024; 14:1380358. [PMID: 38628673 PMCID: PMC11018927 DOI: 10.3389/fonc.2024.1380358] [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: 02/01/2024] [Accepted: 03/19/2024] [Indexed: 04/19/2024] Open
Abstract
Anemia is common in cancer patients and impacts on quality of life and prognosis. It is typically multifactorial, often involving different pathophysiological mechanisms, making treatment a difficult task. In patients undergoing active anticancer treatments like chemotherapy, decreased red blood cell (RBC) production due to myelosuppression generally predominates, but absolute or functional iron deficiency frequently coexists. Current treatments for chemotherapy-related anemia include blood transfusions, erythropoiesis-stimulating agents, and iron supplementation. Each option has limitations, and there is an urgent need for novel approaches. After decades of relative immobilism, several promising anti-anemic drugs are now entering the clinical scenario. Emerging novel classes of anti-anemic drugs recently introduced or in development for other types of anemia include activin receptor ligand traps, hypoxia-inducible factor-prolyl hydroxylase inhibitors, and hepcidin antagonists. Here, we discuss their possible role in the treatment of anemia observed in patients receiving anticancer therapies.
Collapse
Affiliation(s)
- Claudia Bozzini
- Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy
- EuroBloodNet Referral Center, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Fabiana Busti
- Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy
- EuroBloodNet Referral Center, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Giacomo Marchi
- Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy
- EuroBloodNet Referral Center, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Alice Vianello
- Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy
- EuroBloodNet Referral Center, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Claudio Cerchione
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Giovanni Martinelli
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
| | - Domenico Girelli
- Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy
- EuroBloodNet Referral Center, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| |
Collapse
|
|
8
|
Wang Y, Nguyen JH, de Ruiter RD, Mendell J, Srinivasan D, Davis JD, Eekhoff EMW. Garetosmab in Fibrodysplasia Ossificans Progressiva: Clinical Pharmacology Results from the Phase 2 LUMINA-1 Trial. J Clin Pharmacol 2024; 64:264-274. [PMID: 37694449 DOI: 10.1002/jcph.2344] [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: 05/23/2023] [Accepted: 09/06/2023] [Indexed: 09/12/2023]
Abstract
Here, we report the clinical pharmacology data from LUMINA-1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty-four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double-blind 28-week treatment period, followed by a 28-week open-label treatment period with garetosmab, and subsequent open-label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure-response analyses for efficacy and safety were performed with trough concentrations (Ctrough ) of garetosmab prior to dosing. Steady-state PK was reached 12-16 weeks after the first dose of garetosmab, with mean (standard deviation) Ctrough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti-garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration-time profiles between patients who did and did not experience epistaxis or death. The comparative exposure-response analyses demonstrated no association between Ctrough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target-mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial.
Collapse
Affiliation(s)
- Yuhuan Wang
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | | | - Ruben D de Ruiter
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers (UMC), Vrije Universiteit, Amsterdam UMC Expert Center in Rare Bone Disease, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| | | | | | | | - E Marelise W Eekhoff
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers (UMC), Vrije Universiteit, Amsterdam UMC Expert Center in Rare Bone Disease, Amsterdam Movement Sciences, Amsterdam, The Netherlands
| |
Collapse
|
|
9
|
Richardson L, Wilcockson SG, Guglielmi L, Hill CS. Context-dependent TGFβ family signalling in cell fate regulation. Nat Rev Mol Cell Biol 2023; 24:876-894. [PMID: 37596501 DOI: 10.1038/s41580-023-00638-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2023] [Indexed: 08/20/2023]
Abstract
The transforming growth factor-β (TGFβ) family are a large group of evolutionarily conserved cytokines whose signalling modulates cell fate decision-making across varying cellular contexts at different stages of life. Here we discuss new findings in early embryos that reveal how, in contrast to our original understanding of morphogen interpretation, robust cell fate specification can originate from a noisy combination of signalling inputs and a broad range of signalling levels. We compare this evidence with novel findings on the roles of TGFβ family signalling in tissue maintenance and homeostasis during juvenile and adult life, spanning the skeletal, haemopoietic and immune systems. From these comparisons, it emerges that in contrast to robust developing systems, relatively small perturbations in TGFβ family signalling have detrimental effects at later stages in life, leading to aberrant cell fate specification and disease, for example in cancer or congenital disorders. Finally, we highlight novel strategies to target and amend dysfunction in signalling and discuss how gleaning knowledge from different fields of biology can help in the development of therapeutics for aberrant TGFβ family signalling in disease.
Collapse
Affiliation(s)
- Louise Richardson
- Developmental Signalling Laboratory, The Francis Crick Institute, London, UK
| | - Scott G Wilcockson
- Developmental Signalling Laboratory, The Francis Crick Institute, London, UK
| | - Luca Guglielmi
- Developmental Signalling Laboratory, The Francis Crick Institute, London, UK
- Division of Cell Biology, MRC Laboratory of Molecular Biology, Cambridge, UK
| | - Caroline S Hill
- Developmental Signalling Laboratory, The Francis Crick Institute, London, UK.
| |
Collapse
|
|
10
|
Lan Z, Lv Z, Zuo W, Xiao Y. From bench to bedside: The promise of sotatercept in hematologic disorders. Biomed Pharmacother 2023; 165:115239. [PMID: 37516019 DOI: 10.1016/j.biopha.2023.115239] [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: 05/30/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 07/31/2023] Open
Abstract
Sotatercept (ACE-011) is an activin receptor IIA-Fc (ActRIIA-Fc) fusion protein currently under investigation for its potential in the treatment of hematologic diseases. By impeding the activities of the overexpressed growth and differentiation factor 11 (GDF11), activin A, and other members of the transforming growth factor-β (TGF-β) superfamily, commonly found in hematologic disorders, sotatercept aims to restore the normal functioning of red blood cell maturation and osteoblast differentiation. This action is anticipated to enhance anemia management and hinder the progression of myeloma. Simultaneously, comprehensive research is ongoing to investigate sotatercept's pharmacokinetics and potential adverse reactions, thus laying a robust foundation for its prospective clinical use. In this review, we provide a detailed overview of TGF-β pathways in physiological and hematologic disorder contexts, outline the potential mechanism of sotatercept, and delve into its pharmacokinetics and clinical research advancements in various hematologic diseases. A particular emphasis is given to the relationship between sotatercept dosage and its efficacy or associated adverse reactions.
Collapse
Affiliation(s)
- Zehao Lan
- Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, China; Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Zhaohua Lv
- Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, China; Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Wanyun Zuo
- Department of Hematology, Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Yichao Xiao
- Department of Cardiovascular Medicine, Second Xiangya Hospital of Central South University, Changsha 410011, China.
| |
Collapse
|
|
11
|
Gielen E, Dupont J, Dejaeger M, Laurent MR. Sarcopenia, osteoporosis and frailty. Metabolism 2023; 145:155638. [PMID: 37348597 DOI: 10.1016/j.metabol.2023.155638] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/21/2023] [Accepted: 06/17/2023] [Indexed: 06/24/2023]
Abstract
Muscles and bones are intricately connected tissues displaying marked co-variation during development, growth, aging, and in many diseases. While the diagnosis and treatment of osteoporosis are well established in clinical practice, sarcopenia has only been classified internationally as a disease in 2016. Both conditions are associated with an increased risk of adverse health outcomes such as fractures, dysmobility and mortality. Rather than focusing on one dimension of bone or muscle mass or weakness, the concept of musculoskeletal frailty captures the overall loss of physiological reserves in the locomotor system with age. The term osteosarcopenia in particular refers to the double jeopardy of osteoporosis and sarcopenia. Muscle-bone interactions at the biomechanical, cellular, paracrine, endocrine, neuronal or nutritional level may contribute to the pathophysiology of osteosarcopenia. The paradigm wherein muscle force controls bone strength is increasingly facing competition from a model centering on the exchange of myokines, osteokines and adipokines. The most promising results have been obtained in preclinical models where common drug targets have been identified to treat these conditions simultaneously. In this narrative review, we critically summarize the current understanding of the definitions, epidemiology, pathophysiology, and treatment of osteosarcopenia as part of an integrative approach to musculoskeletal frailty.
Collapse
Affiliation(s)
- Evelien Gielen
- Gerontology and Geriatrics Unit, Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium; Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Jolan Dupont
- Gerontology and Geriatrics Unit, Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium
| | - Marian Dejaeger
- Gerontology and Geriatrics Unit, Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium; Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium
| | - Michaël R Laurent
- Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium; Geriatrics Department, Imelda Hospital, Bonheiden, Belgium.
| |
Collapse
|
|
12
|
Teawtrakul N, Chansai S, Yamsri S, Chansung K, Wanitpongpun C, Lanamtieng T, Phiphitaporn P, Fucharoen S, Pongchaiyakul C. The association of growth differentiation factor-15 levels and osteoporosis in patients with thalassemia. Am J Med Sci 2023:S0002-9629(23)01173-4. [PMID: 37146903 DOI: 10.1016/j.amjms.2023.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 05/01/2023] [Indexed: 05/07/2023]
Abstract
INTRODUCTION Ineffective erythropoiesis (IE) is a significant risk factor for osteoporosis in individuals with thalassemia. Growth differentiation factor-15 (GDF15), a biomarker of IE, was found to be elevated in thalassemia patients. This study aimed to examine the association between GDF15 levels and osteoporosis in patients with thalassemia. METHODS A cross-sectional study was conducted in 130 adult patients with thalassemia in Thailand. Bone mineral density (BMD) at the lumbar spine was evaluated by dual-energy X-ray absorptiometry (DXA), and with a Z-score of less than -2.0 SD was defined as osteoporosis. GDF-15 was measured using the enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to examine the associated factors with the development of osteoporosis. Receiver operator characteristic (ROC) curve analysis was used to estimate the threshold of GDF15 in predicting osteoporosis. RESULTS Osteoporosis was detected in 55.4% (72/130) of the patients. Advanced age and high GDF15 levels were positively associated with osteoporosis, while an increased hemoglobin level was negatively associated with osteoporosis in patients with thalassemia. In this study, the GDF15 level's ROC demonstrated a good performance in predicting osteoporosis (AUC=0.77). CONCLUSIONS The prevalence of osteoporosis is high among adult thalassemia patients. Age and high GDF15 levels were significantly associated with osteoporosis in this study. A higher hemoglobin level is associated with a lower risk of osteoporosis. This study suggest that GDF15 could be used as a predictive biomarker for osteoporosis in patients with thalassemia. Adequate red blood cell transfusions and suppression of GDF15 function may be beneficial in preventing osteoporosis.
Collapse
Affiliation(s)
- Nattiya Teawtrakul
- Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 40002.
| | - Siriyakorn Chansai
- Medical science program, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand 40002; Centre for Research and Development of Medical Diagnostics Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Supawadee Yamsri
- Centre for Research and Development of Medical Diagnostics Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Kanchana Chansung
- Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Chinadol Wanitpongpun
- Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Theerin Lanamtieng
- Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Pisa Phiphitaporn
- Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Supan Fucharoen
- Centre for Research and Development of Medical Diagnostics Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand. 40002
| | - Chatlert Pongchaiyakul
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 40002
| |
Collapse
|
|
13
|
Anastasilakis AD, Polyzos SA, Rodopaios NE, Makras P, Kumar A, Kalra B, Mantzoros CS. Activins, follistatins and inhibins in postmenopausal osteoporosis: A proof of concept, case-control study. Metabolism 2023; 141:155397. [PMID: 36587801 DOI: 10.1016/j.metabol.2022.155397] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/24/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Bone metabolism has been proposed to be affected by the activins-follistatins-inhibins (AFI) hormonal system. We aimed to evaluate AFI in patients with osteoporosis and osteopenia compared with postmenopausal and premenopausal controls. METHODS In this case-control study, circulating levels of the AFI system were evaluated, individually and jointly, between postmenopausal women with osteoporosis (BMD T-score ≤-2.5; n = 25) or osteopenia (BMD T-score >-2.5 and ≤-1; n = 25) and postmenopausal women with normal BMD (T-score >-1.0; n = 25) or premenopausal women with normal BMD (Z-score >-1.0; n = 25), with and without adjustment for potential confounders. RESULTS In the sum of participants, AFI molecules and their ratios followed an opposite pattern of correlations for age and BMI vs. BMD. In unadjusted models, FSTL3 concentrations were higher, whereas activin B, inhibin A and inhibin B and the ratios of activin B/follistatin and activin B/FSTL3 were lower in the three postmenopausal groups compared with the premenopausal group. Activin A/follistatin and activin AB/follistatin ratios were lower in the osteoporosis group than the other three groups. After adjustment for BMI and age, inhibin B (p = 0.005), and the ratios of activin A/follistatin (p = 0.009), activin B/follistatin (p = 0.040) and activin AB/follistatin (p = 0.003) were lower in the osteoporotic group compared with the other groups. In fully adjusted logistic regression analysis log(inhibin B) (p = 0.041), log(activinA/follistatin) (p = 0.014), log(activinB/follistatin) (p = 0.025) and log(activinAB/follistatin) (p = 0.021), but not FSTL3, remained independently associated with the presence of osteoporosis. CONCLUSIONS Lower inhibin B and higher ratios of activins A, B, and AB to follistatin are associated with lumbar spine BMD and the presence of osteoporosis independently from age or BMI.
Collapse
Affiliation(s)
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos E Rodopaios
- Department of Social Medicine, Preventive Medicine and Nutrition Clinic, School of Medicine, University of Crete, Voutes, 71003 Iraklion, Greece
| | - Polyzois Makras
- Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece; Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | | | | | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
14
|
Brent MB. Pharmaceutical treatment of bone loss: From animal models and drug development to future treatment strategies. Pharmacol Ther 2023; 244:108383. [PMID: 36933702 DOI: 10.1016/j.pharmthera.2023.108383] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/18/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023]
Abstract
Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.
Collapse
Affiliation(s)
- Mikkel Bo Brent
- Department of Biomedicine, Aarhus University, Denmark, Wilhelm Meyers Allé 3, 8000 Aarhus C, Denmark.
| |
Collapse
|
|
15
|
Zhao J, Wang Q, Deng X, Qian J, Tian Z, Liu Y, Li M, Zeng X. The treatment strategy of connective tissue disease associated pulmonary arterial hypertension: Evolving into the future. Pharmacol Ther 2022; 239:108192. [DOI: 10.1016/j.pharmthera.2022.108192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 04/07/2022] [Accepted: 04/18/2022] [Indexed: 11/30/2022]
|
|
16
|
Andre P, Joshi SR, Briscoe SD, Alexander MJ, Li G, Kumar R. Therapeutic Approaches for Treating Pulmonary Arterial Hypertension by Correcting Imbalanced TGF-β Superfamily Signaling. Front Med (Lausanne) 2022; 8:814222. [PMID: 35141256 PMCID: PMC8818880 DOI: 10.3389/fmed.2021.814222] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/15/2021] [Indexed: 12/19/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease characterized by high blood pressure in the pulmonary circulation driven by pathological remodeling of distal pulmonary arteries, leading typically to death by right ventricular failure. Available treatments improve physical activity and slow disease progression, but they act primarily as vasodilators and have limited effects on the biological cause of the disease—the uncontrolled proliferation of vascular endothelial and smooth muscle cells. Imbalanced signaling by the transforming growth factor-β (TGF-β) superfamily contributes extensively to dysregulated vascular cell proliferation in PAH, with overactive pro-proliferative SMAD2/3 signaling occurring alongside deficient anti-proliferative SMAD1/5/8 signaling. We review the TGF-β superfamily mechanisms underlying PAH pathogenesis, superfamily interactions with inflammation and mechanobiological forces, and therapeutic strategies under development that aim to restore SMAD signaling balance in the diseased pulmonary arterial vessels. These strategies could potentially reverse pulmonary arterial remodeling in PAH by targeting causative mechanisms and therefore hold significant promise for the PAH patient population.
Collapse
|
|
17
|
Vescini F, Chiodini I, Falchetti A, Palermo A, Salcuni AS, Bonadonna S, De Geronimo V, Cesareo R, Giovanelli L, Brigo M, Bertoldo F, Scillitani A, Gennari L. Management of Osteoporosis in Men: A Narrative Review. Int J Mol Sci 2021; 22:ijms222413640. [PMID: 34948434 PMCID: PMC8705761 DOI: 10.3390/ijms222413640] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.
Collapse
Affiliation(s)
- Fabio Vescini
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, 33100 Udine, Italy; (F.V.); (A.S.S.)
| | - Iacopo Chiodini
- Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy; (A.F.); (S.B.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy;
- Correspondence:
| | - Alberto Falchetti
- Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy; (A.F.); (S.B.)
| | - Andrea Palermo
- Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy;
| | - Antonio Stefano Salcuni
- Endocrinology and Metabolism Unit, University-Hospital S. Maria della Misericordia, 33100 Udine, Italy; (F.V.); (A.S.S.)
| | - Stefania Bonadonna
- Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy; (A.F.); (S.B.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy;
| | | | - Roberto Cesareo
- Center of Metabolic Disease, S.M. Goretti Hospital, 04100 Latina, Italy;
| | - Luca Giovanelli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy;
| | - Martina Brigo
- Department of Medicine, University of Verona, 37129 Verona, Italy; (M.B.); (F.B.)
| | - Francesco Bertoldo
- Department of Medicine, University of Verona, 37129 Verona, Italy; (M.B.); (F.B.)
| | - Alfredo Scillitani
- Unit of Endocrinology, Ospedale “Casa Sollievo della Sofferenza”, IRCCS, San Giovanni Rotondo, 71013 Foggia, Italy;
| | - Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy;
| |
Collapse
|
|
18
|
Functionally diverse heteromeric traps for ligands of the transforming growth factor-β superfamily. Sci Rep 2021; 11:18341. [PMID: 34526551 PMCID: PMC8443706 DOI: 10.1038/s41598-021-97203-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/18/2021] [Indexed: 01/19/2023] Open
Abstract
Ligands of the transforming growth factor-β (TGF-β) superfamily are important targets for therapeutic intervention but present challenges because they signal combinatorially and exhibit overlapping activities in vivo. To obtain agents capable of sequestering multiple TGF-β superfamily ligands with novel selectivity, we generated soluble, heterodimeric ligand traps by pairing the extracellular domain (ECD) of the native activin receptor type IIB (ActRIIB) alternately with the ECDs of native type I receptors activin receptor-like kinase 4 (ALK4), ALK7, or ALK3. Systematic analysis of these heterodimeric constructs by surface plasmon resonance, and comparison with their homodimeric counterparts, revealed that each type I receptor partner confers a distinct ligand-binding profile to the heterodimeric construct. Additional characterization in cell-based reporter gene assays confirmed that the heterodimeric constructs possessed different profiles of signaling inhibition in vitro, which translated into altered patterns of pharmacological activity when constructs were administered systemically to wild-type mice. Our results detail a versatile platform for the modular recombination of naturally occurring receptor domains, giving rise to inhibitory ligand traps that could aid in defining the physiological roles of TGF-β ligand sets or be directed therapeutically to human diseases arising from dysregulated TGF-β superfamily signaling.
Collapse
|
|
19
|
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.
Collapse
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.)
| |
Collapse
|
|
20
|
Bohaczuk SC, Cassin J, Slaiwa TI, Thackray VG, Mellon PL. Distal Enhancer Potentiates Activin- and GnRH-Induced Transcription of FSHB. Endocrinology 2021; 162:6213400. [PMID: 33824966 PMCID: PMC8157479 DOI: 10.1210/endocr/bqab069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Indexed: 11/19/2022]
Abstract
FSH is critical for fertility. Transcription of FSHB, the gene encoding the beta subunit, is rate-limiting in FSH production and is regulated by both GnRH and activin. Activin signals through SMAD transcription factors. Although the mechanisms and importance of activin signaling in mouse Fshb transcription are well-established, activin regulation of human FSHB is less well understood. We previously reported a novel enhancer of FSHB that contains a fertility-associated single nucleotide polymorphism (rs10031006) and requires a region resembling a full (8 base-pair) SMAD binding element (SBE). Here, we investigated the role of the putative SBE within the enhancer in activin and GnRH regulation of FSHB. In mouse gonadotrope-derived LβT2 cells, the upstream enhancer potentiated activin induction of both the human and mouse FSHB proximal promoters and conferred activin responsiveness to a minimal promoter. Activin induction of the enhancer required the SBE and was blocked by the inhibitory SMAD7, confirming involvement of the classical SMAD signaling pathway. GnRH induction of FSHB was also potentiated by the enhancer and dependent on the SBE, consistent with known activin/GnRH synergy regulating FSHB transcription. In DNA pull-down, the enhancer SBE bound SMAD4, and chromatin immunoprecipitation demonstrated SMAD4 enrichment at the enhancer in native chromatin. Combined activin/GnRH treatment elevated levels of the active transcriptional histone marker, histone 3 lysine 27 acetylation, at the enhancer. Overall, this study indicates that the enhancer is directly targeted by activin signaling and identifies a novel, evolutionarily conserved mechanism by which activin and GnRH can regulate FSHB transcription.
Collapse
Affiliation(s)
- Stephanie C Bohaczuk
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California 92093, USA
| | - Jessica Cassin
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California 92093, USA
| | - Theresa I Slaiwa
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California 92093, USA
| | - Varykina G Thackray
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California 92093, USA
| | - Pamela L Mellon
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California 92093, USA
- Correspondence: Pamela L. Mellon, Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. E-mail:
| |
Collapse
|
|
21
|
Lodberg A. Principles of the activin receptor signaling pathway and its inhibition. Cytokine Growth Factor Rev 2021; 60:1-17. [PMID: 33933900 DOI: 10.1016/j.cytogfr.2021.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 01/19/2023]
Abstract
This review captures the anabolic and stimulatory effects observed with inhibition of the transforming growth factor β superfamily in muscle, blood, and bone. New medicinal substances that rectify activin, myostatin, and growth differentiation factor 11 signaling give hope to the many whose lives are affected by deterioration of these tissues. The review first covers the origin, structure, and common pathway of activins, myostatin, and growth differentiation factor 11 along with the pharmacodynamics of the new class of molecules designed to oppose the activin receptor signaling pathway. Current terminology surrounding this new class of molecules is inconsistent and does not infer functionality. Adopting inhibitors of the activin receptor signaling pathway (IASPs) as a generic term is proposed because it encapsulates the molecular mechanisms along the pathway trajectory. To conclude, a pragmatic classification of IASPs is presented that integrates functionality and side effects based on the data available from animals and humans. This provides researchers and clinicians with a tool to tailor IASPs therapy according to the need of projects or patients and with respect to side effects.
Collapse
Affiliation(s)
- Andreas Lodberg
- Department of Biomedicine, Aarhus University, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Wilhelm Meyers Allé, DK-8000, Aarhus, Denmark.
| |
Collapse
|
|
22
|
Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, Badesch DB. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2021; 384:1204-1215. [PMID: 33789009 DOI: 10.1056/nejmoa2024277] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).
Collapse
Affiliation(s)
- Marc Humbert
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Vallerie McLaughlin
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - J Simon R Gibbs
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Mardi Gomberg-Maitland
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Marius M Hoeper
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Ioana R Preston
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Rogerio Souza
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Aaron Waxman
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Pilar Escribano Subias
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Jeremy Feldman
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Gisela Meyer
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - David Montani
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Karen M Olsson
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Solaiappan Manimaran
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Jennifer Barnes
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Peter G Linde
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - Janethe de Oliveira Pena
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| | - David B Badesch
- From the Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, INSERM Unité Mixte de Recherche 999, Université Paris-Saclay, Le Kremlin-Bicêtre, France (M.H., D.M.); the Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor (V.M.); the National Heart and Lung Institute, Imperial College London, and the National Pulmonary Hypertension Service, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (J.S.R.G.); the Department of Medicine, George Washington University, Washington, DC (M.G.-M.); the Department of Respiratory Medicine, Hannover Medical School, and the German Center for Lung Research - both in Hannover, Germany (M.M.H., K.M.O.); the Division of Pulmonary, Critical Care and Sleep Medicine, Tufts Medical Center (I.R.P.), and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital (A.W.), Boston, and Acceleron Pharma, Cambridge (S.M., J.B., P.G.L., J.O.P.) - all in Massachusetts; the Pulmonary Division-Heart Institute, University of São Paulo Medical School, São Paulo (R.S.), and Complexo Hospitalar Santa Casa de Porto Alegre, Pulmonary Vascular Research Institute, Porto Alegre (G.M.) - both in Brazil; the Department of Cardiology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Hospital Universitario 12 de Octubre, Universidad Complutense, Madrid (P.E.S.); Arizona Pulmonary Specialists, Phoenix (J.F.); and the Divisions of Pulmonary Sciences and Critical Care Medicine, and Cardiology, University of Colorado, Anschutz Medical Campus, Aurora (D.B.B.)
| |
Collapse
|
|
23
|
Qanash H, Li Y, Smith RH, Linask K, Young-Baird S, Hakami W, Keyvanfar K, Choy JS, Zou J, Larochelle A. Eltrombopag Improves Erythroid Differentiation in a Human Induced Pluripotent Stem Cell Model of Diamond Blackfan Anemia. Cells 2021; 10:734. [PMID: 33810313 PMCID: PMC8065708 DOI: 10.3390/cells10040734] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 12/15/2022] Open
Abstract
Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. Ribosomal dysfunction delays globin synthesis, resulting in excess toxic free heme in erythroid progenitors, early differentiation arrest, and pure red cell aplasia. In this study, DBA induced pluripotent stem cell (iPSC) lines were generated from blood mononuclear cells of DBA patients with inactivating mutations in RPS19 and subjected to hematopoietic differentiation to model disease phenotypes. In vitro differentiated hematopoietic cells were used to investigate whether eltrombopag, an FDA-approved mimetic of thrombopoietin with robust intracellular iron chelating properties, could rescue erythropoiesis in DBA by restricting the labile iron pool (LIP) derived from excessive free heme. DBA iPSCs exhibited RPS19 haploinsufficiency, reduction in the 40S/60S ribosomal subunit ratio and early erythroid differentiation arrest in the absence of eltrombopag, compared to control isogenic iPSCs established by CRISPR/Cas9-mediated correction of the RPS19 point mutation. Notably, differentiation of DBA iPSCs in the presence of eltrombopag markedly improved erythroid maturation. Consistent with a molecular mechanism based on intracellular iron chelation, we observed that deferasirox, a clinically licensed iron chelator able to permeate into cells, also enhanced erythropoiesis in our DBA iPSC model. In contrast, erythroid maturation did not improve substantially in DBA iPSC differentiation cultures supplemented with deferoxamine, a clinically available iron chelator that poorly accesses LIP within cellular compartments. These findings identify eltrombopag as a promising new therapeutic to improve anemia in DBA.
Collapse
Affiliation(s)
- Husam Qanash
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; (H.Q.); (Y.L.); (R.H.S.); (W.H.)
- Department of Biology, Catholic University of America, Washington, DC 20064, USA;
- Department of Medical Laboratory Science, College of Applied Medical Sciences, The University of Hail, Hail 55476, Saudi Arabia
| | - Yongqin Li
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; (H.Q.); (Y.L.); (R.H.S.); (W.H.)
| | - Richard H. Smith
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; (H.Q.); (Y.L.); (R.H.S.); (W.H.)
| | - Kaari Linask
- iPSC Core Facility, NHLBI, NIH, Bethesda, MD 20892, USA; (K.L.); (J.Z.)
| | - Sara Young-Baird
- Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA;
- National Institute of General Medical Sciences (NIGMS), NIH, Bethesda, MD 20892, USA
| | - Waleed Hakami
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; (H.Q.); (Y.L.); (R.H.S.); (W.H.)
- Department of Biology, Catholic University of America, Washington, DC 20064, USA;
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Keyvan Keyvanfar
- Clinical Flow Core Facility, NHLBI, NIH, Bethesda, MD 20892, USA;
| | - John S. Choy
- Department of Biology, Catholic University of America, Washington, DC 20064, USA;
| | - Jizhong Zou
- iPSC Core Facility, NHLBI, NIH, Bethesda, MD 20892, USA; (K.L.); (J.Z.)
| | - Andre Larochelle
- Cellular and Molecular Therapeutics Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; (H.Q.); (Y.L.); (R.H.S.); (W.H.)
| |
Collapse
|
|
24
|
Abstract
PURPOSE OF REVIEW This review highlights recent discoveries and advances that have been made in understanding the role of the TGFβ superfamily members activins, and in particular, activin A (ActA), in renal disease. RECENT FINDINGS A deleterious role for ActA in renal disease and its complications has begun to emerge. We summarize data supporting an important contribution of ActA to kidney fibrosis and inflammation of varying causes, as well as its role in the development of a particular bone mineral disorder seen in chronic kidney disease (CKD) called mineral bone disorder (MBD), including vascular calcification. Finally, we discuss ActA in the context of anemia associated with chronic kidney disease and review potential approaches to treatment based on ActA blockade. SUMMARY ActA is an important contributor to the pathogenesis of acute and chronic kidney disease of varying causes. Preclinical studies show that ActA inhibition, through various approaches, is protective in rodent models of kidney disease. The potential adverse effects of some of these approaches can be attributed to their targeting of other TGFβ family ligands. Further preclinical and clinical investigations testing the therapeutic efficacy of more selective ActA inhibition on the progression of acute and chronic kidney disease and its impact on bone-mineral disorder would more definitively establish its role in renal disease.
Collapse
|
|
25
|
Parisi S, Finelli C, Fazio A, De Stefano A, Mongiorgi S, Ratti S, Cappellini A, Billi AM, Cocco L, Follo MY, Manzoli L. Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia. Int J Mol Sci 2021; 22:ijms22020827. [PMID: 33467674 PMCID: PMC7830211 DOI: 10.3390/ijms22020827] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/12/2021] [Accepted: 01/13/2021] [Indexed: 01/19/2023] Open
Abstract
Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.
Collapse
Affiliation(s)
- Sarah Parisi
- Department of Oncology and Hematology, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.P.); (C.F.)
- Department of Experimental, Diagnostic and Specialty Medicine DIMES, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
| | - Carlo Finelli
- Department of Oncology and Hematology, IRCCS-Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.P.); (C.F.)
- Department of Experimental, Diagnostic and Specialty Medicine DIMES, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
| | - Antonietta Fazio
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Alessia De Stefano
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Sara Mongiorgi
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Stefano Ratti
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Alessandra Cappellini
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Anna Maria Billi
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Lucio Cocco
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| | - Matilde Y. Follo
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
- Correspondence:
| | - Lucia Manzoli
- Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy; (A.F.); (A.D.S.); (S.M.); (S.R.); (A.C.); (A.M.B.); (L.C.); (L.M.)
| |
Collapse
|
|
26
|
Meier D, Lodberg A, Gvozdenovic A, Pellegrini G, Neklyudova O, Born W, Fuchs B, Eijken M, M. Botter S. Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma. Cancer Med 2021; 10:286-296. [PMID: 33179858 PMCID: PMC7826474 DOI: 10.1002/cam4.3581] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 01/02/2023] Open
Abstract
Osteosarcoma is a cancer of pathological bone remodeling with high mortality and severe comorbidity. New therapies are urgently needed. Activin A, a member of the transforming growth factor β (TGFβ) superfamily, has been suggested to stimulate proliferation and invasion of osteosarcoma cells in vitro, thus representing a potential therapeutic target. In this study, inhibition of the activin receptor signaling pathway was explored as a therapy for osteosarcoma. In a murine intratibial osteosarcoma xenograft model, two types of inhibitors were tested: (a) a soluble activin type IIA decoy receptor (ActRIIA-mFc), or (b) a modified variant of follistatin (FSTΔHBS -hFc), either alone or in combination with a bisphosphonate. Both inhibitors reduced primary tumor development by nearly 50% compared to vehicle treatment. When ActRIIA-mFc was combined with bisphosphonate, the effect on tumor size became even more pronounced (78% reduction vs. vehicle). Moreover, FSTΔHBS -hFc increased body weight in the face of tumor progression (14% increase vs. vehicle), and ActRIIA-mFc reduced the number of lung metastases when combined with bisphosphonate. The present study demonstrates a novel approach to treating osteosarcoma and encourages further investigation of inhibition of the activin receptor signaling pathway as an intervention against the disease.
Collapse
Affiliation(s)
- Daniela Meier
- Department of OrthopedicsBalgrist University HospitalZurichSwitzerland
| | - Andreas Lodberg
- Department of BiomedicineAarhus UniversityAarhusDenmark
- Department of Pulmonary MedicineAarhus University HospitalAarhusDenmark
| | - Ana Gvozdenovic
- Department of OrthopedicsBalgrist University HospitalZurichSwitzerland
| | - Giovanni Pellegrini
- Laboratory for Animal Model PathologyInstitute of Veterinary Pathology, University of ZurichZurichSwitzerland
| | - Olga Neklyudova
- Department of OrthopedicsBalgrist University HospitalZurichSwitzerland
| | - Walter Born
- Department of OrthopedicsBalgrist University HospitalZurichSwitzerland
| | - Bruno Fuchs
- Department of OrthopedicsBalgrist University HospitalZurichSwitzerland
| | - Marco Eijken
- Department of Renal MedicineAarhus University HospitalAarhusDenmark
- Department of Clinical ImmunologyAarhus University HospitalAarhusDenmark
| | - Sander M. Botter
- Department of OrthopedicsBalgrist University HospitalZurichSwitzerland
| |
Collapse
|
|
27
|
Activin Receptor-Ligand Trap for the Treatment of β-thalassemia: A Serendipitous Discovery. Mediterr J Hematol Infect Dis 2020; 12:e2020075. [PMID: 33194149 PMCID: PMC7643807 DOI: 10.4084/mjhid.2020.075] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/09/2020] [Indexed: 12/17/2022] Open
Abstract
β-thalassemia is a hereditary disorder caused by defective production of β-globin chains of hemoglobin (Hb) that leads to an increased α/β globins ratio with subsequent free α-globins. Alpha globin excess causes oxidative stress, red blood cells membrane damage, premature death of late-stage erythroid precursors, resulting in ineffective erythropoiesis. The transforming growth factor β (TGF-β) superfamily signaling acts on biological processes, such as cell quiescence, apoptosis, proliferation, differentiation, and migration, and plays an essential role in regulating the hematopoiesis. This pathway can lose its physiologic regulation in pathologic conditions, leading to anemia and ineffective erythropoiesis. Activin receptor-ligand trap molecules such as Sotatercept and Luspatercept downregulate the TGF-β pathway, thus inhibiting the Smad2/3 cascade and alleviating anemia in patients with β-thalassemia and myelodysplastic syndromes. In this review, we describe in extenso the TGF-β pathway, as well as the molecular and biological basis of activin receptors ligand traps, focusing on their role in various β-thalassemia experimental models. The most recent results from clinical trials on sotatercept and luspatercept will also be reviewed.
Collapse
|
|
28
|
Zhuang Z, John JV, Liao H, Luo J, Rubery P, Mesfin A, Boda SK, Xie J, Zhang X. Periosteum Mimetic Coating on Structural Bone Allografts via Electrospray Deposition Enhances Repair and Reconstruction of Segmental Defects. ACS Biomater Sci Eng 2020; 6:6241-6252. [PMID: 33449646 DOI: 10.1021/acsbiomaterials.0c00421] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Structural bone allograft transplantation remains one of the common strategies for repair and reconstruction of large bone defects. Due to the loss of periosteum that covers the outer surface of the cortical bone, the healing and incorporation of allografts is extremely slow and limited. To enhance the biological performance of allografts, herein, we report a novel and simple approach for engineering a periosteum mimetic coating on the surface of structural bone allografts via polymer-mediated electrospray deposition. This approach enables the coating on allografts with precisely controlled composition and thickness. In addition, the periosteum mimetic coating can be tailored to achieve desired drug release profiles by making use of an appropriate biodegradable polymer or polymer blend. The efficacy study in a murine segmental femoral bone defect model demonstrates that the allograft coating composed of poly(lactic-co-glycolic acid) and bone morphogenetic protein-2 mimicking peptide significantly improves allograft healing as evidenced by decreased fibrotic tissue formation, increased periosteal bone formation, and enhanced osseointegration. Taken together, this study provides a platform technology for engineering a periosteum mimetic coating which can greatly promote bone allograft healing. This technology could eventually result in an off-the-shelf and multifunctional structural bone allograft for highly effective repair and reconstruction of large segmental bone defects. The technology can also be used to ameliorate the performance of other medical implants by modifying their surfaces.
Collapse
Affiliation(s)
- Zhou Zhuang
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14621, United States
| | - Johnson V John
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska, Omaha, Nebraska 68198, United States
| | - Haofu Liao
- Department of Computer Science, University of Rochester, Rochester, New York 14627, United States
| | - Jiebo Luo
- Department of Computer Science, University of Rochester, Rochester, New York 14627, United States
| | - Paul Rubery
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, United States
| | - Addisu Mesfin
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, United States
| | - Sunil Kumar Boda
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska, Omaha, Nebraska 68198, United States
| | - Jingwei Xie
- Department of Surgery-Transplant and Mary & Dick Holland Regenerative Medicine Program, University of Nebraska, Omaha, Nebraska 68198, United States
| | - Xinping Zhang
- Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, United States
| |
Collapse
|
|
29
|
Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions. Int J Mol Sci 2020; 21:ijms21207597. [PMID: 33066607 PMCID: PMC7589189 DOI: 10.3390/ijms21207597] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/09/2020] [Accepted: 10/10/2020] [Indexed: 12/19/2022] Open
Abstract
The balance between bone forming cells (osteoblasts/osteocytes) and bone resorbing cells (osteoclasts) plays a crucial role in tissue homeostasis and bone repair. Several hormones, cytokines, and growth factors-in particular the members of the TGF-β superfamily such as the bone morphogenetic proteins-not only regulate the proliferation, differentiation, and functioning of these cells, but also coordinate the communication between them to ensure an appropriate response. Therefore, this review focuses on TGF-β superfamily and its influence on bone formation and repair, through the regulation of osteoclastogenesis, osteogenic differentiation of stem cells, and osteoblasts/osteoclasts balance. After introducing the main types of bone cells, their differentiation and cooperation during bone remodeling and fracture healing processes are discussed. Then, the TGF-β superfamily, its signaling via canonical and non-canonical pathways, as well as its regulation by Wnt/Notch or microRNAs are described and discussed. Its important role in bone homeostasis, repair, or disease is also highlighted. Finally, the clinical therapeutic uses of members of the TGF-β superfamily and their associated complications are debated.
Collapse
|
|
30
|
Suh J, Lee YS. Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders? J Bone Metab 2020; 27:151-165. [PMID: 32911580 PMCID: PMC7571243 DOI: 10.11005/jbm.2020.27.3.151] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 06/23/2020] [Indexed: 01/19/2023] Open
Abstract
Myostatin, also known as growth differentiation factor 8 (GDF8), is a transforming growth factor-β (TGF-β) family member that functions to limit skeletal muscle growth. Accordingly, loss-of-function mutations in myostatin result in a dramatic increase in muscle mass in humans and various animals, while its overexpression leads to severe muscle atrophy. Myostatin also exerts a significant effect on bone metabolism, as demonstrated by enhanced bone mineral density and bone regeneration in myostatin null mice. The identification of myostatin as a negative regulator of muscle and bone mass has sparked an enormous interest in developing myostatin inhibitors as therapeutic agents for treating a variety of clinical conditions associated with musculoskeletal disorders. As a result, various myostatin-targeting strategies involving antibodies, myostatin propeptides, soluble receptors, and endogenous antagonists have been generated, and many of them have progressed to clinical trials. Importantly, most myostatin inhibitors also repress the activities of other closely related TGF-β family members including GDF11, activins, and bone morphogenetic proteins (BMPs), increasing the potential for unwanted side effects, such as vascular side effects through inhibition of BMP 9/10 and bone weakness induced by follistatin through antagonizing several TGF-β family members. Therefore, a careful distinction between targets that may enhance the efficacy of an agent and those that may cause adverse effects is required with the improvement of the target specificity. In this review, we discuss the current understanding of the endogenous function of myostatin, and provide an overview of clinical trial outcomes from different myostatin inhibitors.
Collapse
Affiliation(s)
- Joonho Suh
- Department of Molecular Genetics and Dental Pharmacology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Yun-Sil Lee
- Department of Molecular Genetics and Dental Pharmacology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| |
Collapse
|
|
31
|
De Rosa G, Andolfo I, Marra R, Manna F, Rosato BE, Iolascon A, Russo R. RAP-011 Rescues the Disease Phenotype in a Cellular Model of Congenital Dyserythropoietic Anemia Type II by Inhibiting the SMAD2-3 Pathway. Int J Mol Sci 2020; 21:ijms21155577. [PMID: 32759740 PMCID: PMC7432210 DOI: 10.3390/ijms21155577] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 01/12/2023] Open
Abstract
Congenital dyserythropoietic anemia type II (CDA II) is a hypo-productive anemia defined by ineffective erythropoiesis through maturation arrest of erythroid precursors. CDA II is an autosomal recessive disorder due to loss-of-function mutations in SEC23B. Currently, management of patients with CDA II is based on transfusions, splenectomy, or hematopoietic stem-cell transplantation. Several studies have highlighted benefits of ACE-011 (sotatercept) treatment of ineffective erythropoiesis, which acts as a ligand trap against growth differentiation factor (GDF)11. Herein, we show that GDF11 levels are increased in CDA II, which suggests sotatercept as a targeted therapy for treatment of these patients. Treatment of stable clones of SEC23B-silenced erythroleukemia K562 cells with the iron-containing porphyrin hemin plus GDF11 increased expression of pSMAD2 and reduced nuclear localization of the transcription factor GATA1, with subsequent reduced gene expression of erythroid differentiation markers. We demonstrate that treatment of these SEC23B-silenced K562 cells with RAP-011, a "murinized" ortholog of sotatercept, rescues the disease phenotype by restoring gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway. Our data also demonstrate the effect of RAP-011 treatment in reducing the expression of erythroferrone in vitro, thus suggesting a possible beneficial role of the use of sotatercept in the management of iron overload in patients with CDA II.
Collapse
Affiliation(s)
- Gianluca De Rosa
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; (G.D.R.); (R.M.); (B.E.R.); (A.I.)
- Ceinge Biotecnologie Avanzate, 80145 Naples, Italy;
| | - Immacolata Andolfo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; (G.D.R.); (R.M.); (B.E.R.); (A.I.)
- Ceinge Biotecnologie Avanzate, 80145 Naples, Italy;
- Correspondence: (I.A.); (R.R.); Tel.: +39-081-3737736 (I.A.); +39-081-3737736 (R.R.)
| | - Roberta Marra
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; (G.D.R.); (R.M.); (B.E.R.); (A.I.)
- Ceinge Biotecnologie Avanzate, 80145 Naples, Italy;
| | | | - Barbara Eleni Rosato
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; (G.D.R.); (R.M.); (B.E.R.); (A.I.)
- Ceinge Biotecnologie Avanzate, 80145 Naples, Italy;
| | - Achille Iolascon
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; (G.D.R.); (R.M.); (B.E.R.); (A.I.)
- Ceinge Biotecnologie Avanzate, 80145 Naples, Italy;
| | - Roberta Russo
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy; (G.D.R.); (R.M.); (B.E.R.); (A.I.)
- Ceinge Biotecnologie Avanzate, 80145 Naples, Italy;
- Correspondence: (I.A.); (R.R.); Tel.: +39-081-3737736 (I.A.); +39-081-3737736 (R.R.)
| |
Collapse
|
|
32
|
Feld J, Navada SC, Silverman LR. Myelo-deception: Luspatercept & TGF-Beta ligand traps in myeloid diseases & anemia. Leuk Res 2020; 97:106430. [PMID: 32763582 DOI: 10.1016/j.leukres.2020.106430] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 01/19/2023]
Abstract
Myelodysplastic syndromes (MDS) encompass a clinically heterogenous group of diseases defined by a clonal bone marrow failure state. Patients with lower-risk MDS primarily suffer from the consequences of anemia, with a subset having increased risks of bleeding and infection. There are few good therapeutic options for this patient population, as patients are dependent on cytokine support to improve hematopoiesis. Our review will discuss luspatercept, a transforming growth factor (TGF)-Beta ligand trap, the first new Food & Drug Administration (FDA)-approved treatment in MDS in over a decade. We will explore the different TGF-Beta ligand traps that have been developed for a number of diseases, with a focus on myeloid malignancies.
Collapse
Affiliation(s)
- Jonathan Feld
- Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY, 10029, United States.
| | - Shyamala C Navada
- Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY, 10029, United States.
| | - Lewis R Silverman
- Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY, 10029, United States.
| |
Collapse
|
|
33
|
Komrokji RS. Activin Receptor II Ligand Traps: New Treatment Paradigm for Low-Risk MDS. Curr Hematol Malig Rep 2020; 14:346-351. [PMID: 31203517 DOI: 10.1007/s11899-019-00517-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Alleviating cytopenias, namely anemia, is the main goal of therapy in lower-risk myelodysplastic syndromes (MDS). Current available treatment options remain limited. We review the role of TGF-B pathway in MDS, the current available data on luspatercept and sotatercept development. RECENT FINDINGS TGF-B pathway is overactivated in MDS contributing to observed myelosuppression. SMADs, the downstream proteins of TGF-B pathway, are upregulated. GDF-11 is a negative regulator of terminal erythroid differentiation and an activin receptor ligand. Sotatercept and luspatercept are fusion ligand trap novel agents for activin II receptors A and B, respectively. Early promising results have been reported with those novel agents for treating anemia in lower-risk MDS patients, and higher responses were observed among patients with ring sideroblasts and SF3B1 mutation. A phase III randomized clinical trial with luspatercept was recently conducted. Activin receptor II ligand traps may represent a new paradigm for anemia treatment in MDS.
Collapse
Affiliation(s)
- Rami S Komrokji
- Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
| |
Collapse
|
|
34
|
Schang G, Ongaro L, Schultz H, Wang Y, Zhou X, Brûlé E, Boehm U, Lee SJ, Bernard DJ. Murine FSH Production Depends on the Activin Type II Receptors ACVR2A and ACVR2B. Endocrinology 2020; 161:5818077. [PMID: 32270195 PMCID: PMC7286621 DOI: 10.1210/endocr/bqaa056] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/06/2020] [Indexed: 12/31/2022]
Abstract
Activins are selective regulators of FSH production by pituitary gonadotrope cells. In a gonadotrope-like cell line, LβT2, activins stimulate FSH via the activin type IIA receptor (ACVR2A) and/or bone morphogenetic protein type II receptor (BMPR2). Consistent with these observations, FSH is greatly reduced, though still present, in global Acvr2a knockout mice. In contrast, FSH production is unaltered in gonadotrope-specific Bmpr2 knockout mice. In light of these results, we questioned whether an additional type II receptor might mediate the actions of activins or related TGF-β ligands in gonadotropes. We focused on the activin type IIB receptor (ACVR2B), even though it does not mediate activin actions in LβT2 cells. Using a Cre-lox strategy, we ablated Acvr2a and/or Acvr2b in murine gonadotropes. The resulting conditional knockout (cKO) animals were compared with littermate controls. Acvr2a cKO (cKO-A) females were subfertile (~70% reduced litter size), cKO-A males were hypogonadal, and both sexes showed marked decreases in serum FSH levels compared with controls. Acvr2b cKO (cKO-B) females were subfertile (~20% reduced litter size), cKO-B males had a moderate decrease in testicular weight, but only males showed a significant decrease in serum FSH levels relative to controls. Simultaneous deletion of both Acvr2a and Acvr2b in gonadotropes led to profound hypogonadism and FSH deficiency in both sexes; females were acyclic and sterile. Collectively, these data demonstrate that ACVR2A and ACVR2B are the critical type II receptors through which activins or related TGF-β ligands induce FSH production in mice in vivo.
Collapse
Affiliation(s)
- Gauthier Schang
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Luisina Ongaro
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Hailey Schultz
- Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada
| | - Ying Wang
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Xiang Zhou
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Emilie Brûlé
- Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada
| | - Ulrich Boehm
- Department of Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany
| | - Se-Jin Lee
- The Jackson Laboratory, Farmington, Connecticut
- University of Connecticut School of Medicine, Department of Genetics and Genome Sciences, Farmington, Connecticut
| | - Daniel J Bernard
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada
- Correspondence: Daniel J. Bernard, PhD, Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler room 1320, Montreal H3G 1Y6, QC, Canada. E-mail:
| |
Collapse
|
|
35
|
Ongaro L, Schang G, Zhou Z, Kumar TR, Treier M, Deng CX, Boehm U, Bernard DJ. Human Follicle-Stimulating Hormone ß Subunit Expression Depends on FOXL2 and SMAD4. Endocrinology 2020; 161:5805118. [PMID: 32191302 PMCID: PMC7182064 DOI: 10.1210/endocr/bqaa045] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/09/2020] [Indexed: 12/11/2022]
Abstract
Follicle-stimulating hormone (FSH), an essential regulator of mammalian fertility, is synthesized by pituitary gonadotrope cells in response to activins. In mice, activins signal via SMAD3, SMAD4, and FOXL2 to regulate transcription of the FSHβ subunit (Fshb) gene. Gonadotrope-specific deletion of Foxl2, alone or in combination with Smad4, renders mice FSH-deficient. Whether human FSHB expression is similarly regulated is not known. Here, we used a combination of transgenic and conditional knockout mouse strains to assess the roles of activins, FOXL2, and SMAD4 in regulation of the human FSHB gene. First, we cultured pituitaries from mice harboring a human FSHB transgene (hFSHB mice) and measured both murine Fshb and human FSHB messenger ribonucleic acid (mRNA) expression in response to exogenous activins or two antagonists of endogenous activin-like signaling (follistatin-288 and SB431542). Both murine Fshb and human FSHB expression were stimulated by activins and reduced by the inhibitors. Next, we analyzed human FSHB expression in hFSHB mice carrying floxed Foxl2 and Smad4 alleles. Cre-mediated ablation of FOXL2 and SMAD4 strongly reduced basal and activin-stimulated murine Fshb and human FSHB expression in cultured pituitaries. Finally, the hFSHB transgene was previously shown to rescue FSH production and fertility in Fshb knockout mice. However, gonadotrope-specific Foxl2/Smad4 knockout females carrying the hFSHB transgene have significantly reduced murine Fshb and human FSHB pituitary mRNA levels and are hypogonadal. Collectively, these data suggest that similar to Fshb regulation in mice, FOXL2 and SMAD4 play essential roles in human FSHB expression.
Collapse
Affiliation(s)
- Luisina Ongaro
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Gauthier Schang
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Ziyue Zhou
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - T Rajendra Kumar
- Department of Obstetrics and Gynecology, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO, US
| | - Mathias Treier
- Max-Delbrück Center for Molecular Medicine (MDC), Genetics of Metabolic and Reproductive Disorders, Berlin, Germany
| | - Chu-Xia Deng
- Faculty of Health Sciences, University of Macau, China
| | - Ulrich Boehm
- Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
| | - Daniel J Bernard
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
- Correspondence: Daniel J. Bernard Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada. E-mail:
| |
Collapse
|
|
36
|
Gennari L, Merlotti D, Falchetti A, Eller Vainicher C, Cosso R, Chiodini I. Emerging therapeutic targets for osteoporosis. Expert Opin Ther Targets 2020; 24:115-130. [PMID: 32050822 DOI: 10.1080/14728222.2020.1726889] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Osteoporosis is a chronic, skeletal disorder characterized by compromised bone strength and increased fracture risk; it affects 50% of women and 20% of men. In the past two decades, there have been substantial improvements in the pharmacotherapy of osteoporosis which have yielded potent inhibitors of bone resorption or stimulators of bone formation.Areas covered: This review discusses newly identified targets and pathways and conceptual approaches to the prevention of multiple age-related disorders. Furthermore, it summarizes existing therapeutic strategies for osteoporosis.Expert opinion: Our enhanced understanding of bone biology and the reciprocal interactions between bone and other tissues have allowed the identification of new targets that may facilitate the development of novel drugs. These drugs will hopefully achieve the uncoupling of bone formation from resorption and possibly exert a dual anabolic and antiresorptive effect on bone. Alas, limitations regarding adherence, efficacy on nonvertebral fracture prevention and the long-term adverse events still exist for currently available therapeutics. Moreover, the efficacy of most agents is limited by the tight coupling of osteoblasts and osteoclasts; hence the reduction of bone resorption invariably reduces bone formation, and vice versa. This field is very much 'a work in progress.'
Collapse
Affiliation(s)
- Luigi Gennari
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Daniela Merlotti
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Alberto Falchetti
- Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy
| | - Cristina Eller Vainicher
- Endocrinology and Diabetology Units, Department of Medical Sciences and Community, Fondazione Ca'Granda Ospedale Maggiore Policlinico IRCCS, Milan, Italy
| | - Roberta Cosso
- EndOsMet Villa Donatello Private Hospital, Florence, Italy
| | - Iacopo Chiodini
- Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy
| |
Collapse
|
|
37
|
Marino S, Petrusca DN, Roodman GD. Therapeutic targets in myeloma bone disease. Br J Pharmacol 2020; 178:1907-1922. [PMID: 31647573 DOI: 10.1111/bph.14889] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 09/09/2019] [Accepted: 09/17/2019] [Indexed: 12/13/2022] Open
Abstract
Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by a clonal proliferation of neoplastic plasma cells within the bone marrow. MM is the most frequent cancer involving the skeleton, causing osteolytic lesions, bone pain and pathological fractures that dramatically decrease MM patients' quality of life and survival. MM bone disease (MBD) results from uncoupling of bone remodelling in which excessive bone resorption is not compensated by new bone formation, due to a persistent suppression of osteoblast activity. Current management of MBD includes antiresorptive agents, bisphosphonates and denosumab, that are only partially effective due to their inability to repair the existing lesions. Thus, research into agents that prevent bone destruction and more importantly repair existing lesions by inducing new bone formation is essential. This review discusses the mechanisms regulating the uncoupled bone remodelling in MM and summarizes current advances in the treatment of MBD. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
Collapse
Affiliation(s)
- Silvia Marino
- Department of Medicine, Division Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Daniela N Petrusca
- Department of Medicine, Division Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - G David Roodman
- Department of Medicine, Division Hematology/Oncology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Roudebush VA Medical Center, Indianapolis, Indiana, USA
| |
Collapse
|
|
38
|
Coyne DW, Singh HN, Smith WT, Giuseppi AC, Connarn JN, Sherman ML, Dellanna F, Malluche HH, Hruska KA. Sotatercept Safety and Effects on Hemoglobin, Bone, and Vascular Calcification. Kidney Int Rep 2019; 4:1585-1597. [PMID: 31891000 PMCID: PMC6933454 DOI: 10.1016/j.ekir.2019.08.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/29/2019] [Accepted: 08/03/2019] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Patients with end-stage kidney disease (ESKD) exhibit anemia, chronic kidney disease‒mineral bone disorder (CKD-MBD), and cardiovascular disease. The REN-001 and REN-002 phase II, multicenter, randomized studies examined safety, tolerability, and effects of sotatercept, an ActRIIA-IgG1 fusion protein trap, on hemoglobin concentration; REN-001 also explored effects on bone mineral density (BMD) and abdominal aortic vascular calcification. METHODS Forty-three patients were treated in REN-001 (dose range: sotatercept 0.3‒0.7 mg/kg or placebo subcutaneously [s.c.] for 200 days) and 50 in REN-002 (dose range: 0.1‒0.4 mg/kg i.v. and 0.13‒0.5 mg/kg s.c. for 99 days). RESULTS In REN-001, frequency of achieving target hemoglobin response (>10 g/dl [6.21 mmol/l]) with sotatercept was dose-related and greater than placebo (0.3 mg/kg: 33.3%; 0.5 mg/kg: 62.5%; 0.7 mg/kg: 77.8%; 0.7 mg/kg [doses 1 and 2]/0.4 mg/kg [doses 3‒15]: 33.3%; placebo: 27.3%). REN-002 hemoglobin findings were similar (i.v.: 16.7%-57.1%; s.c.: 11.1%‒42.9%). Dose-related achievement of ≥2% increase in femoral neck cortical BMD was seen among only REN-001 patients receiving sotatercept (0.3‒0.7 mg/kg: 20.0%‒57.1%; placebo: 0.0%). Abdominal aortic vascular calcification was slowed in a dose-related manner, with a ≤15% increase in Agatston score achieved by more REN-001 sotatercept versus placebo patients (60%‒100% vs. 16.7%). The most common adverse events during treatment were hypertension, muscle spasm, headache, arteriovenous fistula site complication, and influenza observed in both treatment and placebo groups. CONCLUSION In patients with ESKD, sotatercept exhibited a favorable safety profile and was associated with trends in dose-related slowing of vascular calcification. Less-consistent trends in improved hemoglobin concentration and BMD were observed.
Collapse
Affiliation(s)
- Daniel W. Coyne
- Department of Medicine, Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | | | | | | | | | | | - Hartmut H. Malluche
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Keith A. Hruska
- Department of Medicine, Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
- Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA
| |
Collapse
|
|
39
|
Sánchez-Duffhues G, Williams E, Benderitter P, Orlova V, van Wijhe M, Garcia de Vinuesa A, Kerr G, Caradec J, Lodder K, de Boer HC, Goumans MJ, Eekhoff EMW, Morales-Piga A, Bachiller-Corral J, Koolwijk P, Bullock AN, Hoflack J, Ten Dijke P. Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva-Derived Endothelial Cells. JBMR Plus 2019; 3:e10230. [PMID: 31768489 PMCID: PMC6874179 DOI: 10.1002/jbm4.10230] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/17/2019] [Accepted: 08/06/2019] [Indexed: 12/23/2022] Open
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone-inducing agents. To date, there is no cure for FOP. The further development of FOP patient-derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood-derived endothelial colony-forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial-to-mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Gonzalo Sánchez-Duffhues
- Department of Cell and Chemical Biology, Oncode Institute Leiden University Medical Center Leiden The Netherlands
| | | | | | - Valeria Orlova
- Department of Anatomy and Embryology Leiden University Medical Center Leiden The Netherlands
| | - Michiel van Wijhe
- Amsterdam Cardiovascular Sciences, Department of Physiology and Amsterdam Bone Center Vrije University Medical Center Amsterdam The Netherlands
| | - Amaya Garcia de Vinuesa
- Department of Cell and Chemical Biology, Oncode Institute Leiden University Medical Center Leiden The Netherlands
| | - Georgina Kerr
- Structural Genomics Consortium University of Oxford Oxford UK
| | | | - Kirsten Lodder
- Department of Cell and Chemical Biology, Oncode Institute Leiden University Medical Center Leiden The Netherlands
| | - Hetty C de Boer
- Department of Nephrology Leiden University Medical Center and the Einthoven Laboratory for Experimental Vascular Medicine Leiden The Netherlands
| | - Marie-José Goumans
- Department of Cell and Chemical Biology, Oncode Institute Leiden University Medical Center Leiden The Netherlands
| | - Elisabeth M W Eekhoff
- Amsterdam Cardiovascular Sciences, Department of Physiology and Amsterdam Bone Center Vrije University Medical Center Amsterdam The Netherlands
| | - Antonio Morales-Piga
- Disease Research Institute, Carlos III Institute of Health (ISCIII) Madrid Spain
| | | | - Pieter Koolwijk
- Amsterdam Cardiovascular Sciences, Department of Physiology and Amsterdam Bone Center Vrije University Medical Center Amsterdam The Netherlands
| | - Alex N Bullock
- Structural Genomics Consortium University of Oxford Oxford UK
| | | | - Peter Ten Dijke
- Department of Cell and Chemical Biology, Oncode Institute Leiden University Medical Center Leiden The Netherlands
| |
Collapse
|
|
40
|
|
|
41
|
Wang J, Khodabukus A, Rao L, Vandusen K, Abutaleb N, Bursac N. Engineered skeletal muscles for disease modeling and drug discovery. Biomaterials 2019; 221:119416. [PMID: 31419653 DOI: 10.1016/j.biomaterials.2019.119416] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 08/01/2019] [Accepted: 08/05/2019] [Indexed: 01/04/2023]
Abstract
Skeletal muscle is the largest organ of human body with several important roles in everyday movement and metabolic homeostasis. The limited ability of small animal models of muscle disease to accurately predict drug efficacy and toxicity in humans has prompted the development in vitro models of human skeletal muscle that fatefully recapitulate cell and tissue level functions and drug responses. We first review methods for development of three-dimensional engineered muscle tissues and organ-on-a-chip microphysiological systems and discuss their potential utility in drug discovery research and development of new regenerative therapies. Furthermore, we describe strategies to increase the functional maturation of engineered muscle, and motivate the importance of incorporating multiple tissue types on the same chip to model organ cross-talk and generate more predictive drug development platforms. Finally, we review the ability of available in vitro systems to model diseases such as type II diabetes, Duchenne muscular dystrophy, Pompe disease, and dysferlinopathy.
Collapse
Affiliation(s)
- Jason Wang
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | | | - Lingjun Rao
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Keith Vandusen
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Nadia Abutaleb
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Nenad Bursac
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
| |
Collapse
|
|
42
|
Nordholm A, Egstrand S, Gravesen E, Mace ML, Morevati M, Olgaard K, Lewin E. Circadian rhythm of activin A and related parameters of mineral metabolism in normal and uremic rats. Pflugers Arch 2019; 471:1079-1094. [PMID: 31236663 PMCID: PMC6614158 DOI: 10.1007/s00424-019-02291-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/04/2019] [Accepted: 06/05/2019] [Indexed: 12/11/2022]
Abstract
Activin A is a new fascinating player in chronic kidney disease-mineral and bone disorder (CKD-MBD), which is implicated in progressive renal disease, vascular calcification, and osteodystrophy. Plasma activin A rises early in the progression of renal disease. Disruption of circadian rhythms is related to increased risk of several diseases and circadian rhythms are observed in mineral homeostasis, bone parameters, and plasma levels of phosphate and PTH. Therefore, we examined the circadian rhythm of activin A and CKD-MBD-related parameters (phosphate, PTH, FGF23, and klotho) in healthy controls and CKD rats (5/6 nephrectomy) on high-, standard- and low-dietary phosphate contents as well as during fasting conditions. Plasma activin A exhibited circadian rhythmicity in healthy control rats with fourfold higher values at acrophase compared with nadir. The rhythm was obliterated in CKD. Activin A was higher in CKD rats compared with controls when measured at daytime but not significantly when measured at evening/nighttime, stressing the importance of time-specific reference intervals when interpreting plasma values. Plasma phosphate, PTH, and FGF23 all showed circadian rhythms in control rats, which were abolished or disrupted in CKD. Plasma klotho did not show circadian rhythm. Thus, the present investigation shows, for the first time, circadian rhythm of plasma activin A. The rhythmicity is severely disturbed by CKD and is associated with disturbed rhythms of phosphate and phosphate-regulating hormones PTH and FGF23, indicating that disturbed circadian rhythmicity is an important feature of CKD-MBD.
Collapse
Affiliation(s)
- Anders Nordholm
- Nephrological Department, Herlev Hospital, University of Copenhagen, 2730, Herlev, Denmark.,Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Søren Egstrand
- Nephrological Department, Herlev Hospital, University of Copenhagen, 2730, Herlev, Denmark.,Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Eva Gravesen
- Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Maria L Mace
- Nephrological Department, Herlev Hospital, University of Copenhagen, 2730, Herlev, Denmark.,Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Marya Morevati
- Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Klaus Olgaard
- Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark
| | - Ewa Lewin
- Nephrological Department, Herlev Hospital, University of Copenhagen, 2730, Herlev, Denmark. .,Nephrological Department, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.
| |
Collapse
|
|
43
|
Bataller A, Montalban-Bravo G, Soltysiak KA, Garcia-Manero G. The role of TGFβ in hematopoiesis and myeloid disorders. Leukemia 2019; 33:1076-1089. [PMID: 30816330 PMCID: PMC11789621 DOI: 10.1038/s41375-019-0420-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/10/2019] [Accepted: 01/15/2019] [Indexed: 02/06/2023]
Abstract
The role of transforming growth factor-β (TGFβ) signaling in embryological development and tissue homeostasis has been thoroughly characterized. Its canonical downstream cascade is well known, even though its true complexity and other non-canonical pathways are still being explored. TGFβ signaling has been described as an important pathway involved in carcinogenesis and cancer progression. In the hematopoietic compartment, the TGFβ pathway is an important regulator of proliferation and differentiation of different cell types and has been implicated in the pathogenesis of a diverse variety of bone marrow disorders. Due to its importance in hematological diseases, novel inhibitors of this pathway are being developed against a number of hematopoietic disorders, including myelodysplastic syndromes (MDS). In this review, we provide an overview of the TGFβ pathway, focusing on its role in hematopoiesis and impact on myeloid disorders. We will discuss therapeutic interventions with promising results against MDS.
Collapse
Affiliation(s)
- Alex Bataller
- Hematology Department, IDIBAPS, Hospital Clínic de Barcelona, Barcelona, Spain
| | | | - Kelly A Soltysiak
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | |
Collapse
|
|
44
|
Development of two complementary LC–HRMS methods for analyzing sotatercept in dried blood spots for doping controls. Bioanalysis 2019; 11:923-940. [DOI: 10.4155/bio-2018-0313] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: sotatercept is a therapeutic Fc-fusion protein with erythropoiesis-stimulating activity. Due to a potential abuse of the drug by athletes in professional sports, a sensitive detection method is required. In sports drug testing, alternative matrices such as dried blood spots (DBS) are gaining increasing attention as they can provide several advantages over conventional matrices. Materials & methods: Herein, two complementary LC–high-resolution mass spectrometry (HRMS) detection methods for sotatercept from DBS, an initial testing procedure (ITP) and a confirmation procedure (CP) were developed and validated for the first time. Both methods comprise an ultrasonication-assisted extraction, affinity enrichment, proteolytic digestion and HRMS detection. Results & conclusion: For the multianalyte ITP, artificial samples fortified with sotatercept, luspatercept and bimagrumab, and authentic specimens containing bimagrumab were successfully analyzed as proof-of-concept. The validated detection methods for sotatercept are fit for purpose and the ITP was shown to be suitable for the detection of novel IgG-based pharmaceuticals in doping control DBS samples.
Collapse
|
|
45
|
Activin-A is elevated in patients with thalassemia major and double heterozygous sickle cell/beta-thalassemia and correlates with markers of hemolysis and bone mineral density. Ann Hematol 2019; 98:1583-1592. [PMID: 31041514 DOI: 10.1007/s00277-019-03695-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 04/15/2019] [Indexed: 01/11/2023]
Abstract
Despite the advances in the management of hemoglobinopathies, further insight into disease pathophysiology is necessary to improve our therapeutic approach. Activin-A has emerged as a regulator of erythropoiesis and bone turnover in malignant disorders; however, clinical data in hemoglobinopathies are currently scarce. Thus, we aimed to investigate the role of activin-A among hemoglobinopathy patients and evaluate the rationale of its targeting. Circulating levels of activin-A were measured in patients (n = 227) with beta-thalassemia major (TM) (n = 58), beta-thalassemia intermedia (TI) (n = 43), double heterozygous sickle cell/beta-thalassemia (HbS/beta-thal) (n = 109), or homozygous sickle cell disease (n = 17), and we explored possible correlations with clinical and laboratory data. Seventeen age- and gender-matched, healthy individuals served as controls. Bone marrow density (BMD) was determined using dual-energy X-ray absorptiometry. TM and HbS/beta-thal patients had elevated activin-A compared to controls (p = 0.041 and p = 0.038, respectively). In TM patients, high circulating activin-A showed strong correlations with hemolysis markers, namely reticulocyte count (p = 0.011) and high lactate dehydrogenase (LDH; p = 0.024). Similarly, in HbS/beta-thal patients, activin-A showed positive correlations with indirect bilirubin (p < 0.001), ferritin (p = 0.005), and LDH (p = 0.044). High activin-A correlated with low Z-score of both lumbar spine BMD in TI patients (p < 0.01) and femoral neck BMD in TM patients (p < 0.01). Serum activin-A is elevated in patients with TM and HbS/beta-thal and correlates with markers of hemolysis and low BMD. These data support a role of activin-A in the biology of these disorders and provide further rationale for the broader clinical development of activin-A inhibitors in this setting.
Collapse
|
|
46
|
Abstract
PURPOSE OF REVIEW Sotatercept and luspatercept are recombinant soluble activin type-II receptor-IgG-Fc fusion proteins that are tested in clinical trials for the treatment of various types of anemias, including renal anemia. The mechanism of the action of the novel drugs is incompletely understood, but it seems to be based on the inactivation of soluble proteins of the transforming growth factor-ß (TGFß) family. This review considers pros and cons of the clinical use of the drugs in reference to the current therapy with recombinant erythropoiesis-stimulating agents (ESAs). RECENT FINDINGS One or more activin type-II receptor (ActRII) ligands appear to inhibit erythroid precursors, for example growth and differentiation factor 11. Trapping of these ligands by the recombinant ActRII fusion proteins, sotatercept and luspatercept increases red blood cell numbers and hemoglobin levels in humans. Reportedly, the novel compounds were well tolerated in trials on healthy volunteers and patients suffering from anemia due to chronic kidney disease or malignancies. On approval, the drugs may prove particularly useful in patients suffering from ineffective erythropoiesis, such as in myelodysplastic syndrome, multiple myeloma or ß-thalassemia, where ESAs are of little use. Independent of their effect on erythropoiesis, ActRII ligand traps were found to exert beneficial effects on renal tissue in experimental animals. SUMMARY ESAs are likely to remain standard of care in renal anemia. There is a need for a better understanding of the effects of ActRII ligand traps on TGFß-like proteins. The novel drugs have not been approved for sale as therapeutics so far. Their long-term efficacy and safety still needs to be proven, particularly with respect to immunogenicity. Antifibrotic effects may be worthy to be investigated in humans.
Collapse
|
|
47
|
Khandros E, Kwiatkowski JL. Beta Thalassemia: Monitoring and New Treatment Approaches. Hematol Oncol Clin North Am 2019; 33:339-353. [PMID: 31030806 DOI: 10.1016/j.hoc.2019.01.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Beta thalassemias are a significant global health problem. Globin chain imbalance leads to a complex physiologic cascade of hemolytic anemia, ineffective erythropoiesis, and iron overload. Management of the broad spectrum of phenotypes requires the careful use of red blood transfusions, supportive care, monitoring, and management of iron overload. In this article, the authors discuss recommendations for monitoring of individuals with thalassemia, as well as ongoing preclinical and clinical trials of therapies targeting different aspects of thalassemia pathophysiology.
Collapse
Affiliation(s)
- Eugene Khandros
- Division of Hematology, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Colket Translational Research Building, Room 11024, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
| | - Janet L Kwiatkowski
- Division of Hematology, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Colket Translational Research Building, Room 11024, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
|
48
|
Lodberg A, van der Eerden BCJ, Boers-Sijmons B, Thomsen JS, Brüel A, van Leeuwen JPTM, Eijken M. A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice. FASEB J 2019; 33:6001-6010. [PMID: 30759349 DOI: 10.1096/fj.201801969rr] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Inhibitors of the activin receptor signaling pathway (IASPs) have become candidate therapeutics for sarcopenia and bone remodeling disorders because of their ability to increase muscle and bone mass. However, IASPs utilizing activin type IIA and IIB receptors are also potent stimulators of erythropoiesis, a feature that may restrict their usage to anemic patients because of increased risk of venous thromboembolism. Based on the endogenous TGF-β superfamily antagonist follistatin (FST), a molecule in the IASP class, FSTΔHBS-mFc, was generated and tested in both ovariectomized and naive BALB/c and C57BL/6 mice. In ovariectomized mice, FSTΔHBS-mFc therapy dose-dependently increased cancellous bone mass up to 42% and improved bone microstructural indices. For the highest dosage of FSTΔHBS-mFc (30 mg/kg, 2 times/wk), the increase in cancellous bone mass was similar to that observed with parathyroid hormone therapy (1-34, 80 µg/kg, 5 times/wk). Musculus quadriceps femoris mass dose-dependently increased up to 21% in ovariectomized mice. In both ovariectomized and naive mice, FSTΔHBS-mFc therapy did not influence red blood cell count or hematocrit or hemoglobin levels. If the results are reproduced, a human FSTΔHBS-mFc version could be applicable in patients with musculoskeletal conditions irrespective of hematocrit status.-Lodberg, A., van der Eerden, B. C. J., Boers-Sijmons, B., Thomsen, J. S., Brüel, A., van Leeuwen, J. P. T. M., Eijken, M. A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice.
Collapse
Affiliation(s)
- Andreas Lodberg
- Department of Pulmonary Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Bianca Boers-Sijmons
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Annemarie Brüel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Marco Eijken
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
49
|
Rivella S. Iron metabolism under conditions of ineffective erythropoiesis in β-thalassemia. Blood 2019; 133:51-58. [PMID: 30401707 PMCID: PMC6318430 DOI: 10.1182/blood-2018-07-815928] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/06/2018] [Indexed: 12/24/2022] Open
Abstract
β-Thalassemia (BT) is an inherited genetic disorder that is characterized by ineffective erythropoiesis (IE), leading to anemia and abnormal iron metabolism. IE is an abnormal expansion of the number of erythroid progenitor cells with unproductive synthesis of enucleated erythrocytes, leading to anemia and hypoxia. Anemic patients affected by BT suffer from iron overload, even in the absence of chronic blood transfusion, suggesting the presence of ≥1 erythroid factor with the ability to modulate iron metabolism and dietary iron absorption. Recent studies suggest that decreased erythroid cell differentiation and survival also contribute to IE, aggravating the anemia in BT. Furthermore, hypoxia can also affect and increase iron absorption. Understanding the relationship between iron metabolism and IE could provide important insights into the BT condition and help to develop novel treatments. In fact, genetic or pharmacological manipulations of iron metabolism or erythroid cell differentiation and survival have been shown to improve IE, iron overload, and anemia in animal models of BT. Based on those findings, new therapeutic approaches and drugs have been proposed; clinical trials are underway that have the potential to improve erythrocyte production, as well as to reduce the iron overload and organ toxicity in BT and in other disorders characterized by IE.
Collapse
Affiliation(s)
- Stefano Rivella
- Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and Cell and Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA
| |
Collapse
|
|
50
|
Abstract
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.
Collapse
Affiliation(s)
- Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
| | - Vicki Rosen
- Division of Biomedical Science, Marian University College of Osteopathic Medicine , Indianapolis, Indiana ; and Department of Developmental Biology, Harvard School of Dental Medicine , Boston, Massachusetts
| |
Collapse
|