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Zhang HA, Zhang BY, Tang HB. Effects of macrophages on the osteogenic differentiation of adipose tissue-derived stem cells in two-dimensional and three-dimensional cocultures. World J Stem Cells 2025; 17:99326. [DOI: 10.4252/wjsc.v17.i2.99326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/24/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Fracture is one of the most pervasive injuries in the musculoskeletal system, and there is a complex interaction between macrophages and adipose tissue-derived stem cells (ADSCs) in fracture healing. However, two-dimensional (2D) coculture of macrophages and ADSCs can not accurately mimic the in vivo cell microenvironment.
AIM To establish both 2D and 3D osteogenic coculture models to investigate the interaction between macrophages and ADSCs.
METHODS After obtaining ADSCs from surgery and inducing differentiation of the THP1 cell line, we established 2D and 3D osteogenic coculture models. To assess the level of osteogenic differentiation, we used alizarin red staining and measured the relative expression levels of osteogenic differentiation markers osteocalcin, Runt-related transcription factor 2, and alkaline phosphatase through polymerase chain reaction. Verification was conducted by analyzing the expression changes of N-cadherin and the activation of the Wnt/β-catenin signaling pathway using western blotting.
RESULTS In this study, it was discovered that macrophages in 3D culture inhibited osteogenic differentiation of ADSCs, contrary to the effect in 2D culture. This observation confirmed the significance of intricate intercellular connections in the 3D culture environment. Additionally, the 3D culture group exhibited significantly higher N-cadherin expression and showed reduced β-catenin and Wnt1 protein levels compared to the 2D culture group.
CONCLUSION Macrophages promoted ADSC osteogenic differentiation in 2D culture conditions but inhibited it in 3D culture. The 3D culture environment might inhibit the Wnt/β-catenin signaling pathway by upregulating N-cadherin expression, ultimately hindering the osteogenic differentiation of ADSCs. By investigating the process of osteogenesis in ADSCs, this study provides novel ideas for exploring 3D osteogenesis in ADSCs, fracture repair, and other bone trauma repair.
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Affiliation(s)
- He-Ao Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Bo-Yu Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hong-Bo Tang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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2
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Malard F, Neri P, Bahlis NJ, Terpos E, Moukalled N, Hungria VTM, Manier S, Mohty M. Multiple myeloma. Nat Rev Dis Primers 2024; 10:45. [PMID: 38937492 DOI: 10.1038/s41572-024-00529-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/16/2024] [Indexed: 06/29/2024]
Abstract
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
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Affiliation(s)
- Florent Malard
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.
| | - Paola Neri
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
| | - Nizar J Bahlis
- Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada
| | - Evangelos Terpos
- Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Nour Moukalled
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Salomon Manier
- Department of Hematology, Lille University Hospital and INSERM UMR-S1277 and CNRS UMR9020, Lille, France
| | - Mohamad Mohty
- Sorbonne Université, Centre de Recherche Saint-Antoine INSERM UMRs938, Service d'Hématologie Clinique et de Thérapie Cellulaire, Hôpital Saint Antoine, AP-HP, Paris, France.
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3
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Walker M, Pringle EW, Ciccone G, Oliver‐Cervelló L, Tassieri M, Gourdon D, Cantini M. Mind the Viscous Modulus: The Mechanotransductive Response to the Viscous Nature of Isoelastic Matrices Regulates Stem Cell Chondrogenesis. Adv Healthc Mater 2024; 13:e2302571. [PMID: 38014647 PMCID: PMC11481034 DOI: 10.1002/adhm.202302571] [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: 10/06/2023] [Revised: 11/14/2023] [Indexed: 11/29/2023]
Abstract
The design of hydrogels as mimetics of tissues' matrices typically disregards the viscous nature of native tissues and focuses only on their elastic properties. In the case of stem cell chondrogenesis, this has led to contradictory results, likely due to unreported changes in the matrices' viscous modulus. Here, by employing isoelastic matrices with Young's modulus of ≈12 kPa, variations in viscous properties alone (i.e., loss tangent between 0.1 and 0.25) are demonstrated to be sufficient to drive efficient growth factor-free chondrogenesis of human mesenchymal stem cells, both in 2D and 3D cultures. The increase of the viscous component of RGD-functionalized polyacrylamide or polyethylene glycol maleimide hydrogels promotes a phenotype with reduced adhesion, alters mechanosensitive signaling, and boosts cell-cell contacts. In turn, this upregulates the chondrogenic transcription factor SOX9 and supports neocartilage formation, demonstrating that the mechanotransductive response to the viscous nature of the matrix can be harnessed to direct cell fate.
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Affiliation(s)
- Matthew Walker
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG128QQUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
| | - Eonan William Pringle
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG128QQUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
| | - Giuseppe Ciccone
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG128QQUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
| | - Lluís Oliver‐Cervelló
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG128QQUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
| | - Manlio Tassieri
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
| | - Delphine Gourdon
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG128QQUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
| | - Marco Cantini
- Centre for the Cellular MicroenvironmentUniversity of GlasgowGlasgowG128QQUK
- Division of Biomedical Engineering, James Watt School of EngineeringUniversity of GlasgowGlasgowG128QQUK
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Otte EA, Smith TN, Glass N, Wolvetang EJ, Cooper-White JJ. Exploring the cell interactome: deciphering relative impacts of cell-cell communication in cell co-culture using a novel microfluidic device. LAB ON A CHIP 2024; 24:537-548. [PMID: 38168806 DOI: 10.1039/d3lc00670k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
The human body is made up of approximately 40 trillion cells in close contact, with the cellular density of individual tissues varying from 1 million to 1 billion cells per cubic centimetre. Interactions between different cell types (termed heterotypic) are thus common in vivo. Communication between cells can take the form of direct cell-cell contact mediated by plasma membrane proteins or through paracrine signalling mediated through the release, diffusion, and receipt of soluble factors. There is currently no systematic method to investigate the relative contributions of these mechanisms to cell behaviour. In this paper, we detail the conception, development and validation of a microfluidic device that allows cell-cell contact and paracrine signalling in defined areas and over a variety of biologically relevant length scales, referred to as the interactome-device or 'I-device'. Importantly, by intrinsic device design features, cells in different regions in the device are exposed to four different interaction types, including a) no heterotypic cell interaction, b) only paracrine signalling, c) only cell-cell direct contact, or d) both forms of interaction (paracrine and cell-cell direct contact) together. The device design was validated by both mathematical modelling and experiments. Perfused stem cell culture over the medium term and the formation of direct contact between cells in the culture chambers was confirmed. The I-device offers significant flexibility, being able to be applied to any combination of adherent cells to determine the relative contributions of different communication mechanisms to cellular outcomes.
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Affiliation(s)
- Ellen A Otte
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, St Lucia, QLD, Australia.
- Commonwealth Scientific and Industrial Research Organization (CSIRO), Manufacturing, Clayton, VIC, Australia
| | - Taryn N Smith
- School of Chemical Engineering, University of Queensland, St Lucia, QLD, Australia
| | - Nick Glass
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, St Lucia, QLD, Australia.
- The UQ Centre in Stem Cell Ageing and Regenerative Engineering (StemCARE), Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD, Australia
| | - Ernst J Wolvetang
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, St Lucia, QLD, Australia.
- The UQ Centre in Stem Cell Ageing and Regenerative Engineering (StemCARE), Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD, Australia
| | - Justin J Cooper-White
- Tissue Engineering and Microfluidics Laboratory (TE&M), Australian Institute for Bioengineering and Nanotechnology (AIBN), University of Queensland, St Lucia, QLD, Australia.
- The UQ Centre in Stem Cell Ageing and Regenerative Engineering (StemCARE), Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, QLD, Australia
- School of Chemical Engineering, University of Queensland, St Lucia, QLD, Australia
- Commonwealth Scientific and Industrial Research Organization (CSIRO), Manufacturing, Clayton, VIC, Australia
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Ma L, Wang W, Xu G, Li H, Liu F, Shao H, Zhang X, Ma Y, Li G, Li H, Gao S, Ling P. Connexin 43 in the function and homeostasis of osteocytes: a narrative review. ANNALS OF JOINT 2023; 9:10. [PMID: 38529291 PMCID: PMC10929443 DOI: 10.21037/aoj-23-65] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 11/29/2023] [Indexed: 03/27/2024]
Abstract
Background and Objective Connexin 43 (Cx43) is the main gap junction (GJ) protein and hemichannel protein in bone tissue. It is involved in the formation of hemichannels and GJs and establishes channels that can communicate directly to exchange substances and signals, affecting the structure and function of osteocytes. CX43 is very important for the normal development of bone tissue and the establishment and balance of bone reconstruction. However, the molecular mechanisms by which CX43 regulates osteoblast function and homeostasis have been less well studied, and this article provides a review of research in this area. Methods We searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for studies published up to June 2023 using the keywords Connexin 43/Cx43 and Osteocytes. Screening of literatures according to inclusion and exclusion guidelines and summarized the results. Key Content and Findings Osteocytes, osteoblasts, and osteoclasts all express Cx43 and form an overall network through the interaction between GJs. Cx43 is not only involved in the mechanical response of bone tissue but also in the regulation of signal transduction, which could provide new molecular markers and novel targets for the treatment of certain bone diseases. Conclusions Cx43 is expressed in osteoblasts, osteoclasts, and osteoclasts and plays an important role in regulating the function, signal transduction, and mechanotransduction of osteocytes. This review offers a new contribution to the literature by summarizing the relationship between Cx43, a key protein of bone tissue, and osteoblasts.
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Affiliation(s)
- Liang Ma
- Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Post-doctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan, China
- Post-doctoral Station of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenzhao Wang
- Department of Orthopedics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guixuan Xu
- Department of Pathology and Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Hao Li
- Department of Joint Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Fei Liu
- Post-doctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Huarong Shao
- Post-doctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Xiuhua Zhang
- Post-doctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Yuxia Ma
- Post-doctoral Station of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Gang Li
- Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hui Li
- Department of Operating Room, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shuzhong Gao
- Post-doctoral Station of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Peixue Ling
- Post-doctoral Scientific Research Workstation, Shandong Academy of Pharmaceutical Science, Jinan, China
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6
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Nethander M, Movérare-Skrtic S, Kämpe A, Coward E, Reimann E, Grahnemo L, Borbély É, Helyes Z, Funck-Brentano T, Cohen-Solal M, Tuukkanen J, Koskela A, Wu J, Li L, Lu T, Gabrielsen ME, Mägi R, Hoff M, Lerner UH, Henning P, Ullum H, Erikstrup C, Brunak S, Langhammer A, Tuomi T, Oddsson A, Stefansson K, Pettersson-Kymmer U, Ostrowski SR, Pedersen OBV, Styrkarsdottir U, Mäkitie O, Hveem K, Richards JB, Ohlsson C. An atlas of genetic determinants of forearm fracture. Nat Genet 2023; 55:1820-1830. [PMID: 37919453 PMCID: PMC10632131 DOI: 10.1038/s41588-023-01527-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 09/13/2023] [Indexed: 11/04/2023]
Abstract
Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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Grants
- Wellcome Trust
- IngaBritt och Arne Lundbergs Forskningsstiftelse (Ingabritt and Arne Lundberg Research Foundation)
- Novo Nordisk Fonden (Novo Nordisk Foundation)
- Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
- the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-720331 and ALFGBG-965235)
- the Hungarian Brain research Program 3.0, Hungarian National Research, Development and Innovation Office (OTKA K- 138046, OTKA FK-137951, TKP2021-EGA-16), New National Excellence Program of the Ministry for Innovation and Technology (ÚNKP-22-5-PTE-1447), János Bolyai János Scholarship (BO/00496/21/5) of the Hungarian Academy of Sciences, Eotvos Lorad Research Network, National Laboratory for Drug Research and Development.
- Vetenskapsrådet (Swedish Research Council)
- Svenska Läkaresällskapet (Swedish Society of Medicine)
- Kempestiftelserna (Kempe Foundations)
- the Swedish Sports Research Council (87/06) the Medical Faculty of Umeå University (ALFVLL:968:22-2005, ALFVLL: 937-2006, ALFVLL:223:11-2007, ALFVLL:78151-2009) the county council of Västerbotten (Spjutspetsanslag VLL:159:33-2007)
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Affiliation(s)
- Maria Nethander
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sofia Movérare-Skrtic
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Anders Kämpe
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Eivind Coward
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ene Reimann
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Louise Grahnemo
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Éva Borbély
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
- Eotvos Lorand Research Network, Chronic Pain Research Group, University of Pécs, Pécs, Hungary
| | - Thomas Funck-Brentano
- BIOSCAR UMRS 1132, Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France
| | - Martine Cohen-Solal
- BIOSCAR UMRS 1132, Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France
| | - Juha Tuukkanen
- Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
| | - Antti Koskela
- Department of Anatomy and Cell Biology, Faculty of Medicine, Institute of Cancer Research and Translational Medicine, University of Oulu, Oulu, Finland
| | - Jianyao Wu
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lei Li
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tianyuan Lu
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
| | - Maiken E Gabrielsen
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Reedik Mägi
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Mari Hoff
- Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Rheumatology, St Olavs Hospital, Trondheim, Norway
| | - Ulf H Lerner
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Tiinamaija Tuomi
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden
- Department of Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | | | - Kari Stefansson
- deCODE genetics, Reykjavik, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | | | - Sisse Rye Ostrowski
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Copenhagen Hospital Biobank Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Ole Birger Vesterager Pedersen
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Immunology, Zealand University Hospital, Koege, Denmark
| | | | - Outi Mäkitie
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Folkhälsan Institute of Genetics, Helsinki, Finland
- Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kristian Hveem
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, and Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - J Brent Richards
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
| | - Claes Ohlsson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Drug Treatment, Gothenburg, Sweden.
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7
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Gessler L, Kurtek C, Merholz M, Jian Y, Hashemolhosseini S. In Adult Skeletal Muscles, the Co-Receptors of Canonical Wnt Signaling, Lrp5 and Lrp6, Determine the Distribution and Size of Fiber Types, and Structure and Function of Neuromuscular Junctions. Cells 2022; 11:cells11243968. [PMID: 36552732 PMCID: PMC9777411 DOI: 10.3390/cells11243968] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/01/2022] [Accepted: 12/04/2022] [Indexed: 12/14/2022] Open
Abstract
Canonical Wnt signaling is involved in skeletal muscle cell biology. The exact way in which this pathway exerts its contribution to myogenesis or neuromuscular junctions (NMJ) is a matter of debate. Next to the common co-receptors of canonical Wnt signaling, Lrp5 and Lrp6, the receptor tyrosine kinase MuSK was reported to bind at NMJs WNT glycoproteins by its extracellular cysteine-rich domain. Previously, we reported canonical Wnt signaling being active in fast muscle fiber types. Here, we used conditional Lrp5 or Lrp6 knockout mice to investigate the role of these receptors in muscle cells. Conditional double knockout mice died around E13 likely due to ectopic expression of the Cre recombinase. Phenotypes of single conditional knockout mice point to a very divergent role for the two receptors. First, muscle fiber type distribution and size were changed. Second, canonical Wnt signaling reporter mice suggested less signaling activity in the absence of Lrps. Third, expression of several myogenic marker genes was changed. Fourth, NMJs were of fragmented phenotype. Fifth, recordings revealed impaired neuromuscular transmission. In sum, our data show fundamental differences in absence of each of the Lrp co-receptors and suggest a differentiated view of canonical Wnt signaling pathway involvement in adult skeletal muscle cells.
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Affiliation(s)
- Lea Gessler
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Christopher Kurtek
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Mira Merholz
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Yongzhi Jian
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Said Hashemolhosseini
- Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
- Muscle Research Center, Friedrich-Alexander-University of Erlangen-Nürnberg, 91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-85-24634
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8
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Li G, Brumback BD, Huang L, Zhang DM, Yin T, Lipovsky CE, Hicks SC, Jimenez J, Boyle PM, Rentschler SL. Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction. JACC Basic Transl Sci 2022; 7:1001-1017. [PMID: 36337924 PMCID: PMC9626903 DOI: 10.1016/j.jacbts.2022.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 01/14/2023]
Abstract
Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered.
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Key Words
- ABC, active β-catenin
- APD, action potential duration
- BDM, 2,3-butanedione monoxime
- CV, conduction velocity
- Cx43, connexin 43
- GNa, sodium-channel conductance
- GOF, gain of function
- GSK-3 inhibitor
- GSK-3, glycogen synthase kinase 3
- INa, sodium current
- LV, left ventricle
- NaV1.5, pore-forming α-subunit protein of the voltage-gated cardiac sodium channel
- PCR, polymerase chain reaction
- RMP, resting membrane potential
- RT-qPCR, reverse transcription-quantitative polymerase chain reaction
- SB2, SB216763
- SB216763
- cDNA, complementary DNA
- dVm/dtmax, maximum upstroke velocity
- electrophysiology
- human cardiac slices
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Affiliation(s)
- Gang Li
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University McKelvey School of Engineering in St. Louis, Missouri, USA
| | - Brittany D. Brumback
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University McKelvey School of Engineering in St. Louis, Missouri, USA
| | - Lei Huang
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
| | - David M. Zhang
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
| | - Tiankai Yin
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
| | - Catherine E. Lipovsky
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
- Department of Developmental Biology, Washington University School of Medicine in St. Louis, Missouri, USA
| | - Stephanie C. Hicks
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
| | - Jesus Jimenez
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
| | - Patrick M. Boyle
- Department of Bioengineering, Center for Cardiovascular Biology, and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA
| | - Stacey L. Rentschler
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine in St. Louis, Missouri, USA
- Department of Biomedical Engineering, Washington University McKelvey School of Engineering in St. Louis, Missouri, USA
- Department of Developmental Biology, Washington University School of Medicine in St. Louis, Missouri, USA
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9
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Rao VV, Wechsler ME, Cravens E, Wojda SJ, Caldwell AS, Kirkpatrick BE, Donahue SW, Anseth KS. Granular PEG hydrogels mediate osteoporotic MSC clustering via N-cadherin influencing the pro-resorptive bias of their secretory profile. Acta Biomater 2022; 145:77-87. [PMID: 35460910 PMCID: PMC9133190 DOI: 10.1016/j.actbio.2022.04.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 12/13/2022]
Abstract
Postmenopausal osteoporosis results from a pro-resorptive bone environment, which decreases bone mineral density causing increased fracture risk. Bone marrow derived mesenchymal stem/stromal cells (MSCs) secrete factors involved in bone homeostasis, but osteoporosis mediated changes to their secretions remain understudied. Herein, we examined the secretome of MSCs isolated from ovariectomized rats (OVX rMSCs), a model of post-menopausal osteoporosis, as a function of cell-cell interactions. Specifically, we controlled clustering of OVX and SHAM rMSCs by assembling them in granular hydrogels synthesized from poly(ethylene glycol) microgels with average diameters of ∼10, 100, and 200 µm. We directed both the sizes of rMSC clusters (single cells to ∼30 cells/cluster) and the percentages of cells within clusters (∼20-90%) by controlling the scaffold pore dimensions. Large clusters of OVX rMSCs had a pro-resorptive secretory profile, with increased concentrations of Activin A, CXCL1, CX3CL1, MCP-1, TIMP-1, and TNF-ɑ, compared to SHAM rMSCs. As this pro-resorptive bias was only observed in large cell clusters, we characterized the expression of several cadherins, mediators of cell-cell contacts. N-cadherin expression was elevated (∼4-fold) in OVX relative to SHAM rMSCs, in both cell clusters and single cells. Finally, TIMP-1 and MCP-1 secretion was only decreased in large cell clusters of OVX rMSCs when N-cadherin interactions were blocked, highlighting the dependence of OVX rMSC secretion of pro-resorptive cytokines on N-cadherin mediated cell-cell contacts. Further elucidation of the N-cadherin mediated osteoporotic MSC secretome may have implications for developing therapies for postmenopausal osteoporosis. STATEMENT OF SIGNIFICANCE: Postmenopausal osteoporosis is a prevalent bone disorder that affects tens of millions of women worldwide. This disease is characterized by severe bone loss resulting from a pro-resorptive bone marrow environment, where the rates of bone resorption outpace the rates of bone deposition. The paracrine factors secreted by bone marrow MSCs can influence cell types responsible for bone homeostasis, but the osteoporosis-mediated changes to MSC secretory properties remains understudied. In this study, we used PEG-based porous granular scaffolds to study the influence of cell clustering on the secretory properties of osteoporotic MSCs. We observed increased secretion of several pro-resorptive factors by osteoporotic MSCs in large clusters. Further, we explored the dependence of this altered secretion profile on N-cadherin mediated cell-cell contacts.
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Affiliation(s)
- Varsha V Rao
- Department of Chemical and Biological Engineering, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States; BioFrontiers Institute, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States
| | - Marissa E Wechsler
- Department of Biomedical Engineering and Chemical Engineering, University of Texas San Antonio, One UTSA Circle, San Antonio, TX 78249, United States
| | - Emily Cravens
- Department of Biomedical Engineering, University of Massachusetts Amherst, 240 Thatcher Road, Amherst, MA 01003, United States
| | - Samantha J Wojda
- Department of Biomedical Engineering, University of Massachusetts Amherst, 240 Thatcher Road, Amherst, MA 01003, United States
| | - Alexander S Caldwell
- Department of Chemical and Biological Engineering, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States; BioFrontiers Institute, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States
| | - Bruce E Kirkpatrick
- Department of Chemical and Biological Engineering, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States; BioFrontiers Institute, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, 13001 East 17th Aurora, CO 80045, United States
| | - Seth W Donahue
- Department of Biomedical Engineering, University of Massachusetts Amherst, 240 Thatcher Road, Amherst, MA 01003, United States
| | - Kristi S Anseth
- Department of Chemical and Biological Engineering, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States; BioFrontiers Institute, University of Colorado - Boulder, 3415 Colorado Avenue, Boulder, CO 80303, United States.
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10
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Yuan G, Yang S. Effect of Regulator of G Protein Signaling Proteins on Bone. Front Endocrinol (Lausanne) 2022; 13:842421. [PMID: 35573989 PMCID: PMC9098968 DOI: 10.3389/fendo.2022.842421] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 04/01/2022] [Indexed: 01/08/2023] Open
Abstract
Regulator of G protein signaling (RGS) proteins are critical negative molecules of G protein-coupled receptor (GPCR) signaling, which mediates a variety of biological processes in bone homeostasis and diseases. The RGS proteins are divided into nine subfamilies with a conserved RGS domain which plays an important role in regulating the GTPase activity. Mutations of some RGS proteins change bone development and/or metabolism, causing osteopathy. In this review, we summarize the recent findings of RGS proteins in regulating osteoblasts, chondrocytes, and osteoclasts. We also highlight the impacts of RGS on bone development, bone remodeling, and bone-related diseases. Those studies demonstrate that RGS proteins might be potential drug targets for bone diseases.
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Affiliation(s)
- Gongsheng Yuan
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Shuying Yang
- Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
- The Penn Center for Musculoskeletal Disorders, Penn Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Center for Innovation and Precision Dentistry, Penn Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, United States
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11
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Zerdan MB, Nasr L, Kassab J, Saba L, Ghossein M, Yaghi M, Dominguez B, Chaulagain CP. Adhesion molecules in multiple myeloma oncogenesis and targeted therapy. Int J Hematol Oncol 2022; 11:IJH39. [PMID: 35663420 PMCID: PMC9136637 DOI: 10.2217/ijh-2021-0017] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 04/07/2022] [Indexed: 11/21/2022] Open
Abstract
Every day we march closer to finding the cure for multiple myeloma. The myeloma cells inflict their damage through specialized cellular meshwork and cytokines system. Implicit in these interactions are cellular adhesion molecules and their regulators which include but are not limited to integrins and syndecan-1/CD138, immunoglobulin superfamily cell adhesion molecules, such as CD44, cadherins such as N-cadherin, and selectins, such as E-selectin. Several adhesion molecules are respectively involved in myelomagenesis such as in the transition from the precursor disorder monoclonal gammopathy of undetermined significance to indolent asymptomatic multiple myeloma (smoldering myeloma) then to active multiple myeloma or primary plasma cell leukemia, and in the pathological manifestations of multiple myeloma.
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Affiliation(s)
- Maroun Bou Zerdan
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Lewis Nasr
- Saint-Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Joseph Kassab
- Saint-Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Ludovic Saba
- Saint-Joseph University, Faculty of Medicine, Beirut, Lebanon
| | - Myriam Ghossein
- Department of Medicine & Medical Sciences, University of Balamand, Balamand, Lebanon
| | - Marita Yaghi
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Barbara Dominguez
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
| | - Chakra P Chaulagain
- Department of Hematology-Oncology, Myeloma & Amyloidosis Program, Maroone Cancer Center, Cleveland Clinic Florida, Weston, FL 33331, USA
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12
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Expression of Beta-Catenin, Cadherins and P-Runx2 in Fibro-Osseous Lesions of the Jaw: Tissue Microarray Study. Biomolecules 2022; 12:biom12040587. [PMID: 35454175 PMCID: PMC9024991 DOI: 10.3390/biom12040587] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 01/27/2023] Open
Abstract
Fibrous dysplasia (FD) and hyperparathyroidism-jaw tumor syndrome (HPT-JT) are well-characterized benign bone fibro-osseous lesions. The intracellular mechanism leading to excessive deposition of fibrous tissue and alteration of differentiation processes leading to osteomalacia have not yet been fully clarified. Tissue Microarray (TMA)-based immunohistochemical expression of β-catenin, CK-AE1/AE3, Ki-67, cadherins and P-Runx2 were analyzed in archival samples from nine patients affected by FD and HPT-JT and in seven controls, with the aim of elucidating the contribution of these molecules (β-catenin, cadherins and P-Runx2) in the osteoblast differentiation pathway. β-catenin was strongly upregulated in FD, showing a hyper-cellulated pattern, while it was faintly expressed in bone tumors associated with HPT-JT. Furthermore, the loss of expression of OB-cadherin in osteoblast lineage in FD was accompanied by N-cadherin and P-cadherin upregulation (p < 0.05), while E-cadherin showed a minor role in these pathological processes. P-Runx2 showed over-expression in six out of eight cases of FD and stained moderately positive in the rimming lining osteoblasts in HPT-JT syndrome. β-catenin plays a central role in fibrous tissue proliferation and accompanies the lack of differentiation of osteoblast precursors in mature osteoblasts in FD. The study showed that the combined evaluation of the histological characteristics and the histochemical and immunohistochemical profile of key molecules involved in osteoblast differentiation are useful in the diagnosis, classification and therapeutic management of fibrous-osseous lesions.
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13
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Alioli C, Demesmay L, Peyruchaud O, Machuca-Gayet I. Autotaxin/Lysophosphatidic Acid Axis: From Bone Biology to Bone Disorders. Int J Mol Sci 2022; 23:ijms23073427. [PMID: 35408784 PMCID: PMC8998661 DOI: 10.3390/ijms23073427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/18/2022] [Accepted: 03/19/2022] [Indexed: 02/01/2023] Open
Abstract
Lysophosphatidic acid (LPA) is a natural bioactive phospholipid with pleiotropic activities affecting multiple tissues, including bone. LPA exerts its biological functions by binding to G-protein coupled LPA receptors (LPA1-6) to stimulate cell migration, proliferation, and survival. It is largely produced by autotaxin (ATX), a secreted enzyme with lysophospholipase D activity that converts lysophosphatidylcholine (LPC) into active LPA. Beyond its enzymatic activity, ATX serves as a docking molecule facilitating the efficient delivery of LPA to its specific cell surface receptors. Thus, LPA effects are the result of local production by ATX in a given tissue or cell type. As a consequence, the ATX/LPA axis should be considered as an entity to better understand their roles in physiology and pathophysiology and to propose novel therapeutic strategies. Herein, we provide not only an extensive overview of the relevance of the ATX/LPA axis in bone cell commitment and differentiation, skeletal development, and bone disorders, but also discuss new working hypotheses emerging from the interplay of ATX/LPA with well-established signaling pathways regulating bone mass.
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14
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Zweifler LE, Koh AJ, Daignault-Newton S, McCauley LK. Anabolic actions of PTH in murine models: two decades of insights. J Bone Miner Res 2021; 36:1979-1998. [PMID: 34101904 PMCID: PMC8596798 DOI: 10.1002/jbmr.4389] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/26/2021] [Accepted: 06/02/2021] [Indexed: 01/19/2023]
Abstract
Parathyroid hormone (PTH) is produced by the parathyroid glands in response to low serum calcium concentrations where it targets bones, kidneys, and indirectly, intestines. The N-terminus of PTH has been investigated for decades for its ability to stimulate bone formation when administered intermittently (iPTH) and is used clinically as an effective anabolic agent for the treatment of osteoporosis. Despite great interest in iPTH and its clinical use, the mechanisms of PTH action remain complicated and not fully defined. More than 70 gene targets in more than 90 murine models have been utilized to better understand PTH anabolic actions. Because murine studies utilized wild-type mice as positive controls, a variety of variables were analyzed to better understand the optimal conditions under which iPTH functions. The greatest responses to iPTH were in male mice, with treatment starting later than 12 weeks of age, a treatment duration lasting 5-6 weeks, and a PTH dose of 30-60 μg/kg/day. This comprehensive study also evaluated these genetic models relative to the bone formative actions with a primary focus on the trabecular compartment revealing trends in critical genes and gene families relevant for PTH anabolic actions. The summation of these data revealed the gene deletions with the greatest increase in trabecular bone volume in response to iPTH. These included PTH and 1-α-hydroxylase (Pth;1α(OH)ase, 62-fold), amphiregulin (Areg, 15.8-fold), and PTH related protein (Pthrp, 10.2-fold). The deletions with the greatest inhibition of the anabolic response include deletions of: proteoglycan 4 (Prg4, -9.7-fold), low-density lipoprotein receptor-related protein 6 (Lrp6, 1.3-fold), and low-density lipoprotein receptor-related protein 5 (Lrp5, -1.0-fold). Anabolic actions of iPTH were broadly affected via multiple and diverse genes. This data provides critical insight for future research and development, as well as application to human therapeutics. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Laura E Zweifler
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | - Amy J Koh
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | | | - Laurie K McCauley
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.,Department of Pathology, Medical School, University of Michigan, Ann Arbor, Michigan, USA
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15
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Liu Y, Yang Z, Wang L, Sun L, Kim BYS, Jiang W, Yuan Y, Liu C. Spatiotemporal Immunomodulation Using Biomimetic Scaffold Promotes Endochondral Ossification-Mediated Bone Healing. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100143. [PMID: 34105266 PMCID: PMC8188258 DOI: 10.1002/advs.202100143] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Indexed: 05/16/2023]
Abstract
Biomaterials play an important role in treating bone defects by promoting direct osteogenic healing through intramembranous ossification (IO). However, majority of the body's bones form via cartilaginous intermediates by endochondral ossification (EO), a process that has not been well mimicked by engineered scaffolds, thus limiting their clinical utility in treating large segmental bone defects. Here, by entrapping corticosteroid dexamethasone within biomimetic recombinant human bone morphogenetic protein (rhBMP)-loaded porous mesoporous bioglass scaffolds and regulating their release kinetics, significant degree of ectopic bone formation through endochondral ossification is achieved. By regulating the recruitment and polarization of immune suppressive macrophage phenotypes, the scaffold promotes rapid chondrogenesis by activating Hif-3α signaling pathway in mesenchymal stem cells, which upregulates the expression of downstream chondrogenic genes. Inhibition of Hif-3α signaling reverses the endochondral ossification phenotype. Together, these results reveal a strategy to facilitate developmental bone growth process using immune modulating biomimetic scaffolds, thus providing new opportunities for developing biomaterials capable of inducing natural tissue regeneration.
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Affiliation(s)
- Yutong Liu
- Key Laboratory for Ultrafine Materials of Ministry of EducationSchool of Materials Science and Engineering, and Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
| | - Zhaogang Yang
- Department of Radiation OncologyUniversity of Texas Southwestern Medical CenterDallasTX75390USA
| | - Lixuan Wang
- Key Laboratory for Ultrafine Materials of Ministry of EducationSchool of Materials Science and Engineering, and Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
| | - Lili Sun
- Key Laboratory for Ultrafine Materials of Ministry of EducationSchool of Materials Science and Engineering, and Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
| | - Betty Y. S. Kim
- Department of NeurosurgeryThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Wen Jiang
- Department of Radiation OncologyUniversity of Texas Southwestern Medical CenterDallasTX75390USA
| | - Yuan Yuan
- Key Laboratory for Ultrafine Materials of Ministry of EducationSchool of Materials Science and Engineering, and Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
| | - Changsheng Liu
- Key Laboratory for Ultrafine Materials of Ministry of EducationSchool of Materials Science and Engineering, and Engineering Research Center for Biomedical Materials of Ministry of EducationEast China University of Science and TechnologyShanghai200237P. R. China
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16
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Ren Q, Chen J, Liu Y. LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence. Front Cell Dev Biol 2021; 9:670960. [PMID: 34026761 PMCID: PMC8134664 DOI: 10.3389/fcell.2021.670960] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/14/2021] [Indexed: 12/15/2022] Open
Abstract
The canonical Wnt/β-catenin signaling plays a fundamental role in regulating embryonic development, injury repair and the pathogenesis of human diseases. In vertebrates, low density lipoprotein receptor-related proteins 5 and 6 (LRP5 and LRP6), the single-pass transmembrane proteins, act as coreceptors of Wnt ligands and are indispensable for Wnt signal transduction. LRP5 and LRP6 are highly homologous and widely co-expressed in embryonic and adult tissues, and they share similar function in mediating Wnt signaling. However, they also exhibit distinct characteristics by interacting with different protein partners. As such, each of them possesses its own unique functions. In this review, we systematically discuss the similarity and divergence of LRP5 and LRP6 in mediating Wnt and other signaling in the context of kidney diseases. A better understanding of the precise role of LRP5 and LRP6 may afford us to identify and refine therapeutic targets for the treatment of a variety of human diseases.
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Affiliation(s)
- Qian Ren
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiongcheng Chen
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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17
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Yang Y, Liu W, Wei J, Cui Y, Zhang D, Xie J. Transforming growth factor-β1-induced N-cadherin drives cell-cell communication through connexin43 in osteoblast lineage. Int J Oral Sci 2021; 13:15. [PMID: 33850101 PMCID: PMC8044142 DOI: 10.1038/s41368-021-00119-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/29/2020] [Accepted: 02/01/2021] [Indexed: 02/05/2023] Open
Abstract
Gap junction (GJ) has been indicated to have an intimate correlation with adhesion junction. However, the direct interaction between them partially remains elusive. In the current study, we aimed to elucidate the role of N-cadherin, one of the core components in adhesion junction, in mediating connexin 43, one of the functional constituents in gap junction, via transforming growth factor-β1(TGF-β1) induction in osteoblasts. We first elucidated the expressions of N-cadherin induced by TGF-β1 and also confirmed the upregulation of Cx43, and the enhancement of functional gap junctional intercellular communication (GJIC) triggered by TGF-β1 in both primary osteoblasts and MC3T3 cell line. Colocalization analysis and Co-IP experimentation showed that N-cadherin interacts with Cx43 at the site of cell-cell contact. Knockdown of N-cadherin by siRNA interference decreased the Cx43 expression and abolished the promoting effect of TGF-β1 on Cx43. Functional GJICs in living primary osteoblasts and MC3T3 cell line were also reduced. TGF-β1-induced increase in N-cadherin and Cx43 was via Smad3 activation, whereas knockdown of Smad3 signaling by using siRNA decreased the expressions of both N-cadherin and Cx43. Overall, these data indicate the direct interactions between N-cadherin and Cx43, and reveal the intervention of adhesion junction in functional gap junction in living osteoblasts.
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Affiliation(s)
- Yueyi Yang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wenjing Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - JieYa Wei
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yujia Cui
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Demao Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jing Xie
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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18
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Özsoy Ş, Vujovic F, Simonian M, Valova V, Hunter N, Farahani RM. Cannibalized erythroblasts accelerate developmental neurogenesis by regulating mitochondrial dynamics. Cell Rep 2021; 35:108942. [PMID: 33826895 DOI: 10.1016/j.celrep.2021.108942] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/18/2020] [Accepted: 03/12/2021] [Indexed: 11/29/2022] Open
Abstract
Metabolic support was long considered to be the only developmental function of hematopoiesis, a view that is gradually changing. Here, we disclose a mechanism triggered during neurulation that programs brain development by donation of sacrificial yolk sac erythroblasts to neuroepithelial cells. At embryonic day (E) 8.5, neuroepithelial cells transiently integrate with the endothelium of yolk sac blood vessels and cannibalize intravascular erythroblasts as transient heme-rich endosymbionts. This cannibalistic behavior instructs precocious neuronal differentiation of neuroepithelial cells in the proximity of blood vessels. By experiments in vitro, we show that access to erythroblastic heme accelerates the pace of neurogenesis by induction of a truncated neurogenic differentiation program from a poised state. Mechanistically, the poised state is invoked by activation of the mitochondrial electron transport chain that leads to amplified production of reactive oxygen species in addition to omnipresent guanosine triphosphate (GTP) with consequential upregulation of pro-differentiation β-catenin.
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Affiliation(s)
- Şükran Özsoy
- IDR/Westmead Institute for Medical Research, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Filip Vujovic
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Mary Simonian
- IDR/Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Valentina Valova
- Children's Medical Research Institute, University of Sydney, Westmead, NSW, Australia
| | - Neil Hunter
- IDR/Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Ramin M Farahani
- IDR/Westmead Institute for Medical Research, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
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19
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Deng Z, Yan W, Dai X, Chen M, Qu Q, Wu B, Zhao W. N-Cadherin Regulates the Odontogenic Differentiation of Dental Pulp Stem Cells via β-Catenin Activity. Front Cell Dev Biol 2021; 9:661116. [PMID: 33859987 PMCID: PMC8042212 DOI: 10.3389/fcell.2021.661116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 12/22/2022] Open
Abstract
Dental pulp stem cell (DPSC) transplantation has shown new prospects in dental pulp regeneration, and is of great significance in the treatment of pulpitis and pulp necrosis. The fate and regenerative potential of stem cells are dependent, to a great extent, on their microenvironment, which is composed of various tissue components, cell populations, and soluble factors. N-cadherin-mediated cell–cell interaction has been implicated as an important factor in controlling the cell-fate commitment of mesenchymal stem cells. In this study, the effect of N-cadherin on odontogenic differentiation of DPSCs and the potential underlying mechanisms, both in vitro and in vivo, was investigated using a cell culture model and a subcutaneous transplantation mouse model. It was found that the expression of N-cadherin was reversely related to the expression of odontogenic markers (dentin sialophosphoprotein, DSPP, and runt-related transcription factor 2, Runx2) during the differentiation process of DPSCs. Specific shRNA-mediated knockdown of N-cadherin expression in DPSCs significantly increased the expression of DSPP and Runx2, alkaline phosphatase (ALP) activity, and the formation of mineralized nodules. Notably, N-cadherin silencing promoted nucleus translocation and accumulation of β-catenin. Inhibition of β-catenin by a specific inhibitor XAV939, reversed the facilitating effects of N-cadherin downregulation on odontogenic differentiation of DPSCs. In addition, knockdown of N-cadherin promoted the formation of odontoblast-like cells and collagenous matrix in β-tricalcium phosphate/DPSCs composites transplanted into mice. In conclusion, N-cadherin acted as a negative regulator via regulating β-catenin activity during odontogenic differentiation of DPSCs. These data may help to guide DPSC behavior by tuning the N-cadherin-mediated cell–cell interactions, with implications for pulp regeneration.
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Affiliation(s)
- Zilong Deng
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenjuan Yan
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xingzhu Dai
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ming Chen
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Qian Qu
- Stomatology Healthcare Center, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China
| | - Buling Wu
- Shenzhen Stomatology Hospital (Pingshan), Southern Medical University, Shenzhen, China
| | - Wanghong Zhao
- Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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20
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N-cadherin in osteolineage cells modulates stromal support of tumor growth. J Bone Oncol 2021; 28:100356. [PMID: 33912383 PMCID: PMC8065282 DOI: 10.1016/j.jbo.2021.100356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/03/2021] [Accepted: 02/09/2021] [Indexed: 12/02/2022] Open
Abstract
N-cadherin in osteolineage, Osterix+ cells restrains extraskeletal tumor growth. Osterix+ cells are present in the stromal microenvironment of extraskeletal tumors. Osterix+ cells are present in normal tissues frequent sites of metastasis. N-cadherin modulates pro-tumorigenic signaling in tumor associated Osterix+ cells. Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell–cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (Cdh2) in osteolineage cells using Osx-cre (cKO). Contrary to expectations, the metastatic breast cancer cell line PyMT-BO1 was able to form tumors in bone and to induce osteolysis in cKO as well as in control mice. Despite absence of Ncad, bone marrow stromal cells isolated from cKO mice were able to engage in direct cell–cell interactions with tumor cells expressing either N- or E-cadherin. However, subcutaneous PyMT-BO1 and B16F10 tumors grew larger in cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells. Gene expression analysis by RNAseq of Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in cKO cells relative to control Osx+ cells. Thus, Ncad in Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.
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21
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Walker M, Luo J, Pringle EW, Cantini M. ChondroGELesis: Hydrogels to harness the chondrogenic potential of stem cells. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 121:111822. [PMID: 33579465 DOI: 10.1016/j.msec.2020.111822] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 01/01/2023]
Abstract
The extracellular matrix is a highly complex microenvironment, whose various components converge to regulate cell fate. Hydrogels, as water-swollen polymer networks composed by synthetic or natural materials, are ideal candidates to create biologically active substrates that mimic these matrices and target cell behaviour for a desired tissue engineering application. Indeed, the ability to tune their mechanical, structural, and biochemical properties provides a framework to recapitulate native tissues. This review explores how hydrogels have been engineered to harness the chondrogenic response of stem cells for the repair of damaged cartilage tissue. The signalling processes involved in hydrogel-driven chondrogenesis are also discussed, identifying critical pathways that should be taken into account during hydrogel design.
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Affiliation(s)
- Matthew Walker
- Centre for the Cellular Microenvironment, James Watt School of Engineering, University of Glasgow, UK
| | - Jiajun Luo
- Centre for the Cellular Microenvironment, James Watt School of Engineering, University of Glasgow, UK
| | - Eonan William Pringle
- Centre for the Cellular Microenvironment, James Watt School of Engineering, University of Glasgow, UK
| | - Marco Cantini
- Centre for the Cellular Microenvironment, James Watt School of Engineering, University of Glasgow, UK.
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22
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Mrozik KM, Cheong CM, Hewett DR, Noll JE, Opperman KS, Adwal A, Russell DL, Blaschuk OW, Vandyke K, Zannettino ACW. LCRF-0006, a small molecule mimetic of the N-cadherin antagonist peptide ADH-1, synergistically increases multiple myeloma response to bortezomib. FASEB Bioadv 2020; 2:339-353. [PMID: 32617520 PMCID: PMC7325588 DOI: 10.1096/fba.2019-00073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 12/13/2022] Open
Abstract
N-cadherin is a homophilic cell-cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre-clinical studies have shown that the N-cadherin antagonist peptide, ADH-1, increases the permeability of tumor-associated vasculature thereby increasing anti-cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF-0006, that is a mimetic of the classical cadherin His-Ala-Val sequence-containing region of ADH-1. Here, we evaluated the vascular permeability-enhancing and anti-cancer properties of LCRF-0006 using in vitro vascular disruption and cell apoptosis assays, and a well-established pre-clinical model (C57BL/KaLwRij/5TGM1) of the hematological cancer multiple myeloma (MM). We found that LCRF-0006 disrupted endothelial cell junctions in a rapid, transient and reversible manner, and increased vascular permeability in vitro and at sites of MM tumor in vivo. Notably, LCRF-0006 synergistically increased the in vivo anti-MM tumor response to low-dose bortezomib, a frontline anti-MM agent, leading to regression of disease in 100% of mice. Moreover, LCRF-0006 and bortezomib synergistically induced 5TGM1 MM tumor cell apoptosis in vitro. Our findings demonstrate the potential clinical utility of LCRF-0006 to significantly increase bortezomib effectiveness and enhance the depth of tumor response in patients with MM.
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Affiliation(s)
- Krzysztof M. Mrozik
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
| | - Chee M. Cheong
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
| | - Duncan R. Hewett
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
| | - Jacqueline E. Noll
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
| | - Khatora S. Opperman
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
| | - Alaknanda Adwal
- Ovarian and Reproductive Cancer Biology LaboratoryRobinson Research InstituteThe University of AdelaideAdelaideAustralia
| | - Darryl L. Russell
- Ovarian and Reproductive Cancer Biology LaboratoryRobinson Research InstituteThe University of AdelaideAdelaideAustralia
| | - Orest W. Blaschuk
- Division of UrologyDepartment of SurgeryMcGill UniversityMontrealCanada
| | - Kate Vandyke
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
| | - Andrew C. W. Zannettino
- Myeloma Research LaboratoryAdelaide Medical SchoolFaculty of Health and Medical SciencesThe University of AdelaideAdelaideAustralia
- Precision Medicine ThemeSouth Australian Health and Medical Research Institute (SAHMRI)AdelaideAustralia
- Central Adelaide Local Health NetworkAdelaideAustralia
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23
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Loh CY, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, Chong PP, Looi CY. The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells 2019; 8:E1118. [PMID: 31547193 PMCID: PMC6830116 DOI: 10.3390/cells8101118] [Citation(s) in RCA: 829] [Impact Index Per Article: 138.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/16/2019] [Accepted: 09/19/2019] [Indexed: 12/17/2022] Open
Abstract
Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside.
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Affiliation(s)
- Chin-Yap Loh
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia.
| | - Jian Yi Chai
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia.
| | - Ting Fang Tang
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
| | - Muthu Kumaraswamy Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
| | - Pei Pei Chong
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia.
| | - Chung Yeng Looi
- School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya 47500, Malaysia.
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24
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Rezaei-Lotfi S, Hunter N, Farahani RM. Coupled cycling programs multicellular self-organization of neural progenitors. Cell Cycle 2019; 18:2040-2054. [PMID: 31286803 PMCID: PMC6681778 DOI: 10.1080/15384101.2019.1638692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/12/2019] [Accepted: 06/14/2019] [Indexed: 02/06/2023] Open
Abstract
Self-organization is central to the morphogenesis of multicellular organisms. However, the molecular platform that coordinates the robust emergence of complex morphological patterns from local interactions between cells remains unresolved. Here we demonstrate that neural self- organization is driven by coupled cycling of progenitor cells. In a coupled cycling mode, intercellular contacts relay extrinsic cues to override the intrinsic cycling rhythm of an individual cell and synchronize the population. The stringency of coupling and hence the synchronicity of the population is programmed by recruitment of a key coupler, β-catenin, into junctional complexes. As such, multicellular self-organization is driven by the same basic mathematical principle that governs synchronized behavior of macro-scale biological systems as diverse as the synchronized chirping of crickets, flashing of fireflies and schooling of fish; that is synchronization by coupling. It is proposed that coupled cycling foreshadows a fundamental adaptive change that facilitated evolution and diversification of multicellular life forms.
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Affiliation(s)
- Saba Rezaei-Lotfi
- IDR/Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Neil Hunter
- IDR/Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Ramin M Farahani
- IDR/Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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25
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Aaron M, Nadeau G, Ouimet-Grennan E, Drouin S, Bertout L, Beaulieu P, St-Onge P, Shalmiev A, Veilleux LN, Rauch F, Petrykey K, Laverdière C, Sinnett D, Alos N, Krajinovic M. Identification of a single-nucleotide polymorphism within CDH2 gene associated with bone morbidity in childhood acute lymphoblastic leukemia survivors. Pharmacogenomics 2019; 20:409-420. [PMID: 30983502 DOI: 10.2217/pgs-2018-0169] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aim: To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). Patients & methods: To this end, we measured the association between reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models. Results: The minor allele of rs1944294 in CDH2 gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002). Conclusion: The variant in CDH2 gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.
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Affiliation(s)
- Michelle Aaron
- Department of Medicine, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada
| | - Geneviève Nadeau
- Department of Medicine, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada
| | - Erika Ouimet-Grennan
- Department of Medicine, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada
| | - Simon Drouin
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada
| | - Laurence Bertout
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada
| | - Patrick Beaulieu
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada
| | - Pascal St-Onge
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada
| | - Albert Shalmiev
- Department of Pharmacology and Physiology, Université de Montréal, Quebec, H3T 1J4, Canada
| | | | - Frank Rauch
- Montreal Shriners Hospital for Children, Montreal, Quebec, H4A 0A9, Canada
| | - Kateryna Petrykey
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada.,Department of Pharmacology and Physiology, Université de Montréal, Quebec, H3T 1J4, Canada
| | - Caroline Laverdière
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada.,Department of Pediatrics, Université de Montréal, Quebec, H3T 1J4, Canada
| | - Daniel Sinnett
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada.,Department of Pediatrics, Université de Montréal, Quebec, H3T 1J4, Canada
| | - Nathalie Alos
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada.,Department of Pediatrics, Université de Montréal, Quebec, H3T 1J4, Canada.,Division of Endocrinology, Sainte-Justine University Hospital Center, Montreal, Quebec, H3T 1C5, Canada
| | - Maja Krajinovic
- Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada.,Department of Pharmacology and Physiology, Université de Montréal, Quebec, H3T 1J4, Canada.,Department of Pediatrics, Université de Montréal, Quebec, H3T 1J4, Canada
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26
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Mechanoactivation of Wnt/β-catenin pathways in health and disease. Emerg Top Life Sci 2018; 2:701-712. [DOI: 10.1042/etls20180042] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/08/2018] [Accepted: 10/09/2018] [Indexed: 11/17/2022]
Abstract
Mechanical forces play an important role in regulating tissue development and homeostasis in multiple cell types including bone, joint, epithelial and vascular cells, and are also implicated in the development of diseases, e.g. osteoporosis, cardiovascular disease and osteoarthritis. Defining the mechanisms by which cells sense and respond to mechanical forces therefore has important implications for our understanding of tissue function in health and disease and may lead to the identification of targets for therapeutic intervention. Mechanoactivation of the Wnt signalling pathway was first identified in osteoblasts with a key role for β-catenin demonstrated in loading-induced osteogenesis. Since then, mechanoregulation of the Wnt pathway has also been observed in stem cells, epithelium, chondrocytes and vascular and lymphatic endothelium. Wnt can signal through both canonical and non-canonical pathways, and evidence suggests that both can mediate responses to mechanical strain, stretch and shear stress. This review will discuss our current understanding of the activation of the Wnt pathway in response to mechanical forces.
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27
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Funck-Brentano T, Nilsson KH, Brommage R, Henning P, Lerner UH, Koskela A, Tuukkanen J, Cohen-Solal M, Movérare-Skrtic S, Ohlsson C. Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice. J Endocrinol 2018; 238:13-23. [PMID: 29720540 PMCID: PMC5987170 DOI: 10.1530/joe-18-0153] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 05/02/2018] [Indexed: 01/23/2023]
Abstract
WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.
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Affiliation(s)
- Thomas Funck-Brentano
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Karin H Nilsson
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Robert Brommage
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Petra Henning
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ulf H Lerner
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Antti Koskela
- Unit of Cancer Research and Translational MedicineMRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland
| | - Juha Tuukkanen
- Unit of Cancer Research and Translational MedicineMRC Oulu and Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland
| | - Martine Cohen-Solal
- BIOSCAR UMRS 1132Université Paris Diderot, Sorbonne Paris Cité, INSERM, Paris, France
| | - Sofia Movérare-Skrtic
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Claes Ohlsson
- Centre for Bone and Arthritis ResearchInstitute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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28
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Curto J, Del Valle-Pérez B, Villarroel A, Fuertes G, Vinyoles M, Peña R, García de Herreros A, Duñach M. CK1ε and p120-catenin control Ror2 function in noncanonical Wnt signaling. Mol Oncol 2018; 12:611-629. [PMID: 29465811 PMCID: PMC5928365 DOI: 10.1002/1878-0261.12184] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 02/02/2018] [Accepted: 02/02/2018] [Indexed: 12/31/2022] Open
Abstract
Canonical and noncanonical Wnt pathways share some common elements but differ in the responses they evoke. Similar to Wnt ligands acting through the canonical pathway, Wnts that activate the noncanonical signaling, such as Wnt5a, promote Disheveled (Dvl) phosphorylation and its binding to the Frizzled (Fz) Wnt receptor complex. The protein kinase CK1ε is required for Dvl/Fz association in both canonical and noncanonical signaling. Here we show that differently to its binding to canonical Wnt receptor complex, CK1ε does not require p120‐catenin for the association with the Wnt5a co‐receptor Ror2. Wnt5a promotes the formation of the Ror2–Fz complex and enables the activation of Ror2‐bound CK1ε by Fz‐associated protein phosphatase 2A. Moreover, CK1ε also regulates Ror2 protein levels; CK1ε association stabilizes Ror2, which undergoes lysosomal‐dependent degradation in the absence of this kinase. Although p120‐catenin is not required for CK1ε association with Ror2, it also participates in this signaling pathway as p120‐catenin binds and maintains Ror2 at the plasma membrane; in p120‐depleted cells, Ror2 is rapidly internalized through a clathrin‐dependent mechanism. Accordingly, downregulation of p120‐catenin or CK1ε affects late responses to Wnt5a that are also sensitive to Ror2, such as SIAH2 transcription, cell invasion, or cortical actin polarization. Our results explain how CK1ε is activated by noncanonical Wnt and identify p120‐catenin and CK1ε as two critical factors controlling Ror2 function.
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Affiliation(s)
- Josué Curto
- Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Beatriz Del Valle-Pérez
- Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Aida Villarroel
- Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Guillem Fuertes
- Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Meritxell Vinyoles
- Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.,Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Raúl Peña
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Antonio García de Herreros
- Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.,Departament de Ciències, Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Mireia Duñach
- Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain
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29
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Marie PJ, Cohen-Solal M. The Expanding Life and Functions of Osteogenic Cells: From Simple Bone-Making Cells to Multifunctional Cells and Beyond. J Bone Miner Res 2018; 33:199-210. [PMID: 29206311 DOI: 10.1002/jbmr.3356] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/27/2017] [Accepted: 11/29/2017] [Indexed: 12/20/2022]
Abstract
During the last three decades, important progress in bone cell biology and in human and mouse genetics led to major advances in our understanding of the life and functions of cells of the osteoblast lineage. Previously unrecognized sources of osteogenic cells have been identified. Novel cellular and molecular mechanisms controlling osteoblast differentiation and senescence have been determined. New mechanisms of communications between osteogenic cells, osteocytes, osteoclasts, and chondrocytes, as well as novel links between osteogenic cells and blood vessels have been identified. Additionally, cells of the osteoblast lineage were shown to be important components of the hematopoietic niche and to be implicated in hematologic dysfunctions and malignancy. Lastly, unexpected interactions were found between osteogenic cells and several soft tissues, including the central nervous system, gut, muscle, fat, and testis through the release of paracrine factors, making osteogenic cells multifunctional regulatory cells, in addition to their bone-making function. These discoveries considerably enlarged our vision of the life and functions of osteogenic cells, which may lead to the development of novel therapeutics with immediate applications in bone disorders. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Pierre J Marie
- Inserm UMR-1132, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Martine Cohen-Solal
- Inserm UMR-1132, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France
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30
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Fujita S, Mukai T, Mito T, Kodama S, Nagasu A, Kittaka M, Sone T, Ueki Y, Morita Y. Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis. Bone 2018; 106:156-166. [PMID: 29055830 PMCID: PMC6912859 DOI: 10.1016/j.bone.2017.10.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/05/2017] [Accepted: 10/18/2017] [Indexed: 12/20/2022]
Abstract
Tankyrase is a poly (ADP-ribose) polymerase that leads to ubiquitination and degradation of target proteins. Since tankyrase inhibitors suppress the degradation of AXIN protein, a negative regulator of the canonical Wnt pathway, they effectively act as Wnt inhibitors. Small molecule tankyrase inhibitors are being investigated as drug candidates for cancer and fibrotic diseases, in which the Wnt pathways are aberrantly activated. Tankyrase is also reported to degrade the adaptor protein SH3BP2 (SH3 domain-binding protein 2). We have previously shown that SH3BP2 gain-of-function mutation enhances receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in murine bone marrow-derived macrophages (BMMs). Although the interaction between tankyrase and SH3BP2 has been reported, it is not clear whether and how the inhibition of tankyrase affects bone cells and bone mass. Here, we have demonstrated that tankyrase inhibitors (IWR-1, XAV939, and G007-LK) enhanced RANKL-induced osteoclast formation and function in murine BMMs and human peripheral blood mononuclear cells through the accumulation of SH3BP2, subsequent phosphorylation of SYK, and nuclear translocation of NFATc1. Tankyrase inhibitors also enhanced osteoblast differentiation and maturation, represented by increased expression of osteoblast-associated genes accompanied by the accumulation of SH3BP2 protein and enhanced nuclear translocation of ABL, TAZ, and Runx2 in primary osteoblasts. Most importantly, pharmacological inhibition of tankyrase in mice significantly decreased tibia and lumbar vertebrae bone volumes in association with increased numbers of osteoclasts. Our findings uncover the role of tankyrase inhibition in bone cells and highlight the potential adverse effects of the inhibitor on bone.
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Affiliation(s)
- Shunichi Fujita
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan
| | - Tomoyuki Mukai
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan.
| | - Takafumi Mito
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan
| | - Shoko Kodama
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan
| | - Akiko Nagasu
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan
| | - Mizuho Kittaka
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, MO, USA
| | - Teruki Sone
- Department of Nuclear Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Yasuyoshi Ueki
- Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, MO, USA
| | - Yoshitaka Morita
- Department of Rheumatology, Kawasaki Medical School, Kurashiki, Japan
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31
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Kureel J, John AA, Prakash R, Singh D. MiR 376c inhibits osteoblastogenesis by targeting Wnt3 and ARF-GEF-1 -facilitated augmentation of beta-catenin transactivation. J Cell Biochem 2017; 119:3293-3303. [PMID: 29125885 DOI: 10.1002/jcb.26490] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 11/09/2017] [Indexed: 01/08/2023]
Abstract
Wnt signaling pathway plays important role in all aspects of skeletal development which include chondrogenesis, osteoblastogenesis, and osteoclastogenesis. Induction of the Wnt-3 signaling pathway promotes bone formation while inactivation of the pathway leads to bone related disorders like osteoporosis. Wnt signaling thus has become a desired target to treat osteogenic disorders. MicroRNAs (miRNAs) represent an important category of elements that interact with Wnt signaling molecules to regulate osteogenesis. Here, we show that miR-376c, a well-characterized tumor suppressor which inhibits cell proliferation and invasion in osteosarcoma by targeting to transforming growth factor-alpha, suppresses osteoblast proliferation, and differentiation. Over-expression of miR-376c inhibited osteoblast differentiation, whereas inhibition of miR-376c function by antimiR-376c promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay along with qRT-PCR identified Wnt-3 and ARF-GEF-1 as direct targets of miR-376c. It was seen that over-expression of miR-376c leads to repression of canonical Wnt/β-catenin signaling. Our overall results suggest that miR-376c targets Wnt-3 and ARF-GEF-1 suppresses ARF-6 activation which prevents the release of β-catenin and its transactivation thereby inhibiting osteoblast differentiation. Although miR-376c is known to be a tumor repressor; we have identified a second complementary function of miR-376c where it inhibits Wnt-3-mediated osteogenesis and promotes bone loss.
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Affiliation(s)
- Jyoti Kureel
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Aijaz A John
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Ravi Prakash
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
| | - Divya Singh
- Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India
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32
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Silva DI, Santos BPD, Leng J, Oliveira H, Amédée J. Dorsal root ganglion neurons regulate the transcriptional and translational programs of osteoblast differentiation in a microfluidic platform. Cell Death Dis 2017; 8:3209. [PMID: 29238079 PMCID: PMC5870602 DOI: 10.1038/s41419-017-0034-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 09/28/2017] [Accepted: 10/02/2017] [Indexed: 11/17/2022]
Abstract
Innervation by the sensory nervous system plays a key role in skeletal development and in orchestration of bone remodeling and regeneration. However, it is unclear how and in which bone cells can sensory nerves act to control these processes. Here, we show a microfluidic coculture system comprising dorsal root ganglion (DRG) neurons and mesenchymal stem cells (MSCs) that more faithfully represents the in vivo scenario of bone sensory innervation. We report that DRG neurons promote the osteogenic differentiation capacity of MSCs, by mediating the increase of alkaline phosphatase activity and the upregulation of osteoblast-specific genes. Furthermore, we show that DRG neurons have a positive impact on Cx43 levels in MSCs during osteoblastogenesis, especially at an early stage of this process. Conversely, we described a negative impact of DRG neurons on MSCs N-cadherin expression at a later stage. Finally, we demonstrate a cytoplasmic accumulation of β-catenin translocation into the nucleus, and subsequently Lymphoid Enhancer Binding Factor 1—responsive transcriptional activation of downstream genes in cocultured MSCs. Together, our study provides a robust body of evidence that the direct interaction of DRG neurons with MSCs in a bone-like microenvironment leads to an enhancement of osteoblast differentiation potential of MSCs. The osteogenic effect of DRG neurons on MSCs is mediated through the regulation of Cx43 and N-cadherin expression and activation of the canonical/β-catenin Wnt signaling pathway.
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Affiliation(s)
- Diana Isabel Silva
- Tissue Bioengineering, University of Bordeaux, U1026, 33076, Bordeaux, France. .,Tissue Bioengineering, INSERM, U1026, 33076, Bordeaux, France.
| | - Bruno Paiva Dos Santos
- Tissue Bioengineering, University of Bordeaux, U1026, 33076, Bordeaux, France.,Tissue Bioengineering, INSERM, U1026, 33076, Bordeaux, France
| | - Jacques Leng
- University of Bordeaux, LOF, UMR5258, 33600, Pessac, France.,CNRS, LOF, UMR5258, 33600, Pessac, France.,Solvay, LOF, UMR5258, 33600, Pessac, France
| | - Hugo Oliveira
- Tissue Bioengineering, University of Bordeaux, U1026, 33076, Bordeaux, France.,Tissue Bioengineering, INSERM, U1026, 33076, Bordeaux, France
| | - Joëlle Amédée
- Tissue Bioengineering, University of Bordeaux, U1026, 33076, Bordeaux, France.,Tissue Bioengineering, INSERM, U1026, 33076, Bordeaux, France
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33
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Li R, Xu J, Wong DSH, Li J, Zhao P, Bian L. Self-assembled N-cadherin mimetic peptide hydrogels promote the chondrogenesis of mesenchymal stem cells through inhibition of canonical Wnt/β-catenin signaling. Biomaterials 2017; 145:33-43. [PMID: 28843065 DOI: 10.1016/j.biomaterials.2017.08.031] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 08/15/2017] [Indexed: 12/14/2022]
Abstract
N-cadherin, a transmembrane protein and major component of adherens junction, mediates cell-cell interactions and intracellular signaling that are important to the regulation of cell behaviors and organ development. Previous studies have identified mimetic peptides that possess similar bioactivity as that of N-cadherin, which promotes chondrogenesis of human mesenchymal stem cells (hMSCs); however, the molecular mechanism remains unknown. In this study, we combined the N-cadherin mimetic peptide (HAVDI) with the self-assembling KLD-12 peptide: the resultant peptide is capable of self-assembling into hydrogels functionalized with N-cadherin peptide in phosphate-buffered saline (PBS) at 37 °C. Encapsulation of hMSCs in these hydrogels showed enhanced expression of chondrogenic marker genes and deposition of cartilage specific extracellular matrix rich in proteoglycan and Type II Collagen compared to control hydrogels, with a scrambled-sequence peptide after 14 days of chondrogenic culture. Furthermore, western blot showed a significantly higher expression of active glycogen synthase kinase-3β (GSK-3β), which phosphorylates β-catenin and facilitates ubiquitin-mediated degradation, as well as a lower expression of β-catenin and LEF1 in the N-cadherin peptide hydrogels versus controls. Immunofluorescence staining revealed significantly less nuclear localization of β-catenin in N-cadherin mimetic peptide hydrogels. Our findings suggest that N-cadherin peptide hydrogels suppress canonical Wnt signaling in hMSCs by reducing β-catenin nuclear translocation and the associated transcriptional activity of β-catenin/LEF-1/TCF complex, thereby enhancing the chondrogenesis of hMSCs. Our biomimetic self-assembled peptide hydrogels can serve as a tailorable and versatile three-dimensional culture platform to investigate the effect of biofunctionalization on stem cell behavior.
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Affiliation(s)
- Rui Li
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Jianbin Xu
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Dexter Siu Hong Wong
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Jinming Li
- Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Pengchao Zhao
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Liming Bian
- Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong; Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; China Orthopedic Regenerative Medicine Group (CORaMed), Hangzhou, PR China; Centre for Novel Biomaterials, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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34
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Mansouri R, Jouan Y, Hay E, Blin-Wakkach C, Frain M, Ostertag A, Le Henaff C, Marty C, Geoffroy V, Marie PJ, Cohen-Solal M, Modrowski D. Osteoblastic heparan sulfate glycosaminoglycans control bone remodeling by regulating Wnt signaling and the crosstalk between bone surface and marrow cells. Cell Death Dis 2017; 8:e2902. [PMID: 28661485 PMCID: PMC5520938 DOI: 10.1038/cddis.2017.287] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 04/21/2017] [Accepted: 05/19/2017] [Indexed: 12/23/2022]
Abstract
Stimulating bone formation is an important challenge for bone anabolism in osteoporotic patients or to repair bone defects. The osteogenic properties of matrix glycosaminoglycans (GAGs) have been explored; however, the functions of GAGs at the surface of bone-forming cells are less documented. Syndecan-2 is a membrane heparan sulfate proteoglycan that is associated with osteoblastic differentiation. We used a transgenic mouse model with high syndecan-2 expression in osteoblasts to enrich the bone surface with cellular GAGs. Bone mass was increased in these transgenic mice. Syndecan-2 overexpression reduced the expression of receptor activator of NF-kB ligand (RANKL) in bone marrow cells and strongly inhibited bone resorption. Osteoblast activity was not modified in the transgenic mice, but bone formation was decreased in 4-month-old transgenic mice because of reduced osteoblast number. Increased proteoglycan expression at the bone surface resulted in decreased osteoblastic and osteoclastic precursors in bone marrow. Indeed, syndecan-2 overexpression increased apoptosis of mesenchymal precursors within the bone marrow. However, syndecan-2 specifically promoted the vasculature characterized by high expression of CD31 and Endomucin in 6-week-old transgenic mice, but this was reduced in 12-week-old transgenic mice. Finally, syndecan-2 functions as an inhibitor of Wnt-β-catenin–T-cell factor signaling pathway, activating glycogen synthase kinase 3 and then decreasing the Wnt-dependent production of Wnt ligands and R-spondin. In conclusion, our results show that GAG supply may improve osteogenesis, but also interfere with the crosstalk between the bone surface and marrow cells, altering the supporting function of osteoblasts.
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Affiliation(s)
- Rafik Mansouri
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Yohann Jouan
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Eric Hay
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Claudine Blin-Wakkach
- CNRS, UMR 7370, LP2M, Faculté de médecine, 28 avenue de Valombrose, Nice, France.,Université Nice Sophia Antipolis, Parc Valrose, Nice, France
| | | | - Agnès Ostertag
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | | | - Caroline Marty
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Valérie Geoffroy
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Pierre J Marie
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Martine Cohen-Solal
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Dominique Modrowski
- Inserm UMR-1132, BIOSCAR, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
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35
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Tang H, Zhang Y, Jansen JA, van den Beucken JJJP. Effect of monocytes/macrophages on the osteogenic differentiation of adipose-derived mesenchymal stromal cells in 3D co-culture spheroids. Tissue Cell 2017; 49:461-469. [PMID: 28684045 DOI: 10.1016/j.tice.2017.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/02/2017] [Accepted: 06/06/2017] [Indexed: 02/08/2023]
Abstract
This study aimed to investigate the distinctive roles of the monocytes and macrophages on osteogenic differentiation of adipose-derived mesenchymal stromal cells (ADMSCs) in 3D spheroid co-cultures. We hypothesized that monocytes or macrophages (subtypes pro-inflammatory M1 and pro-wound healing M2) would affect the osteogenic differentiation of ADMSCs in 3D spheroids and that cell-cell interactions between monocytes/macrophages and ADMSCs play an important role in the osteogenic differentiation process of ADMSCs. The obtained results indicated that the osteogenic differentiation of ADMSCs was inhibited by monocytes and both macrophage subtypes in 3D spheroids. Monocytes and M2 macrophages had a stronger inhibiting effect than M1 macrophages. Cell-cell interactions mediated by N-cadherin likely played a role in the inhibiting effect of monocytes/macrophages on the osteogenic differentiation of ADMSCs.
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Affiliation(s)
- Hongbo Tang
- Department of Biomaterials, Radboudumc, Nijmegen, the Netherlands; Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Zhang
- Department of Biomaterials, Radboudumc, Nijmegen, the Netherlands
| | - John A Jansen
- Department of Biomaterials, Radboudumc, Nijmegen, the Netherlands
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36
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Fontana F, Hickman-Brecks CL, Salazar VS, Revollo L, Abou-Ezzi G, Grimston SK, Jeong SY, Watkins M, Fortunato M, Alippe Y, Link DC, Mbalaviele G, Civitelli R. N-cadherin Regulation of Bone Growth and Homeostasis Is Osteolineage Stage-Specific. J Bone Miner Res 2017; 32:1332-1342. [PMID: 28240364 PMCID: PMC5466462 DOI: 10.1002/jbmr.3112] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/30/2017] [Accepted: 02/20/2017] [Indexed: 12/15/2022]
Abstract
N-cadherin inhibits osteogenic cell differentiation and canonical Wnt/β-catenin signaling in vitro. However, in vivo both conditional Cdh2 ablation and overexpression in osteoblasts lead to low bone mass. We tested the hypothesis that N-cadherin has different effects on osteolineage cells depending upon their differentiation stage. Embryonic conditional osteolineage Cdh2 deletion in mice results in defective growth, low bone mass, and reduced osteoprogenitor number. These abnormalities are prevented by delaying Cdh2 ablation until 1 month of age, thus targeting only committed and mature osteoblasts, suggesting they are the consequence of N-cadherin deficiency in osteoprogenitors. Indeed, diaphyseal trabecularization actually increases when Cdh2 is ablated postnatally. The sclerostin-insensitive Lrp5A214V mutant, associated with high bone mass, does not rescue the growth defect, but it overrides the low bone mass of embryonically Cdh2-deleted mice, suggesting N-cadherin interacts with Wnt signaling to control bone mass. Finally, bone accrual and β-catenin accumulation after administration of an anti-Dkk1 antibody are enhanced in N-cadherin-deficient mice. Thus, although lack of N-cadherin in embryonic and perinatal age is detrimental to bone growth and bone accrual, in adult mice loss of N-cadherin in osteolineage cells favors bone formation. Hence, N-cadherin inhibition may widen the therapeutic window of osteoanabolic agents. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Francesca Fontana
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Cynthia L Hickman-Brecks
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Valerie S Salazar
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.,Department of Development Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Leila Revollo
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.,Department of Development Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Grazia Abou-Ezzi
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.,Division of Oncology, Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Susan K Grimston
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Sung Yeop Jeong
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Marcus Watkins
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Manuela Fortunato
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Yael Alippe
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Daniel C Link
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA.,Division of Oncology, Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gabriel Mbalaviele
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Roberto Civitelli
- Department of Internal Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, USA
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37
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Dubon MJ, Yu J, Choi S, Park KS. Transforming growth factor β induces bone marrow mesenchymal stem cell migration via noncanonical signals and N-cadherin. J Cell Physiol 2017; 233:201-213. [PMID: 28213973 DOI: 10.1002/jcp.25863] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/14/2017] [Accepted: 02/16/2017] [Indexed: 12/15/2022]
Abstract
Transforming growth factor-beta (TGF-β) induces the migration and mobilization of bone marrow-derived mesenchymal stem cells (BM-MSCs) to maintain bone homeostasis during bone remodeling and facilitate the repair of peripheral tissues. Although many studies have reported the mechanisms through which TGF-β mediates the migration of various types of cells, including cancer cells, the intrinsic cellular mechanisms underlying cellular migration, and mobilization of BM-MSCs mediated by TGF-β are unclear. In this study, we showed that TGF-β activated noncanonical signaling molecules, such as Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), focal adhesion kinase (FAK), and p38, via TGF-β type I receptor in human BM-MSCs and murine BM-MSC-like ST2 cells. Inhibition of Rac1 by NSC23766 and Src by PP2 resulted in impaired TGF-β-mediated migration. These results suggested that the Smad-independent, noncanonical signals activated by TGF-β were necessary for migration. We also showed that N-cadherin-dependent intercellular interactions were required for TGF-β-mediated migration using functional inhibition of N-cadherin with EDTA treatment and a neutralizing antibody (GC-4 antibody) or siRNA-mediated knockdown of N-cadherin. However, N-cadherin knockdown did not affect the global activation of noncanonical signals in response to TGF-β. Therefore, these results suggested that the migration of BM-MSCs in response to TGF-β was mediated through N-cadherin and noncanonical TGF-β signals.
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Affiliation(s)
- Maria Jose Dubon
- Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea
| | - Jinyeong Yu
- Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea
| | - Sanghyuk Choi
- Graduate School of Biotechnology, Kyung Hee University, Yongin, Korea
| | - Ki-Sook Park
- East-West Medical Research Institute, Kyung Hee University, Seoul, Korea
- College of Medicine, Kyung Hee University, Seoul, Korea
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38
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Seo T, Sakon T, Nakazawa S, Nishioka A, Watanabe K, Matsumoto K, Akasaka M, Shioi N, Sawada H, Araki S. Haemorrhagic snake venom metalloproteases and human
ADAM
s cleave
LRP
5/6, which disrupts cell–cell adhesions
in vitro
and induces haemorrhage
in vivo. FEBS J 2017; 284:1657-1671. [DOI: 10.1111/febs.14066] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/11/2017] [Accepted: 03/22/2017] [Indexed: 11/25/2022]
Affiliation(s)
- Tadahiko Seo
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Taketo Sakon
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Shiori Nakazawa
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Asuka Nishioka
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Kohei Watanabe
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Kaori Matsumoto
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Mari Akasaka
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Narumi Shioi
- Department of Chemistry Faculty of Science Fukuoka University Japan
| | - Hitoshi Sawada
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
| | - Satohiko Araki
- Sugashima Marine Biological Laboratory Graduate School of Science Nagoya University Japan
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39
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Lee JW, An H, Lee KY. Introduction of N-cadherin-binding motif to alginate hydrogels for controlled stem cell differentiation. Colloids Surf B Biointerfaces 2017; 155:229-237. [PMID: 28432956 DOI: 10.1016/j.colsurfb.2017.04.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 03/09/2017] [Accepted: 04/07/2017] [Indexed: 01/09/2023]
Abstract
Control of stem cell fate and phenotype using biomimetic synthetic extracellular matrices (ECMs) is an important tissue engineering approach. Many studies have focused on improving cell-matrix interactions. However, proper control of cell-cell interactions using synthetic ECMs could be critical for tissue engineering, especially with undifferentiated stem cells. In this study, alginate hydrogels were modified with a peptide derived from the low-density lipoprotein receptor-related protein 5 (LRP5), which is known to bind to N-cadherin, as a cell-cell interaction motif. In vitro changes in the morphology and differentiation of mouse bone marrow stromal cells (D1 stem cells) cultured in LRP5-alginate hydrogels were investigated. LRP5-alginate gels successfully induced stem cell aggregation and enhanced chondrogenic differentiation of D1 stem cells, compared to RGD-alginate gels, at low cell density. This approach to tailoring synthetic biomimetic ECMs using cell-cell interaction motifs may be critical in tissue engineering approaches using stem cells.
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Affiliation(s)
- Jae Won Lee
- Department of Bioengineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Hyoseok An
- Department of Bioengineering, Hanyang University, Seoul 04763, Republic of Korea
| | - Kuen Yong Lee
- Department of Bioengineering, Hanyang University, Seoul 04763, Republic of Korea; Institute of Nano Science and Technology, Hanyang University, Seoul 04763, Republic of Korea.
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Elsafadi M, Manikandan M, Alajez NM, Hamam R, Dawud RA, Aldahmash A, Iqbal Z, Alfayez M, Kassem M, Mahmood A. MicroRNA-4739 regulates osteogenic and adipocytic differentiation of immortalized human bone marrow stromal cells via targeting LRP3. Stem Cell Res 2017; 20:94-104. [PMID: 28340487 DOI: 10.1016/j.scr.2017.03.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 02/25/2017] [Accepted: 03/01/2017] [Indexed: 12/16/2022] Open
Abstract
Understanding the regulatory networks underlying lineage differentiation and fate determination of human bone marrow stromal cells (hBMSC) is a prerequisite for their therapeutic use. The goal of the current study was to unravel the novel role of the low-density lipoprotein receptor-related protein 3 (LRP3) in regulating the osteogenic and adipogenic differentiation of immortalized hBMSCs. Gene expression profiling revealed significantly higher LRP3 levels in the highly osteogenic hBMSC clone imCL1 than in the less osteogenic clone imCL2, as well as a significant upregulation of LRP3 during the osteogenic induction of the imCL1 clone. Data from functional and gene expression assays demonstrated the role of LRP3 as a molecular switch promoting hBMSC lineage differentiation into osteoblasts and inhibiting differentiation into adipocytes. Interestingly, microRNA (miRNA) expression profiling identified miR-4739 as the most under-represented miRNA (-36.11 fold) in imCL1 compared to imCL2. The TargetScan prediction algorithm, combined with functional and biochemical assays, identified LRP3 mRNA as a novel target of miR-4739, with a single potential binding site for miR-4739 located in the LRP3 3' UTR. Regulation of LRP3 expression by miR-4739 was subsequently confirmed by qRT-PCR, western blotting, and luciferase assays. Over-expression of miR-4739 mimicked the effects of LRP3 knockdown on promoting adipogenic and suppressing osteogenic differentiation of hBMSCs. Hence, we report for the first time a novel biological role for the LRP3/hsa-miR-4739 axis in balancing osteogenic and adipocytic differentiation of hBMSCs. Our data support the potential utilization of miRNA-based therapies in regenerative medicine.
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Affiliation(s)
- Mona Elsafadi
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia; KMEB, Department of Endocrinology, University Hospital of Odense, University of Southern Denmark, Winslowsparken 25.1, DK-5000 Odense C, Denmark.
| | - Muthurangan Manikandan
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia
| | - Nehad M Alajez
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia.
| | - Rimi Hamam
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia
| | - Raed Abu Dawud
- Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia
| | - Abdullah Aldahmash
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia; Prince Naif Health Research Center, King Saud University, Riyadh 11461, Saudi Arabia.
| | - Zafar Iqbal
- Department of Basic Sciences, College of applied medical sciences, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), National Guard Health Affairs, Al Ahsa, Saudi Arabia
| | - Musaad Alfayez
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia.
| | - Moustapha Kassem
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia; KMEB, Department of Endocrinology, University Hospital of Odense, University of Southern Denmark, Winslowsparken 25.1, DK-5000 Odense C, Denmark.
| | - Amer Mahmood
- Stem Cell Unit, Department of Anatomy, College of Medicine,King Saud University, Riyadh 11461, Saudi Arabia.
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Duñach M, Del Valle-Pérez B, García de Herreros A. p120-catenin in canonical Wnt signaling. Crit Rev Biochem Mol Biol 2017; 52:327-339. [PMID: 28276699 DOI: 10.1080/10409238.2017.1295920] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Canonical Wnt signaling controls β-catenin protein stabilization, its translocation to the nucleus and the activation of β-catenin/Tcf-4-dependent transcription. In this review, we revise and discuss the recent results describing actions of p120-catenin in different phases of this pathway. More specifically, we comment its involvement in four different steps: (i) the very early activation of CK1ɛ, essential for Dvl-2 binding to the Wnt receptor complex; (ii) the internalization of GSK3 and Axin into multivesicular bodies, necessary for a complete stabilization of β-catenin; (iii) the activation of Rac1 small GTPase, required for β-catenin translocation to the nucleus; and (iv) the release of the inhibitory action caused by Kaiso transcriptional repressor. We integrate these new results with the previously known action of other elements in this pathway, giving a particular relevance to the responses of the Wnt pathway not required for β-catenin stabilization but for β-catenin transcriptional activity. Moreover, we discuss the possible future implications, suggesting that the two cellular compartments where β-catenin is localized, thus, the adherens junction complex and the Wnt signalosome, are more physically connected that previously thought.
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Affiliation(s)
- Mireia Duñach
- a Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina , Universitat Autònoma de Barcelona , Bellaterra , Spain
| | - Beatriz Del Valle-Pérez
- a Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina , Universitat Autònoma de Barcelona , Bellaterra , Spain
| | - Antonio García de Herreros
- b Programa de Recerca en Càncer , Institut Hospital del Mar d'Investigacions Mèdiques (IMIM) , Barcelona , Spain.,c Departament de Ciències Experimentals i de la Salut , Universitat Pompeu Fabra , Barcelona , Spain
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Al-Amer O. E-Cadherin and FGFR1 Expression in Mouse Osteoblastogenesis in Normoxic Cultures. INTERNATIONAL JOURNAL OF BIOMEDICAL SCIENCE : IJBS 2017; 13:13-19. [PMID: 28533732 PMCID: PMC5422640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
E-cadherin is a cell surface adhesion molecules that play an important role in tissue differentiation. FGFR1 is expressed in the developing and mature skeleton in patterns suggestive of both unique and redundant function. Expression levels of E-cadherin and FGFR1 during osteoblastogenesis unclear. In this study primary calvarial mouse osteoblasts were differentiated to mature osteoblasts in osteogenic medium. Alkaline phosphatase (ALP) activity, alizarin red staining, gene expression (Runt-related transcription factor 2 (Runx2), collagen 1 (COL1A2), osteocalcin, E-cadherin and FGFR1) and protein expression (E-cadherin and FGFR1) of osteogenic-cultured primary mouse osteoblast were analysed in this study. The osteogenesis capacity of primary osteoblasts was significantly promoted as ALP activity, alizarin red staining, and the relative expression of Runx2 mRNA and COL1A2 mRNA significantly increased during osteoblastogenesis. The results demonstrated that E-cadherin mRNA and protein were expressed in immature osteoblasts (day 7), but not in mature osteoblasts (day 28). In contrast, the expression of FGFR1 mRNA and protein significantly highly expressed in mature osteoblasts (day 28) compared with immature osteoblasts (day 7). In conclusion, this study demonstrated that E-cadherin could be used as a marker for immature osteoblasts, whereas FGFR1 could be used as a marker for mature osteoblasts during in vitro osteoblastogenesis.
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PS1/ γ-Secretase-Mediated Cadherin Cleavage Induces β-Catenin Nuclear Translocation and Osteogenic Differentiation of Human Bone Marrow Stromal Cells. Stem Cells Int 2016; 2016:3865315. [PMID: 28053606 PMCID: PMC5178376 DOI: 10.1155/2016/3865315] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 11/01/2016] [Indexed: 01/21/2023] Open
Abstract
Bone marrow stromal cells (BMSCs) are considered a promising tool for bone bioengineering. However, the mechanisms controlling osteoblastic commitment are still unclear. Osteogenic differentiation of BMSCs requires the activation of β-catenin signaling, classically known to be regulated by the canonical Wnt pathway. However, BMSCs treatment with canonical Wnts in vitro does not always result in osteogenic differentiation and evidence indicates that a more complex signaling pathway, involving cadherins, would be required to induce β-catenin signaling in these cells. Here we showed that Wnt3a alone did not induce TCF activation in BMSCs, maintaining the cells at a proliferative state. On the other hand, we verified that, upon BMSCs osteoinduction with dexamethasone, cadherins were cleaved by the PS1/γ-secretase complex at the plasma membrane, and this event was associated with an enhanced β-catenin translocation to the nucleus and signaling. When PS1/γ-secretase activity was inhibited, the osteogenic process was impaired. Altogether, we provide evidence that PS1/γ-secretase-mediated cadherin cleavage has as an important role in controlling β-catenin signaling during the onset of BMSCs osteogenic differentiation, as part of a complex signaling pathway responsible for cell fate decision. A comprehensive map of these pathways might contribute to the development of strategies to improve bone repair.
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Yang H, Dong J, Xiong W, Fang Z, Guan H, Li F. N-cadherin restrains PTH repressive effects on sclerostin/SOST by regulating LRP6-PTH1R interaction. Ann N Y Acad Sci 2016; 1385:41-52. [PMID: 27723935 DOI: 10.1111/nyas.13221] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 07/27/2016] [Indexed: 12/20/2022]
Abstract
Sclerostin/SOST is a robust negative regulator of bone formation. Loss-of-function mutations of the sclerostin gene (SOST) cause sclerosteosis and Van Buchem disease characterized by bone overgrowth. Mediated by myocyte enhancer factor 2 (MEF2) transcription factors, parathyroid hormone (PTH) suppresses SOST expression through formation of complexes of parathyroid hormone-parathyroid hormone-related peptide receptor 1 (PTH1R) and lipoprotein receptor-related protein 6 (LRP6). N-cadherin has been shown to negatively regulate Wnt/β-catenin and PTH induced, protein kinase-dependent β-catenin signaling. Here, we investigated whether N-cadherin mediates the inhibitory effects of PTH on sclerostin/SOST. In vitro, overexpression of N-cadherin resulted in blunted PTH suppressive effects on sclerostin/SOST expression, as detected by immunoblot and qPCR analysis; PTH-induced downregulation of MEF2A, C, and D was impaired by N-cadherin; and N-cadherin reduced LRP6-PTHR1 interaction and endocytosis in response to PTH. In vivo, intermittent PTH (iPTH)-induced suppression of sclerostin/SOST was accentuated in Dmp1-cre; Cdh2f/f (Cdh2ΔDmp1 ) mice, compared with Cdh2f/f mice. Additionally, iPTH had greater bone anabolic effects in Cdh2ΔDmp1 mice compared to Cdh2f/f mice. These data indicate that N-cadherin negatively mediates PTH suppressive effects on sclerostin/SOST by regulating LRP6-PTHR1 interaction, ultimately influencing PTH anabolic effects on bone.
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Affiliation(s)
- Hailin Yang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.,Department of Orthopaedics, People's Hospital of Jieshou City, Jieshou, Anhui, P.R. China
| | - Jinbo Dong
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Wei Xiong
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Zhong Fang
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Hanfeng Guan
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Feng Li
- Department of Orthopaedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
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Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling. Oncogene 2016; 36:429-438. [PMID: 27321178 DOI: 10.1038/onc.2016.209] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 03/18/2016] [Accepted: 05/08/2016] [Indexed: 12/21/2022]
Abstract
Canonical Wnt signaling induces the stabilization of β-catenin, its translocation to the nucleus and the activation of target promoters. This pathway is initiated by the binding of Wnt ligands to the Frizzled receptor, the association of the LRP5/6 co-receptor and the formation of a complex comprising Dvl-2, Axin and protein kinases CK1α, ɛ, γ and GSK3. Among these, activation of CK1ɛ, constitutively bound to LRP5/6 through p120-catenin, is required for the association of the rest of the components. We describe here that CK1ɛ is activated by the PP2A/PR61ɛ phosphatase. Binding of Wnt ligands promotes the interaction of LRP5/6-associated CK1ɛ with Frizzled-bound PR61ɛ regulatory subunit, facilitating the access of PP2A catalytic subunit to CK1ɛ and its activation, what enables the recruitment of Dvl-2 to the receptor complex and the initiation of the Wnt pathway. Our results uncover the mechanism of activation of the canonical Wnt pathway by its ligands.
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Haxaire C, Haÿ E, Geoffroy V. Runx2 Controls Bone Resorption through the Down-Regulation of the Wnt Pathway in Osteoblasts. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:1598-609. [DOI: 10.1016/j.ajpath.2016.01.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 12/21/2015] [Accepted: 01/21/2016] [Indexed: 12/27/2022]
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Abstract
The disproportional enlargement of the neocortex through evolution has been instrumental in the success of vertebrates, in particular mammals. The neocortex is a multilayered sheet of neurons generated from a simple proliferative neuroepithelium through a myriad of mechanisms with substantial evolutionary conservation. This developing neuroepithelium is populated by progenitors that can generate additional progenitors as well as post-mitotic neurons. Subtle alterations in the production of progenitors vs. differentiated cells during development can result in dramatic differences in neocortical size. This review article will examine how cadherin adhesion proteins, in particular α-catenin and N-cadherin, function in regulating the neural progenitor microenvironment, cell proliferation, and differentiation in cortical development.
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Key Words
- APC, Adenomatous polyposis coli.
- CBD, catenin binding domain
- CK1, Casein kinase 1
- GSK3β, glycogen synthase kinase 3β
- Hh, Hedgehog
- JMD, juxtamembrane domain
- N-cadherin
- PCP, planar cell polarity
- PI3K, phosphatidylinositol 3-kinase
- PTEN, phosphatase and tensin homolog
- SHH, sonic hedgehog
- SNP, short neural precursor
- VZ, ventricular zone
- adherens junction
- differentiation
- proliferation
- wnt
- α-catenin
- β-catenin
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Affiliation(s)
- Adam M Stocker
- a Molecular Neurobiology Laboratory ; The Salk Institute ; La Jolla , CA USA
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Le Henaff C, Faria Da Cunha M, Hatton A, Tondelier D, Marty C, Collet C, Zarka M, Geoffroy V, Zatloukal K, Laplantine E, Edelman A, Sermet-Gaudelus I, Marie PJ. Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis. Hum Mol Genet 2016; 25:1281-93. [PMID: 26769674 DOI: 10.1093/hmg/ddw009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 01/06/2016] [Indexed: 12/23/2022] Open
Abstract
Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti-osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at low levels. Genetic studies showed that Krt8 deletion (Krt8(-/-)) in F508del-Cftr mice increased the levels of circulating markers of bone formation, corrected the expression of osteoblast phenotypic genes, promoted trabecular bone formation and improved bone mass and microarchitecture. Mechanistically, Krt8 deletion in F508del-Cftr mice corrected overactive NF-κB signaling and decreased Wnt-β-catenin signaling induced by the F508del-Cftr mutation in osteoblasts. In vitro, treatment with compound 407, which specifically disrupts the Krt8-F508del-Cftr interaction in epithelial cells, corrected the abnormal NF-κB and Wnt-β-catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt-β-catenin signaling and bone formation in F508del-Cftr mice. Collectively, the results show that genetic or pharmacologic targeting of Krt8 leads to correction of osteoblast dysfunctions, altered bone formation and osteopenia in F508del-Cftr mice, providing a therapeutic strategy targeting the Krt8-F508del-CFTR interaction to correct the abnormal bone formation and bone loss in cystic fibrosis.
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Affiliation(s)
- Carole Le Henaff
- INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | | | - Aurélie Hatton
- INSERM U-1151, Team 2, University Paris Descartes, Paris, France
| | | | - Caroline Marty
- INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Corinne Collet
- INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Mylène Zarka
- INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Valérie Geoffroy
- INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Kurt Zatloukal
- Institute of Pathology, Medical University of Graz, Graz, Austria and
| | - Emmanuel Laplantine
- Laboratoire de Signalisation et Pathogenèse, Institut Pasteur, Paris, France
| | | | | | - Pierre J Marie
- INSERM UMR-1132, Paris, France, University Paris Diderot, Sorbonne Paris Cité, Paris, France,
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Zhu M, Lin S, Sun Y, Feng Q, Li G, Bian L. Hydrogels functionalized with N-cadherin mimetic peptide enhance osteogenesis of hMSCs by emulating the osteogenic niche. Biomaterials 2016; 77:44-52. [PMID: 26580785 DOI: 10.1016/j.biomaterials.2015.10.072] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/26/2015] [Accepted: 10/26/2015] [Indexed: 01/16/2023]
Abstract
N-cadherin is considered to be the key factor in directing cell-cell interactions during mesenchymal condensation, which is essential to osteogenesis. In this study, hyaluronic acid (HA) hydrogels are biofunctionalized with an N-cadherin mimetic peptide to mimic the pro-osteogenic niche in the endosteal space to promote the osteogenesis of human mesenchymal stem cells (hMSCs). Results show that the conjugation of the N-cadherin peptide in the HA hydrogels enhances the expression of the osteogenic marker genes in the seeded hMSCs. Furthermore, the biofunctionalized HA hydrogels promote the alkaline phosphatase activity, type I collagen deposition, and matrix mineralization by the seeded hMSCs under both in vitro and in vivo condition. We postulate that the biofunctionalized hydrogels emulates the N-cadherin-mediated homotypic cell-cell adhesion among MSCs and the "orthotypic" interaction between the osteoblasts and MSCs. These findings demonstrate that the biofunctionalized HA hydrogels provide a supportive niche microenvironment for the osteogenesis of hMSCs.
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Affiliation(s)
- Meiling Zhu
- Division of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, People's Republic of China; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Sien Lin
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Yuxin Sun
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Qian Feng
- Division of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, People's Republic of China; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Gang Li
- Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Liming Bian
- Division of Biomedical Engineering, The Chinese University of Hong Kong, Hong Kong, People's Republic of China; Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Hong Kong, People's Republic of China; Shun Hing Institute of Advanced Engineering, The Chinese University of Hong Kong, People's Republic of China.
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Khosravi A, Shahrabi S, Shahjahani M, Saki N. The bone marrow metastasis niche in retinoblastoma. Cell Oncol (Dordr) 2015; 38:253-63. [PMID: 26063518 DOI: 10.1007/s13402-015-0232-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Retinoblastoma (Rb) is a progressive cancer which mainly occurs in children, and which is caused by different genetic or epigenetic alterations that lead to inactivation of both alleles of the RB1 gene. Hereditary and non-hereditary forms of Rb do exist, and the hereditary form is associated with an increased risk of secondary malignancies. Metastasis to distant organs is a critical feature of many tumors, and may be caused by various molecular alterations at different stages. Recognition of these alterations and, thus, insight into the processes underlying the development of metastases may result in novel preventive as well as effective targeted treatment options. Rb is associated with metastases to various organs and tissues, including the bone marrow (BM). METHODS Here, we provide an overview of mutations and other molecular changes known to be involved in Rb development and metastasis to the BM. This overview is based on a literature search ranging from 1990 to 2015. CONCLUSIONS The various BM metastasis-related molecular changes identified to date may be instrumental for a better diagnosis, prognosis and classification of Rb patients, as well as for the development of novel comprehensive (targeted) therapies.
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Affiliation(s)
- Abbas Khosravi
- Department of Hematology, Allied Medical School, Tehran University of Medical Sciences, Tehran, Iran
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