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Liu Z, Zhou D, Wang C, Zheng B, Yan Q, Zhou W, Wang G. Genetic Insights Into Craniosynostosis: Identification of Novel IL11RA Variants in Chinese Pediatric Patients. Mol Genet Genomic Med 2025; 13:e70106. [PMID: 40353334 PMCID: PMC12067187 DOI: 10.1002/mgg3.70106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 04/10/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Craniosynostosis (CS), a heterogeneous craniofacial disorder caused by premature fusion of cranial sutures, is sub-classified anatomically by suture involvement (sagittal, metopic, coronal, lambdoid) and phenotypically into isolated/non-syndromic forms or syndromic (CS with extracranial anomalies). Pathogenic variants in multiple genetic loci have been implicated in CS, with particular significance attributed to allelic variants in IL11RA (interleukin-11 receptor alpha subunit; OMIM#600939). Clinical observations of individuals with IL11RA mutations indicate syndromic CS, characterized by dental anomalies and Crouzon-like facial features. METHODS Genetic analyses were carried out utilizing whole-exome sequencing, with subsequent validation through direct Sanger sequencing. IL11RA biallelic pathogenic variants were detected and further analyzed by multiple in silico prediction tools, including 3D protein modeling. RESULTS Our cohort comprises six pediatric patients presenting with CS linked to biallelic pathogenic mutations in IL11RA, including two previously unreported variants (p.Pro218Argfs*140, p.Trp132Ter). Three-dimensional protein structure modeling and molecular docking simulations demonstrated that four missense variants (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for maintaining the IL-11 receptor alpha subunit's tertiary structure, significantly reducing ligand-binding affinity to both interleukin-11 (IL-11) and gp130. CONCLUSION This study describes the clinical phenotype of six children with craniosynostosis and reveals novel variants in the IL11RA gene, thereby broadening the genotypic spectrum associated with this gene. Given the scarcity of patients reported in the literature, a detailed examination of the specific clinical and molecular characteristics will benefit our understanding of craniosynostosis caused by IL11RA variants.
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Affiliation(s)
- Ziwei Liu
- Department of NeurosurgeryChildren's Hospital of Nanjing Medical UniversityNanjingChina
| | - Ding Zhou
- Nanjing Key Laboratory of PediatricsChildren's Hospital of Nanjing Medical UniversityNanjingChina
| | - Chunli Wang
- Department of NeurosurgeryChildren's Hospital of Nanjing Medical UniversityNanjingChina
| | - Bixia Zheng
- Nanjing Key Laboratory of PediatricsChildren's Hospital of Nanjing Medical UniversityNanjingChina
| | - Qing Yan
- Department of NeurosurgeryChildren's Hospital of Nanjing Medical UniversityNanjingChina
| | - Wei Zhou
- Nanjing Key Laboratory of PediatricsChildren's Hospital of Nanjing Medical UniversityNanjingChina
| | - Gang Wang
- Department of NeurosurgeryChildren's Hospital of Nanjing Medical UniversityNanjingChina
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Alperovich M, Tonello C, Mayes LC, Kahle KT. Non-syndromic craniosynostosis. Nat Rev Dis Primers 2025; 11:24. [PMID: 40210850 DOI: 10.1038/s41572-025-00607-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/12/2025] [Indexed: 04/12/2025]
Abstract
Craniosynostosis is characterized by the premature fusion of one or more major cranial sutures at birth or soon after. Single-suture non-syndromic craniosynostosis (NSC) is the most common form of craniosynostosis and includes the sagittal, metopic, unicoronal and unilambdoid subtypes. Characterized by an abnormal head shape specific to the fused suture type, NSC can cause increased intracranial pressure. Cranial sutures either originate from the neural crest or arise from mesoderm-derived mesenchymal stem cells. A mixture of environmental and genetic factors contributes to NSC, with genetic causes following a largely polygenic model. Physical examination is used to identify the majority of patients, but accompanying radiographic imaging can be confirmatory. The three major surgical techniques in use to treat NSC are cranial vault remodelling, strip craniectomy and spring-assisted cranioplasty. Surgical intervention is ideally performed in the first year of life, with a mortality of <1%. Health-care disparities contribute to delayed initial presentation and timely repair. Optimal timing of surgery and comparative outcomes by surgical technique remain under active study. School-age children with treated NSC on average have subtle, but lower cognitive and behavioural performance. However, patient-reported quality of life outcomes are comparable to those in control individuals.
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Affiliation(s)
- Michael Alperovich
- Division of Plastic Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA.
| | - Cristiano Tonello
- Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo, Sao Paulo, Brazil
| | - Linda C Mayes
- Child Study Center, Yale University School of Medicine, New Haven, CT, USA
| | - Kristopher T Kahle
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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3
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Sentosa DD, Metcalfe RD, Sims NA, Putoczki TL, Griffin MDW. The structure of the IL-11 signalling complex provides insight into receptor variants associated with craniosynostosis. FEBS J 2025; 292:500-509. [PMID: 39462650 DOI: 10.1111/febs.17307] [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: 08/04/2024] [Revised: 09/25/2024] [Accepted: 10/15/2024] [Indexed: 10/29/2024]
Abstract
Interleukin 11 (IL-11), a member of the IL-6 family of cytokines, has roles in haematopoiesis, inflammation, bone metabolism, and craniofacial development. IL-11 also has pathological roles in chronic inflammatory diseases, fibrosis, and cancer. In this structural snapshot, we explore our recently published cryo-EM structure of the human IL-11 signalling complex to understand the molecular mechanisms of complex formation and disease-associated mutations. IL-11 signals by binding to its cell surface receptors, the IL-11 receptor α subunit (IL-11Rα) and glycoprotein 130 (gp130), to form a hexameric signalling complex. We examine the locations within the complex of receptor sequence variants that are associated with craniosynostosis and craniosynostosis-like phenotypes and speculate on potential molecular mechanisms leading to defects in signalling function. While these causative amino acid sequence changes in IL-11Rα are generally distal to interfaces between components of the complex, important structural residues are highly represented, including proline residues, cysteine residues involved in disulfide bonds, and residues within or surrounding the tryptophan-arginine ladder. We also note the locations and potential effects of amino acid substitutions within the extracellular domains of gp130 that are associated with craniosynostosis. As focus on the physiological and pathological functions of IL-11 grows, the importance of high-resolution structural knowledge of IL-11 signalling to understand disease-associated mutations and to inform therapeutic strategies will only increase.
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Affiliation(s)
- Darlene D Sentosa
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia
| | - Riley D Metcalfe
- Centre for Structural Biology, Centre for Cancer Research, National Cancer Institute, Frederick, MD, USA
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Australia
- Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| | - Tracy L Putoczki
- Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Australia
- Department of Surgery, University of Melbourne, Parkville, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia
- ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia
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4
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Weitz HT, Ettich J, Rafii P, Wittich C, Schultz L, Frank NC, Heise D, Krusche M, Lokau J, Garbers C, Behnke K, Floss DM, Kolmar H, Moll JM, Scheller J. Interleukin-11 receptor is an alternative α-receptor for interleukin-6 and the chimeric cytokine IC7. FEBS J 2025; 292:523-536. [PMID: 39473075 PMCID: PMC11796321 DOI: 10.1111/febs.17309] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 07/30/2024] [Accepted: 10/16/2024] [Indexed: 02/06/2025]
Abstract
The cytokine interleukin 6 (IL-6) signals via the IL-6 α-receptor (IL-6Rα or IL-6R) in complex with the gp130 β-receptor. Cell type restricted expression of the IL-6R limits the action of IL-6 mainly to hepatocytes and some immune cells. Here, we show that IL-6 also binds to the IL-11 α receptor (IL-11Rα or IL-11R) and induces signaling via IL-11R:gp130 complexes, albeit with a lower affinity compared to IL-11. Antagonistic antibodies directed against IL-11R, but not IL-6R, inhibit IL-6 signaling via IL-11R:gp130 receptor complexes. Notably, IL-11 did not cross-react with IL-6R. IL-11R has also been identified as an alternative α receptor for the CNTF/IL-6-derived chimeric cytokine IC7, which has recently been shown to induce weight loss in mice. Accordingly, the effects of therapeutic monoclonal antibodies against IL-6 or IL-6R, which both block IL-6 signaling, may be slightly different. These findings provide new insights into IL-6 signaling and therefore offer new potential therapeutic intervention options in the future.
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Affiliation(s)
- Hendrik T. Weitz
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Julia Ettich
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Puyan Rafii
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Christoph Wittich
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Laura Schultz
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Nils C. Frank
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Denise Heise
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Matthias Krusche
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Juliane Lokau
- Institute of Clinical BiochemistryHannover Medical SchoolGermany
| | | | - Kristina Behnke
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Doreen M. Floss
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Harald Kolmar
- Institute for Organic Chemistry and BiochemistryTechnical University of DarmstadtGermany
- Centre of Synthetic BiologyTechnical University of DarmstadtGermany
| | - Jens M. Moll
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital DüsseldorfHeinrich Heine University DüsseldorfGermany
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Rose‐John S, Jones SA. More and more pleiotropy within the IL-6 family of cytokines. FEBS J 2025; 292:519-522. [PMID: 39673075 PMCID: PMC11796313 DOI: 10.1111/febs.17355] [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: 11/25/2024] [Revised: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 12/15/2024]
Abstract
Historically, cytokines belonging to the gp130 family bind to specific ligand-binding receptors that stimulate cell signaling through a receptor complex comprising gp130 or gp130 together with another structurally related signaling receptor. However, recent findings increasingly dispel these stereotypes and suggest that the receptor specificity of gp130-activating cytokines is less strict than originally assumed. Weitz et al. now provide the latest example of this pleiotropy and report that human interleukin-6 can bind and stimulate signaling via the interleukin-11 receptor. Possible biological and therapeutic consequences of these findings are discussed.
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Affiliation(s)
- Stefan Rose‐John
- Department of BiochemistryChristian‐Albrechts‐University Medical SchoolKielGermany
| | - Simon A. Jones
- Department of Infection, Immunity and Biochemistry, The School of MedicineCardiff UniversityUK
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Tuerlings M, Houtman E, Muusers EJH, Simon J, de Haan MW, Boone I, Ramos YFM, Mahdad R, Meulenbelt I. Exploring the therapeutic effect of human recombinant IL11 on lesioned OA human osteochondral explants. Arthritis Res Ther 2025; 27:15. [PMID: 39856704 PMCID: PMC11761764 DOI: 10.1186/s13075-025-03480-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
OBJECTIVE To explore IL11 co-expression profiles in our previously reported RNA-sequencing dataset of OA articular cartilage, in interaction with IL6, and to investigate the effects of hrIL11 administration as potential therapeutic strategy for OA articular cartilage using our biomimetic aged human osteochondral explant model of OA. METHODS We used RNA-sequencing datasets of macroscopically preserved and lesioned OA articular cartilage (N = 35 patients). Spearman correlations were calculated between IL11 and IL6 expression levels and genes expressed in cartilage (N = 20048 genes). Osteochondral explants were isolated from macroscopically preserved and lesioned areas of the joint and were kept in culture for two weeks, with or without exposure to 200ng/ml hrIL11. RESULTS We found no overlap in correlating genes between IL11 and IL6, indicating their distinct roles in articular cartilage. Moreover, we identified more genes being correlated to IL11 in the lesioned compared to preserved articular cartilage (N = 203 and 106 genes, respectively). Upon treatment of ex vivo OA articular cartilage with hrIL11, we overall observed unbeneficial effects on chondrocyte phenotype, as illustrated by upregulation of MMP13, EPAS1, RUNX2, and POSTN. We did not observe significant differences in Mankin scores upon addition of hrIL11. CONCLUSION The current study showed that treatment of OA articular cartilage with hrIL11 is unlikely to be beneficial despite previous indications of hrIL11 as potential druggable target. These findings underscore the importance of functionally investigating OA risk genes. Better understanding of IL11 signaling and the underlying pathways is necessary towards the development of OA treatment strategy.
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Affiliation(s)
- Margo Tuerlings
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Evelyn Houtman
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Elisa J H Muusers
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Janneke Simon
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Maurice W de Haan
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Ilja Boone
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Yolande F M Ramos
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
| | - Rachid Mahdad
- Department Orthopaedics, Alrijne Hospital, Leiderdorp, Netherlands
| | - Ingrid Meulenbelt
- Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
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7
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Hiasa M, Endo I, Matsumoto T. Bone-fat linkage via interleukin-11 in response to mechanical loading. J Bone Miner Metab 2024; 42:447-454. [PMID: 38324177 DOI: 10.1007/s00774-023-01493-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/10/2023] [Indexed: 02/08/2024]
Abstract
Positive regulators of bone formation, such as mechanical loading and PTH, stimulate and negative regulators, such as aging and glucocorticoid excess, suppress IL-11 gene transcription in osteoblastic cells. Signal transduction from mechanical loading and PTH stimulation involves two pathways: one is Ca2+-ERK-CREB pathway which facilitates binding of ∆FosB/JunD to the AP-1 site to enhance IL-11 gene transcription, and the other is Smad1/5 phosphorylation that promotes IL-11 gene transcription via SBE binding and complex formation with ∆FosB/JunD. The increased IL-11 suppresses Sost expression via IL-11Rα-STAT1/3-HDAC4/5 pathway and enhances Wnt signaling in the bone to stimulate bone formation. Thus, IL-11 mediates stimulatory and inhibitory signals of bone formation by affecting Wnt signaling. Physiologically important stimulation of bone formation is exercise-induced mechanical loading, but exercise simultaneously requires energy source for muscle contraction. Exercise-induced stimulation of IL-11 expression in the bone increases the secretion of IL-11 from the bone. The increased circulating IL-11 acts like a hormone to enhance adipolysis as an energy source with a reduction in adipogenic differentiation via a suppression of Dkk1/2 expression in the adipose tissue. Such bone-fat linkage can be a mechanism whereby exercise increases bone mass and, at the same time, maintains energy supply from the adipose tissue.
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Affiliation(s)
- Masahiro Hiasa
- Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Dentistry, Tokushima, 770-8503, Japan
| | - Itsuro Endo
- Department of Endocrinology, Metabolism and Hematology, Tokushima University Graduate School of Medical Sciences, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503,, Japan
| | - Toshio Matsumoto
- Department of Endocrinology, Metabolism and Hematology, Tokushima University Graduate School of Medical Sciences, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503,, Japan.
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8
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Sims NA, Griffin MDW. Craniosynostosis-associated variants in the IL-11R complex: new insights and questions. FEBS J 2024; 291:1663-1666. [PMID: 38329021 DOI: 10.1111/febs.17078] [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: 01/11/2024] [Accepted: 01/24/2024] [Indexed: 02/09/2024]
Abstract
Skull growth involves the expansion of both the flat calvarial bones of the skull and the fibrous marginal zones, termed sutures, between them. This process depends on co-ordinated proliferation of mesenchymal-derived progenitor cells within the sutures, and their differentiation to osteoblasts which produce the bone matrix required to expand the size of the bony plates. Defects lead to premature closure of these sutures, termed craniosynostosis, resulting in heterogeneous head shape differences due to restricted growth of one or more sutures. The impact on the individual depends on how many and which sutures are affected and the severity of the effect. Several genetic loci are responsible, including a wide range of variants in the gene for the interleukin 11 receptor (IL11RA, OMIM#600939). Recent work from Kespohl and colleagues provides new insights into how some of these variants influence IL-11R function; we discuss their influences on IL-11R structure and IL-11 function as a stimulus of osteoblast differentiation.
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Affiliation(s)
- Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Australia
- Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Australia
- Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Australia
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9
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Kespohl B, Hegele AL, Düsterhöft S, Bakker H, Buettner FFR, Hartig R, Lokau J, Garbers C. Molecular characterization of the craniosynostosis-associated interleukin-11 receptor variants p.T306_S308dup and p.E364_V368del. FEBS J 2024; 291:1667-1683. [PMID: 37994264 DOI: 10.1111/febs.17015] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/02/2023] [Accepted: 11/21/2023] [Indexed: 11/24/2023]
Abstract
Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines and is an important factor for bone homeostasis. IL-11 binds to and signals via the membrane-bound IL-11 receptor (IL-11R, classic signaling) or soluble forms of the IL-11R (sIL-11R, trans-signaling). Mutations in the IL11RA gene, which encodes the IL-11R, are associated with craniosynostosis, a human condition in which one or several of the sutures close prematurely, resulting in malformation of the skull. The biological mechanisms of how mutations within the IL-11R are linked to craniosynostosis are mostly unexplored. In this study, we analyze two variants of the IL-11R described in craniosynostosis patients: p.T306_S308dup, which results in a duplication of three amino-acid residues within the membrane-proximal fibronectin type III domain, and p.E364_V368del, which results in a deletion of five amino-acid residues in the so-called stalk region adjacent to the plasma membrane. The stalk region connects the three extracellular domains to the transmembrane and intracellular region of the IL-11R and contains cleavage sites for different proteases that generate sIL-11R variants. Using a combination of bioinformatics and different biochemical, molecular, and cell biology methods, we show that the IL-11R-T306_S308dup variant does not mature correctly, is intracellularly retained, and does not reach the cell surface. In contrast, the IL-11R-E364_V368del variant is fully biologically active and processed normally by proteases, thus allowing classic and trans-signaling of IL-11. Our results provide evidence that mutations within the IL11RA gene may not be causative for craniosynostosis and suggest that other regulatory mechanism(s) are involved but remain to be identified.
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Affiliation(s)
- Birte Kespohl
- Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Germany
| | - Anna-Lena Hegele
- Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Germany
| | - Stefan Düsterhöft
- Institute of Molecular Pharmacology, RWTH Aachen University, Germany
| | - Hans Bakker
- Institute of Clinical Biochemistry, Hannover Medical School, Germany
| | - Falk F R Buettner
- Institute of Clinical Biochemistry, Hannover Medical School, Germany
| | - Roland Hartig
- Institute for Molecular and Clinical Immunology and Service Unit Multiparametric Bioimaging and Cytometry, Medical Faculty, University of Magdeburg, Germany
| | - Juliane Lokau
- Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Germany
- Institute of Clinical Biochemistry, Hannover Medical School, Germany
| | - Christoph Garbers
- Institute of Clinical Biochemistry, Hannover Medical School, Germany
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Han Y, Gao H, Gan X, Liu J, Bao C, He C. Roles of IL-11 in the regulation of bone metabolism. Front Endocrinol (Lausanne) 2024; 14:1290130. [PMID: 38352248 PMCID: PMC10862480 DOI: 10.3389/fendo.2023.1290130] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 12/29/2023] [Indexed: 02/16/2024] Open
Abstract
Bone metabolism is the basis for maintaining the normal physiological state of bone, and imbalance of bone metabolism can lead to a series of metabolic bone diseases. As a member of the IL-6 family, IL-11 acts primarily through the classical signaling pathway IL-11/Receptors, IL-11 (IL-11R)/Glycoprotein 130 (gp130). The regulatory role of IL-11 in bone metabolism has been found earlier, but mainly focuses on the effects on osteogenesis and osteoclasis. In recent years, more studies have focused on IL-11's roles and related mechanisms in different bone metabolism activities. IL-11 regulates osteoblasts, osteoclasts, BM stromal cells, adipose tissue-derived mesenchymal stem cells, and chondrocytes. It's involved in bone homeostasis, including osteogenesis, osteolysis, bone marrow (BM) hematopoiesis, BM adipogenesis, and bone metastasis. This review exams IL-11's role in pathology and bone tissue, the cytokines and pathways that regulate IL-11 expression, and the feedback regulations of these pathways.
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Affiliation(s)
| | | | - Xinling Gan
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | | | | | - Chengqi He
- Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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11
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Cook SA. Understanding interleukin 11 as a disease gene and therapeutic target. Biochem J 2023; 480:1987-2008. [PMID: 38054591 PMCID: PMC10754292 DOI: 10.1042/bcj20220160] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/13/2023] [Accepted: 11/27/2023] [Indexed: 12/07/2023]
Abstract
Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3β/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.
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Affiliation(s)
- Stuart A. Cook
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
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12
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Dong B, Zhu J, Chen X, Jiang H, Deng Y, Xu L, Wang Y, Li S. The Emerging Role of Interleukin-(IL)-11/IL-11R in Bone Metabolism and Homeostasis: From Cytokine to Osteokine. Aging Dis 2023; 14:2113-2126. [PMID: 37199584 PMCID: PMC10676798 DOI: 10.14336/ad.2023.0306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/06/2023] [Indexed: 05/19/2023] Open
Abstract
Interleukin-(IL)-11 is a cytokine involved in hematopoiesis, cancer metastasis, and inflammation. IL-11 belongs to the IL-6 cytokine family, binding to the complex of receptors glycoprotein gp130 and the ligand-specific-receptor subunits (IL-11Rα or their soluble counterpart sIL-11R). IL-11/IL-11R signaling enhances osteoblast differentiation and bone formation and mitigates osteoclast-induced bone resorption and cancer bone metastasis. Recent studies have shown that systemic and osteoblast/osteocyte-specific IL-11 deficiency leads to reduced bone mass and formation, but also adiposity, glucose intolerance, and insulin resistance. In humans, mutations of IL-11 and the receptor IL-11RA genes are associated with height reduction, osteoarthritis, and craniosynostosis. In this review, we describe the emerging role of IL-11/IL-11R signaling in bone metabolism by targeting osteoblasts, osteoclasts, osteocytes, and bone mineralization. Furthermore, IL-11 promotes osteogenesis and suppresses adipogenesis, thereby influencing the fate of osteoblast/adipocyte differentiation derived from pluripotent mesenchymal stem cells. We have newly identified IL-11 as a bone-derived cytokine that regulates bone metabolism and the link between bone and other organs. Thus, IL-11 is vital in bone homeostasis and could be considered a potential therapeutic strategy.
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Affiliation(s)
- Bingzi Dong
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jingjing Zhu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xian Chen
- Department of Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongyuan Jiang
- Department of Sports Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yujie Deng
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lili Xu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangang Wang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shufa Li
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
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13
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Torres HM, Arnold KM, Oviedo M, Westendorf JJ, Weaver SR. Inflammatory Processes Affecting Bone Health and Repair. Curr Osteoporos Rep 2023; 21:842-853. [PMID: 37759135 PMCID: PMC10842967 DOI: 10.1007/s11914-023-00824-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2023] [Indexed: 09/29/2023]
Abstract
PURPOSE OF REVIEW The purpose of this article is to review the current understanding of inflammatory processes on bone, including direct impacts of inflammatory factors on bone cells, the effect of senescence on inflamed bone, and the critical role of inflammation in bone pain and healing. RECENT FINDINGS Advances in osteoimmunology have provided new perspectives on inflammatory bone loss in recent years. Characterization of so-called inflammatory osteoclasts has revealed insights into physiological and pathological bone loss. The identification of inflammation-associated senescent markers in bone cells indicates that therapies that reduce senescent cell burden may reverse bone loss caused by inflammatory processes. Finally, novel studies have refined the role of inflammation in bone healing, including cross talk between nerves and bone cells. Except for the initial stages of fracture healing, inflammation has predominately negative effects on bone and increases fracture risk. Eliminating senescent cells, priming the osteo-immune axis in bone cells, and alleviating pro-inflammatory cytokine burden may ameliorate the negative effects of inflammation on bone.
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Affiliation(s)
- Haydee M Torres
- Department of Orthopedic Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Katherine M Arnold
- Department of Orthopedic Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
- Biomedical Engineering and Physiology Track/Regenerative Sciences Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, 55905, USA
| | - Manuela Oviedo
- Department of Orthopedic Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Jennifer J Westendorf
- Department of Orthopedic Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Samantha R Weaver
- Department of Orthopedic Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
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14
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Hao S, Wang M, Yin Z, Jing Y, Bai L, Su J. Microenvironment-targeted strategy steers advanced bone regeneration. Mater Today Bio 2023; 22:100741. [PMID: 37576867 PMCID: PMC10413201 DOI: 10.1016/j.mtbio.2023.100741] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/26/2023] [Accepted: 07/19/2023] [Indexed: 08/15/2023] Open
Abstract
Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Traditional strategies in bone tissue engineering have focused primarily on mimicking the extracellular matrix (ECM) of bone in terms of structure and composition. However, the synergistic effects of other cues from the microenvironment during bone regeneration are often neglected. The bone microenvironment is a sophisticated system that includes physiological (e.g., neighboring cells such as macrophages), chemical (e.g., oxygen, pH), and physical factors (e.g., mechanics, acoustics) that dynamically interact with each other. Microenvironment-targeted strategies are increasingly recognized as crucial for successful bone regeneration and offer promising solutions for advancing bone tissue engineering. This review provides a comprehensive overview of current microenvironment-targeted strategies and challenges for bone regeneration and further outlines prospective directions of the approaches in construction of bone organoids.
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Affiliation(s)
- Shuyue Hao
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Mingkai Wang
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Zhifeng Yin
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai, 201941, China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Long Bai
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China
- Department of Orthopedic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200444, China
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15
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Marasco E, Fabbriciani G, Rotunno L, Longhi M, De Luca P, de Girolamo L, Colombini A. Identification of biomarkers in patients with rheumatoid arthritis responsive to DMARDs but with progressive bone erosion. Front Immunol 2023; 14:1254139. [PMID: 37809106 PMCID: PMC10551039 DOI: 10.3389/fimmu.2023.1254139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/22/2023] [Indexed: 10/10/2023] Open
Abstract
Introduction Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that may cause joint destruction and disability. The pharmacological treatment of RA aims at obtaining disease remission by effectively ceasing joint inflammation and arresting progressive bone erosions. Some patients present bone lesions accrual even after controlling joint inflammation with current therapies. Our study aimed to analyze lymphocyte subsets and levels of circulating cytokines in patients with RA with progressive bone erosions. Methods We enrolled 20 patients with a diagnosis of RA and 12 healthy donors (HD). Patients with RA were divided into patients with bone erosions (RA-BE+) and without bone erosions (RA-BE-). Lymphocyte subsets in peripheral blood were evaluated by flow cytometry. Circulating cytokines levels were evaluated by protein array. Results The distribution of lymphocyte subsets was not able to separate HD from AR patients and RA-BE+ and RA-BE- in cluster analysis. We observed a significant expansion of CXCR5- PD1+ T peripheral helper cells (Tph cells) and a reduction in both total memory B cells and switched memory B cells in RA patients compared to HD. We observed an expansion in the frequency of total B cells in RA-BE+ patients compared to RA-BE- patients. Unsupervised hierarchical clustering analysis of 39 cytokines resulted in a fairly good separation of HD from RA patients but not of RA-BE+ patients from RA-BE- patients. RA-BE+ patients showed significantly higher levels of IL-11 and IL-17A than RA-BE- patients. Conclusion We show that patients with progressive erosive disease are characterized by abnormalities in B cells and in cytokines with a proven role in bone reabsorption. Understanding the role played by B cells and the cytokine IL-11 and IL-17A in progressive erosive disease can help identify novel biomarkers of erosive disease and design treatment approaches aimed at halting joint damage in RA.
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Affiliation(s)
- Emiliano Marasco
- Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy
- Ph.D. Course “Immunology, Molecular Medicine and Applied Biotechnology”, University of Rome Tor Vergata, Rome, Italy
| | | | - Laura Rotunno
- Unit of Rheumatology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Matteo Longhi
- Unit of Rheumatology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Paola De Luca
- Laboratorio di Biotecnologie Applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Laura de Girolamo
- Laboratorio di Biotecnologie Applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | - Alessandra Colombini
- Laboratorio di Biotecnologie Applicate all’Ortopedia, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
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16
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Ahmad I, Lokau J, Kespohl B, Malik NA, Baig SM, Hartig R, Behme D, Schwab R, Altmüller J, Jameel M, Mucha S, Thiele H, Tariq M, Nürnberg P, Erdmann J, Garbers C. The interleukin-11 receptor variant p.W307R results in craniosynostosis in humans. Sci Rep 2023; 13:13479. [PMID: 37596289 PMCID: PMC10439179 DOI: 10.1038/s41598-023-39466-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 07/26/2023] [Indexed: 08/20/2023] Open
Abstract
Craniosynostosis is characterized by the premature fusion and ossification of one or more of the sutures of the calvaria, often resulting in abnormal features of the face and the skull. In cases in which growth of the brain supersedes available space within the skull, developmental delay or cognitive impairment can occur. A complex interplay of different cell types and multiple signaling pathways are required for correct craniofacial development. In this study, we report on two siblings with craniosynostosis and a homozygous missense pathogenic variant within the IL11RA gene (c.919 T > C; p.W307R). The patients present with craniosynostosis, exophthalmos, delayed tooth eruption, mild platybasia, and a basilar invagination. The p.W307R variant is located within the arginine-tryptophan-zipper within the D3 domain of the IL-11R, a structural element known to be important for the stability of the cytokine receptor. Expression of IL-11R-W307R in cells shows impaired maturation of the IL-11R, no transport to the cell surface and intracellular retention. Accordingly, cells stably expressing IL-11R-W307R do not respond when stimulated with IL-11, arguing for a loss-of-function mutation. In summary, the IL-11R-W307R variant, reported here for the first time to our knowledge, is most likely the causative variant underlying craniosynostosis in these patients.
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Affiliation(s)
- Ilyas Ahmad
- Institute for Cardiogenetics, and University Heart Center, University of Lübeck, Building 67, BMF, Ratzeburger Allee 160, 23562, Lübeck, Germany.
- DZHK (German Research Center for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, 23562, Lübeck, Germany.
- Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
| | - Juliane Lokau
- Department of Pathology, Medical Faculty, Otto-Von-Guericke-University, 39120, Magdeburg, Germany
| | - Birte Kespohl
- Department of Pathology, Medical Faculty, Otto-Von-Guericke-University, 39120, Magdeburg, Germany
| | - Naveed Altaf Malik
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, 38000, Pakistan
| | - Shahid Mahmood Baig
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, 38000, Pakistan
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, 74800, Pakistan
| | - Roland Hartig
- Institute for Molecular and Clinical Immunology and Service Unit Multiparametric Bioimaging and Cytometry, Medical Faculty, Otto-Von-Guericke-University, 39120, Magdeburg, Germany
| | - Daniel Behme
- University Clinic for Neuroradiology, Medical Faculty, Otto-Von-Guericke-University, 39120, Magdeburg, Germany
| | - Roland Schwab
- University Clinic for Neuroradiology, Medical Faculty, Otto-Von-Guericke-University, 39120, Magdeburg, Germany
| | - Janine Altmüller
- Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
- Core Facility Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Muhammad Jameel
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, 38000, Pakistan
- Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, 74800, Pakistan
| | - Sören Mucha
- Institute for Cardiogenetics, and University Heart Center, University of Lübeck, Building 67, BMF, Ratzeburger Allee 160, 23562, Lübeck, Germany
- DZHK (German Research Center for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, 23562, Lübeck, Germany
- Institute of Epidemiology, Kiel University, 24105, Kiel, Germany
| | - Holger Thiele
- Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Muhammad Tariq
- National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences (NIBGE-C, PIEAS), Faisalabad, 38000, Pakistan
| | - Peter Nürnberg
- Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany
| | - Jeanette Erdmann
- Institute for Cardiogenetics, and University Heart Center, University of Lübeck, Building 67, BMF, Ratzeburger Allee 160, 23562, Lübeck, Germany
- DZHK (German Research Center for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, 23562, Lübeck, Germany
| | - Christoph Garbers
- Department of Pathology, Medical Faculty, Otto-Von-Guericke-University, 39120, Magdeburg, Germany.
- Health Campus Immunology, Infectiology and Inflammation (GC:I3), Otto-Von-Guericke-University, 39120, Magdeburg, Germany.
- Center for Health and Medical Prevention (ChaMP), Otto-Von-Guericke-University, 39120, Magdeburg, Germany.
- Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
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17
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Xu J, Yu L, Liu F, Wan L, Deng Z. The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review. Front Immunol 2023; 14:1222129. [PMID: 37475866 PMCID: PMC10355373 DOI: 10.3389/fimmu.2023.1222129] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
The complicated connections and cross talk between the skeletal system and the immune system are attracting more attention, which is developing into the field of Osteoimmunology. In this field, cytokines that are among osteoblasts and osteoclasts play a critical role in bone remodeling, which is a pathological process in the pathogenesis and development of osteoporosis. Those cytokines include the tumor necrosis factor (TNF) family, the interleukin (IL) family, interferon (IFN), chemokines, and so on, most of which influence the bone microenvironment, osteoblasts, and osteoclasts. This review summarizes the effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis, aiming to providing the latest reference to the role of immunology in osteoporosis.
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Affiliation(s)
- Jie Xu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Linxin Yu
- Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Liu
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Longbiao Wan
- Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhenhua Deng
- Hubei Provincial Hospital of Traditional Chinese Medicine (TCM), Wuhan, China
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18
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Interleukin 11 confers resistance to dextran sulfate sodium-induced colitis in mice. iScience 2023; 26:105934. [PMID: 36685040 PMCID: PMC9852934 DOI: 10.1016/j.isci.2023.105934] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 11/30/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023] Open
Abstract
Intestinal homeostasis is tightly regulated by epithelial cells, leukocytes, and stromal cells, and its dysregulation is associated with inflammatory bowel diseases. Interleukin (IL)-11, a member of the IL-6 family of cytokines, is produced by inflammatory fibroblasts during acute colitis. However, the role of IL-11 in the development of colitis is still unclear. Herein, we showed that IL-11 ameliorated DSS-induced acute colitis in mouse models. We found that deletion of Il11ra1 or Il11 rendered mice highly susceptible to DSS-induced colitis compared to the respective control mice. The number of apoptotic epithelial cells was increased in DSS-treated Il11ra1- or Il11-deficient mice. Moreover, we showed that IL-11 production was regulated by reactive oxygen species (ROS) produced by lysozyme M-positive myeloid cells. These findings indicate that fibroblast-produced IL-11 plays an important role in protecting the mucosal epithelium in acute colitis. Myeloid cell-derived ROS contribute to the attenuation of colitis through the production of IL-11.
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19
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Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis. Nat Commun 2022; 13:7194. [PMID: 36424386 PMCID: PMC9691688 DOI: 10.1038/s41467-022-34869-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/09/2022] [Indexed: 11/27/2022] Open
Abstract
Exercise results in mechanical loading of the bone and stimulates energy expenditure in the adipose tissue. It is therefore likely that the bone secretes factors to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)-11 is known to be expressed in the bone, it is upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Here, we show that systemic IL-11 deletion (IL-11-/-) results in reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. At the same time, the enhancement of bone resorption by mechanical unloading was unaffected. Unexpectedly, IL-11-/- mice have increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11fl/fl mice have reduced serum IL-11 levels, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11-/- mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre;IL-11fl/fl did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes.
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20
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Isojima T, Walker EC, Poulton IJ, McGregor NE, Wicks IP, Gooi JH, Martin TJ, Sims NA. G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes. J Bone Miner Res 2022; 37:1876-1890. [PMID: 35856245 DOI: 10.1002/jbmr.4654] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 06/27/2022] [Accepted: 07/16/2022] [Indexed: 11/09/2022]
Abstract
Bone strength is determined by the structure and composition of its thickened outer shell (cortical bone), yet the mechanisms controlling cortical consolidation are poorly understood. Cortical bone maturation depends on SOCS3-mediated suppression of IL-6 cytokine-induced STAT3 phosphorylation in osteocytes, the cellular network embedded in bone matrix. Because SOCS3 also suppresses granulocyte-colony-stimulating factor receptor (G-CSFR) signaling, we here tested whether global G-CSFR (Csf3r) ablation altereed bone structure in male and female mice lacking SOCS3 in osteocytes, (Dmp1Cre :Socs3f/f mice). Dmp1Cre :Socs3f/f :Csf3r-/- mice were generated by crossing Dmp1Cre :Socs3f/f mice with Csf3r-/- mice. Although G-CSFR is not expressed in osteocytes, Csf3r deletion further delayed cortical consolidation in Dmp1Cre :Socs3f/f mice. Micro-CT images revealed extensive, highly porous low-density bone, with little true cortex in the diaphysis, even at 26 weeks of age; including more low-density bone and less high-density bone in Dmp1Cre :Socs3f/f :Csf3r-/- mice than controls. By histology, the area where cortical bone would normally be found contained immature compressed trabecular bone in Dmp1Cre :Socs3f/f :Csf3r-/- mice and greater than normal levels of intracortical osteoclasts, extensive new woven bone formation, and the presence of more intracortical blood vessels than the already high levels observed in Dmp1Cre :Socs3f/f controls. qRT-PCR of cortical bone from Dmp1Cre :Socs3f/f :Csf3r-/- mice also showed more than a doubling of mRNA levels for osteoclasts, osteoblasts, RANKL, and angiogenesis markers. The further delay in cortical bone maturation was associated with significantly more phospho-STAT1 and phospho-STAT3-positive osteocytes, and a threefold increase in STAT1 and STAT3 target gene mRNA levels, suggesting G-CSFR deletion further increases STAT signaling beyond that of Dmp1Cre :Socs3f/f bone. G-CSFR deficiency therefore promotes STAT1/3 signaling in osteocytes, and when SOCS3 negative feedback is absent, elevated local angiogenesis, bone resorption, and bone formation delays cortical bone consolidation. This points to a critical role of G-CSF in replacing condensed trabecular bone with lamellar bone during cortical bone formation. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Tsuyoshi Isojima
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan
| | - Emma C Walker
- St. Vincent's Institute of Medical Research, Fitzroy, Australia
| | | | | | - Ian P Wicks
- Walter and Eliza Hall Institute, Parkville, Australia
| | - Jonathan H Gooi
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,Bio21 Molecular Science and Biotechnology Institute, Parkville, Australia
| | - T John Martin
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Australia.,The University of Melbourne, Department of Medicine at St. Vincent's Hospital, Fitzroy, Australia
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21
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Hayer S, Niederreiter B, Kalkgruber M, Wanic K, Maißner J, Smolen JS, Aletaha D, Blüml S, Redlich K. Analysis of combined deficiency of interleukin-1 and -6 versus single deficiencies in TNF-mediated arthritis and systemic bone loss. Bone Joint Res 2022; 11:484-493. [PMID: 35801532 PMCID: PMC9350695 DOI: 10.1302/2046-3758.117.bjr-2021-0481.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Aims Insufficient treatment response in rheumatoid arthritis (RA) patients requires novel treatment strategies to halt disease progression. The potential benefit of combination of cytokine-inhibitors in RA is still unclear and needs further investigation. To explore the impact of combined deficiency of two major cytokines, namely interleukin (IL)-1 and IL-6, in this study double deficient mice for IL-1αβ and IL-6 were investigated in different tumour necrosis factor (TNF)-driven inflammatory bone disorders, namely peripheral arthritis and sacroiliitis, as well as systemic bone loss. Methods Disease course, histopathological features of arthritis, and micro-CT (µCT) bone analysis of local and systemic bone loss were assessed in 15-week-old IL1-/-IL6-/-hTNFtg in comparison to IL1-/-hTNFtg, IL6-/-hTNFtg, and hTNFtg mice. µCT bone analysis of single deficient and wild-type mice was also performed. Results Combined deficiency of IL-1/IL-6 markedly ameliorated TNF-mediated arthritis and bilateral sacroiliitis, but without additive benefits compared to single IL-1 deficiency. This finding confirms the important role of IL-1 and the marginal role of IL-6 in TNF-driven pathways of local joint damage, but questions the efficacy of potential combinatorial therapies of IL-1 and IL-6 in treatment of RA. In contrast, combined deficiency of IL-1/IL-6 led to an additive protective effect on TNF-driven systemic bone loss compared to single IL-1 and IL-6 deficiency. This finding clearly indicates a common contribution of both IL-1 and IL-6 in TNF-driven systemic bone loss, and points to a discrepancy of cytokine dependency in local and systemic TNF-driven mechanisms of inflammatory arthritis. Conclusion Combinatorial treatments in RA might provide different benefits to inflammatory local arthritis and systemic comorbidities. Cite this article: Bone Joint Res 2022;11(7):484–493.
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Affiliation(s)
- Silvia Hayer
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Birgit Niederreiter
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Marlene Kalkgruber
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Konrad Wanic
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Julia Maißner
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Josef S Smolen
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Daniel Aletaha
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Stephan Blüml
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Kurt Redlich
- Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria.,Hietzing Hospital, 2nd Department of Medicine, Vienna, Austria.,Karl Landsteiner Institute for Rheumatology and Clinical Immunology, Vienna, Austria
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22
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de Souza PPC, Henning P, Lerner UH. Stimulation of Osteoclast Formation by Oncostatin M and the Role of WNT16 as a Negative Feedback Regulator. Int J Mol Sci 2022; 23:3287. [PMID: 35328707 PMCID: PMC8953253 DOI: 10.3390/ijms23063287] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/09/2022] [Accepted: 03/15/2022] [Indexed: 02/05/2023] Open
Abstract
Oncostatin M (OSM), which belongs to the IL-6 family of cytokines, is the most potent and effective stimulator of osteoclast formation in this family, as assessed by different in vitro assays. Osteoclastogenesis induced by the IL-6 type of cytokines is mediated by the induction and paracrine stimulation of the osteoclastogenic cytokine receptor activator of nuclear factor κ-B ligand (RANKL), expressed on osteoblast cell membranes and targeting the receptor activator of nuclear factor κ-B (RANK) on osteoclast progenitor cells. The potent effect of OSM on osteoclastogenesis is due to an unusually robust induction of RANKL in osteoblasts through the OSM receptor (OSMR), mediated by a JAK-STAT/MAPK signaling pathway and by unique recruitment of the adapter protein Shc1 to the OSMR. Gene deletion of Osmr in mice results in decreased numbers of osteoclasts and enhanced trabecular bone caused by increased trabecular thickness, indicating that OSM may play a role in physiological regulation of bone remodeling. However, increased amounts of OSM, either through administration of recombinant protein or of adenoviral vectors expressing Osm, results in enhanced bone mass due to increased bone formation without any clear sign of increased osteoclast numbers, a finding which can be reconciled by cell culture experiments demonstrating that OSM can induce osteoblast differentiation and stimulate mineralization of bone nodules in such cultures. Thus, in vitro studies and gene deletion experiments show that OSM is a stimulator of osteoclast formation, whereas administration of OSM to mice shows that OSM is not a strong stimulator of osteoclastogenesis in vivo when administered to adult animals. These observations could be explained by our recent finding showing that OSM is a potent stimulator of the osteoclastogenesis inhibitor WNT16, acting in a negative feedback loop to reduce OSM-induced osteoclast formation.
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Affiliation(s)
- Pedro P. C. de Souza
- The Innovation in Biomaterials Laboratory, School of Dentistry, Federal University of Goiás, Goiânia 74690-900, Brazil;
| | - Petra Henning
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden;
| | - Ulf H. Lerner
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Centre and Centre for Bone and Arthritis Research at the Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden;
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STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential. Cancers (Basel) 2022; 14:cancers14020429. [PMID: 35053592 PMCID: PMC8773745 DOI: 10.3390/cancers14020429] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Many signaling pathways are overactive in breast cancer, and among them is the STAT3 signaling pathway. STAT3 is activated by secreted factors within the breast tumor, many of which are elevated and correlate to advanced disease and poor survival outcomes. This review examines how STAT3 signaling is activated in breast cancer by the proinflammatory, gp130 cytokines, interleukins 6 and 11. We evaluate how this signaling cascade functions in the various cells of the tumor microenvironment to drive disease progression and metastasis. We discuss how our understanding of these processes may lead to the development of novel therapeutics to tackle advanced disease. Abstract Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets.
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John Martin T. Aspects of intercellular communication in bone and implications in therapy. Bone 2021; 153:116148. [PMID: 34389478 DOI: 10.1016/j.bone.2021.116148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/18/2021] [Accepted: 08/08/2021] [Indexed: 11/20/2022]
Abstract
Communication processes among the cells of bone are essential for the structure and function of the organ. After it was proposed that communication from the osteoblast lineage to hemopoietic cells initiated osteoclastogenesis, the molecular controls were identified to be the tumour necrosis factor ligand and receptor families. This was followed by revelation of very many signalling processes among the cells of bone that regulate the three phases of bone remodelling, the resorption, reversal and formation phases. In many instances the ways in which these mechanisms operate can determine how drugs act on bone, whether they be inhibitors of resorption or promoters of formation.
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Affiliation(s)
- T John Martin
- St Vincent's Institute of Medical Research, The University of Melbourne Department of Medicine at St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
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25
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In Silico Identification and Clinical Validation of a Novel Long Non-Coding RNA/mRNA/miRNA Molecular Network for Potential Biomarkers for Discriminating SARS CoV-2 Infection Severity. Cells 2021; 10:cells10113098. [PMID: 34831321 PMCID: PMC8625524 DOI: 10.3390/cells10113098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: The coronavirus (COVID-19) pandemic is still a major global health problem, despite the development of several vaccines and diagnostic assays. Moreover, the broad symptoms, from none to severe pneumonia, and the various responses to vaccines and the assays, make infection control challenging. Therefore, there is an urgent need to develop non-invasive biomarkers to quickly determine the infection severity. Circulating RNAs have been proven to be potential biomarkers for a variety of diseases, including infectious ones. This study aimed to develop a genetic network related to cytokines, with clinical validation for early infection severity prediction. (2) Methods: Extensive analyses of in silico data have established a novel IL11RA molecular network (IL11RNA mRNA, LncRNAs RP11-773H22.4 and hsa-miR-4257). We used different databases to confirm its validity. The differential expression within the retrieved network was clinically validated using quantitative RT-PCR, along with routine assessment diagnostic markers (CRP, LDH, D-dimmer, procalcitonin, Ferritin), in100 infected subjects (mild and severe cases) and 100 healthy volunteers. (3) Results: IL11RNA mRNA and LncRNA RP11-773H22.4, and the IL11RA protein, were significantly upregulated, and there was concomitant downregulation of hsa-miR-4257, in infected patients, compared to the healthy controls, in concordance with the infection severity. (4) Conclusion: The in-silico data and clinical validation led to the identification of a potential RNA/protein signature network for novel predictive biomarkers, which is in agreement with ferritin and procalcitonin for determination of COVID-19 severity.
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26
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Ansari N, Isojima T, Crimeen-Irwin B, Poulton IJ, McGregor NE, Ho PWM, Forwood MR, Kovacs CS, Dimitriadis E, Gooi JH, Martin TJ, Sims NA. Dmp1Cre-directed knockdown of parathyroid hormone-related protein (PTHrP) in murine decidua is associated with a life-long increase in bone mass, width, and strength in male progeny. J Bone Miner Res 2021; 36:1999-2016. [PMID: 34101894 DOI: 10.1002/jbmr.4388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 05/14/2021] [Accepted: 06/02/2021] [Indexed: 12/28/2022]
Abstract
Parathyroid hormone-related protein (PTHrP, gene name Pthlh) is a pleiotropic regulator of tissue homeostasis. In bone, Dmp1Cre-targeted PTHrP deletion in osteocytes causes osteopenia and impaired cortical strength. We report here that this outcome depends on parental genotype. In contrast to our previous report using mice bred from heterozygous (flox/wild type) Dmp1Cre.Pthlhf/w parents, adult (16-week-old and 26-week-old) flox/flox (f/f) Dmp1Cre.Pthlhf/f mice from homozygous parents (Dmp1Cre.Pthlhf/f(hom) ) have stronger bones, with 40% more trabecular bone mass and 30% greater femoral width than controls. This greater bone size was observed in Dmp1Cre.Pthlhf/f(hom) mice as early as 12 days of age, when greater bone width was also found in male and female Dmp1Cre.Pthlhf/f(hom) mice compared to controls, but not in gene-matched mice from heterozygous parents. This suggested a maternal influence on skeletal size prior to weaning. Although Dmp1Cre has previously been reported to cause gene recombination in mammary gland, milk PTHrP protein levels were normal. The wide-bone phenotype was also noted in utero: Dmp1Cre.Pthlhf/f(hom) embryonic femurs were more mineralized and wider than controls. Closer examination revealed that Dmp1Cre caused PTHrP recombination in placenta, and in the maternal-derived decidual layer that resides between the placenta and the uterus. Decidua from mothers of Dmp1Cre.Pthlhf/f(hom) mice also exhibited lower PTHrP levels by immunohistochemistry and were smaller than controls. We conclude that Dmp1Cre leads to gene recombination in decidua, and that decidual PTHrP might, through an influence on decidual cells, limit embryonic bone radial growth. This suggests a maternal-derived developmental origin of adult bone strength. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Niloufar Ansari
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
| | - Tsuyoshi Isojima
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan
| | | | - Ingrid J Poulton
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
| | - Narelle E McGregor
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
| | - Patricia W M Ho
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
| | - Mark R Forwood
- School of Pharmacy and Medical Sciences, Griffith University, Gold Coast, Queensland, Australia
| | - Christopher S Kovacs
- Faculty of Medicine - Endocrinology, Memorial University of Newfoundland, St John's, Newfoundland, Canada
| | - Evdokia Dimitriadis
- Department of Obstetrics and Gynecology, University of Melbourne, The Women's Hospital, Melbourne, Victoria, Australia
| | - Jonathan H Gooi
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia.,Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia
| | - T John Martin
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.,Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia
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27
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Isojima T, Sims NA. Cortical bone development, maintenance and porosity: genetic alterations in humans and mice influencing chondrocytes, osteoclasts, osteoblasts and osteocytes. Cell Mol Life Sci 2021; 78:5755-5773. [PMID: 34196732 PMCID: PMC11073036 DOI: 10.1007/s00018-021-03884-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/06/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Cortical bone structure is a crucial determinant of bone strength, yet for many years studies of novel genes and cell signalling pathways regulating bone strength have focused on the control of trabecular bone mass. Here we focus on mechanisms responsible for cortical bone development, growth, and degeneration, and describe some recently described genetic-driven modifications in humans and mice that reveal how these processes may be controlled. We start with embryonic osteogenesis of preliminary bone structures preceding the cortex and describe how this structure consolidates then matures to a dense, vascularised cortex containing an increasing proportion of lamellar bone. These processes include modelling-induced, and load-dependent, asymmetric cortical expansion, which enables the cortex's transition from a highly porous woven structure to a consolidated and thickened highly mineralised lamellar bone structure, infiltrated by vascular channels. Sex-specific differences emerge during this process. With aging, the process of consolidation reverses: cortical pores enlarge, leading to greater cortical porosity, trabecularisation and loss of bone strength. Each process requires co-ordination between bone formation, bone mineralisation, vascularisation, and bone resorption, with a need for locational-, spatial- and cell-specific signalling pathways to mediate this co-ordination. We will discuss these processes, and a number of cell-signalling pathways identified in both murine and human genetic studies to regulate cortical bone mass, including signalling through gp130, STAT3, PTHR1, WNT16, NOTCH, NOTUM and sFRP4.
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Affiliation(s)
- Tsuyoshi Isojima
- St. Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, VIC, 3122, Australia
- Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, 9 Princes St, Fitzroy, VIC, 3122, Australia.
- Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Fitzroy, VIC, Australia.
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28
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Influences of the IL-6 cytokine family on bone structure and function. Cytokine 2021; 146:155655. [PMID: 34332274 DOI: 10.1016/j.cyto.2021.155655] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/08/2021] [Accepted: 07/12/2021] [Indexed: 01/12/2023]
Abstract
The IL-6 family of cytokines comprises a large group of cytokines that all act via the formation of a signaling complex that includes the glycoprotein 130 (gp130) receptor. Despite this, many of these cytokines have unique roles that regulate the activity of bone forming osteoblasts, bone resorbing osteoclasts, bone-resident osteocytes, and cartilage cells (chondrocytes). These include specific functions in craniofacial development, longitudinal bone growth, and the maintenance of trabecular and cortical bone structure, and have been implicated in musculoskeletal pathologies such as craniosynostosis, osteoporosis, rheumatoid arthritis, osteoarthritis, and heterotopic ossifications. This review will work systematically through each member of this family and provide an overview and an update on the expression patterns and functions of each of these cytokines in the skeleton, as well as their negative feedback pathways, particularly suppressor of cytokine signaling 3 (SOCS3). The specific cytokines described are interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin 1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine factor 1 (CLCF1), neuropoietin, humanin and interleukin 27 (IL-27).
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29
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Ng B, Widjaja AA, Viswanathan S, Dong J, Chothani SP, Lim S, Shekeran SG, Tan J, McGregor NE, Walker EC, Sims NA, Schafer S, Cook SA. Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis. Sci Rep 2021; 11:14088. [PMID: 34239012 PMCID: PMC8266813 DOI: 10.1038/s41598-021-93623-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 06/21/2021] [Indexed: 02/07/2023] Open
Abstract
Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11-/-) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11-/- mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.
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Affiliation(s)
- Benjamin Ng
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Anissa A Widjaja
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Sivakumar Viswanathan
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Jinrui Dong
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Sonia P Chothani
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Stella Lim
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Shamini G Shekeran
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
| | - Jessie Tan
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Narelle E McGregor
- Bone Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Australia
| | - Emma C Walker
- Bone Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Australia
| | - Natalie A Sims
- Bone Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Australia
- Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia
| | - Sebastian Schafer
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore
| | - Stuart A Cook
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore.
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
- MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, UK.
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30
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Maroni P, Bendinelli P, Ferraretto A, Lombardi G. Interleukin 11 (IL-11): Role(s) in Breast Cancer Bone Metastases. Biomedicines 2021; 9:biomedicines9060659. [PMID: 34201209 PMCID: PMC8228851 DOI: 10.3390/biomedicines9060659] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/04/2021] [Accepted: 06/05/2021] [Indexed: 12/11/2022] Open
Abstract
Bone metastases represent the main problem related to the progression of breast cancer, as they are the main cause of death for these patients. Unfortunately, to date, bone metastases are incurable and represent the main challenge for the researcher. Chemokines and cytokines affect different stages of the metastatic process, and in bone metastases, interleukin (IL) -6, IL-8, IL-1β, and IL-11 participate in the interaction between cancer cells and bone cells. This review focuses on IL-11, a pleiotropic cytokine that, in addition to its well-known effects on several tissues, also mediates certain signals in cancer cells. In particular, as IL-11 works on bone remodeling, it plays a relevant role in the osteolytic vicious cycle of bone resorption and tumour growth, which characterizes bone metastasis. IL-11 appears as a candidate for anti-metastatic therapy. Even if different therapeutic approaches have considered IL-11 and the downstream-activated gp130 signaling pathways activated downstream of gp130, further studies are needed to decipher the contribution of the different cytokines and their mechanisms of action in breast cancer progression to define therapeutic strategies.
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Affiliation(s)
- Paola Maroni
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Correspondence: ; Tel.: +39-02-6621-4759
| | - Paola Bendinelli
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, 20133 Milano, Italy;
| | - Anita Ferraretto
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, 20133 Milano, Italy;
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Królowej Jadwigi 27/39, 61-871 Poznań, Poland
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31
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Kespohl B, Schumertl T, Bertrand J, Lokau J, Garbers C. The cytokine interleukin-11 crucially links bone formation, remodeling and resorption. Cytokine Growth Factor Rev 2021; 60:18-27. [PMID: 33940443 DOI: 10.1016/j.cytogfr.2021.04.002] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
Bone development is a complex process that requires the activity of several different signaling pathways and cell types. It involves the coordinated action of osteoclasts (cells that are capable of resorbing bone), osteoblasts (cells that are able to form bone), osteocytes (cells that form a syncytial network within the bone), skeletal muscle cells and the bone marrow. In recent years, the cytokine interleukin-11 (IL-11), a member of the IL-6 family of cytokines, has emerged as an important regulatory protein for bone formation, remodeling and resorption. Furthermore, coding missense mutations in the IL11RA gene, which encodes the IL-11 receptor (IL-11R), have recently been linked to craniosynostosis, a human disease in which the sutures that line the head bones close prematurely. This review summarizes current knowledge about IL-11 and highlights its role in bone development and homeostasis. It further discusses the specificity and redundancy provided by the other members of the IL-6 cytokine family and how they facilitate signaling and cross-talk between skeletal muscle cells, bone cells and the bone marrow. We describe their actions in physiological and in pathological states and discuss how this knowledge could be translated into therapy.
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Affiliation(s)
- Birte Kespohl
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Tim Schumertl
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Jessica Bertrand
- Department of Orthopaedic Surgery, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Juliane Lokau
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany
| | - Christoph Garbers
- Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany.
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32
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Coates BA, McKenzie JA, Yoneda S, Silva MJ. Interleukin-6 (IL-6) deficiency enhances intramembranous osteogenesis following stress fracture in mice. Bone 2021; 143:115737. [PMID: 33181349 PMCID: PMC8408837 DOI: 10.1016/j.bone.2020.115737] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 10/08/2020] [Accepted: 11/06/2020] [Indexed: 12/28/2022]
Abstract
Interleukin-6 (IL-6) is highly upregulated in response to skeletal injury, suggesting it plays a role in the inflammatory phase of fracture repair. However, the impact of IL-6 on successful repair remains incompletely defined. Therefore, we investigated the role of IL-6 in two models of fracture repair (full fracture and stress fracture) using 12-week old IL-6 global knockout mice (IL-6 KO) and wild type (WT) littermate controls. Callus morphology and mineral density 14 days after full femur fracture did not differ between IL-6 knockout mice and controls. In contrast, IL-6 KO mice had an enhanced bone response 7 days after ulnar stress fracture compared to WT, with increased total callus volume (p = 0.020) and callus bone volume (p = 0.045). IL-6 KO did not alter the recruitment of immune cells (Gr-1 or F4/80 positive) to the stress fracture callus. IL-6 KO also did not alter the number of osteoclasts in the stress fracture callus. Using RNA-seq, we identified differentially expressed genes in stress fracture vs. contralateral control ulnae, and observed that IL-6 KO resulted in only modest alterations to the gene expression response to stress fracture (SFx). Wnt1 was more highly upregulated in IL-6 KO SFx callus at both day 1 (fold change 12.5 in KO vs. 5.7 in WT) and day 3 (fold change 4.7 in KO vs. 1.9 in WT). Finally, using tibial compression to induce bone formation without bone injury, we found that IL-6 KO directly impacted osteoblast function, increasing the propensity for woven bone formation. In summary, we report that IL-6 knockout enhanced formation of callus and bone following stress fracture injury, likely through direct action on the osteoblast's ability to produce woven bone. This suggests a novel role of IL-6 as a suppressor of intramembranous bone formation.
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Affiliation(s)
- Brandon A Coates
- Department of Orthopaedic Surgery, Washington University in St. Louis, MO, United States of America; Department of Biomedical Engineering, Washington University in St. Louis, MO, United States of America.
| | - Jennifer A McKenzie
- Department of Orthopaedic Surgery, Washington University in St. Louis, MO, United States of America
| | - Susumu Yoneda
- Department of Orthopaedic Surgery, Washington University in St. Louis, MO, United States of America
| | - Matthew J Silva
- Department of Orthopaedic Surgery, Washington University in St. Louis, MO, United States of America; Department of Biomedical Engineering, Washington University in St. Louis, MO, United States of America
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33
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Ren Y, Deng Z, Gokani V, Kutschke M, Mitchell TW, Aruwajoye O, Adapala NS, Kamiya N, Abu-Amer Y, Kim HK. Anti-Interleukin-6 Therapy Decreases Hip Synovitis and Bone Resorption and Increases Bone Formation Following Ischemic Osteonecrosis of the Femoral Head. J Bone Miner Res 2021; 36:357-368. [PMID: 33053220 DOI: 10.1002/jbmr.4191] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/24/2020] [Accepted: 10/08/2020] [Indexed: 12/22/2022]
Abstract
Legg-Calvé-Perthes disease (LCPD) is a juvenile form of ischemic femoral head osteonecrosis, which produces chronic hip synovitis, permanent femoral head deformity, and premature osteoarthritis. Currently, there is no medical therapy for LCPD. Interleukin-6 (IL-6) is significantly elevated in the synovial fluid of patients with LCPD. We hypothesize that IL-6 elevation promotes chronic hip synovitis and impairs bone healing after ischemic osteonecrosis. We set out to test if anti-IL-6 therapy using tocilizumab can decrease hip synovitis and improve bone healing in the piglet model of LCPD. Fourteen piglets were surgically induced with ischemic osteonecrosis and assigned to two groups: the no treatment group (n = 7) and the tocilizumab group (15 to 20 mg/kg, biweekly intravenous injection, n = 7). All animals were euthanized 8 weeks after the induction of osteonecrosis. Hip synovium and femoral heads were assessed for hip synovitis and bone healing using histology, micro-CT, and histomorphometry. The mean hip synovitis score and the number of synovial macrophages and vessels were significantly lower in the tocilizumab group compared with the no treatment group (p < .0001, p = .01, and p < .01, respectively). Micro-CT analysis of the femoral heads showed a significantly higher bone volume in the tocilizumab group compared with the no treatment group (p = .02). The histologic assessment revealed a significantly lower number of osteoclasts per bone surface (p < .001) in the tocilizumab group compared with the no treatment group. Moreover, fluorochrome labeling showed a significantly higher percent of mineralizing bone surface (p < .01), bone formation rate per bone surface (p < .01), and mineral apposition rate (p = .04) in the tocilizumab group. Taken together, tocilizumab therapy decreased hip synovitis and osteoclastic bone resorption and increased new bone formation after ischemic osteonecrosis. This study provides preclinical evidence that tocilizumab decreases synovitis and improves bone healing in a large animal model of LCPD. © 2020 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Yinshi Ren
- Center for Excellence in Hip Disorders, Scottish Rite for Children, Dallas, TX, USA.,Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Zhuo Deng
- Center for Excellence in Hip Disorders, Scottish Rite for Children, Dallas, TX, USA
| | - Vishal Gokani
- Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Michael Kutschke
- Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Thomas Wesley Mitchell
- Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Olumide Aruwajoye
- Center for Excellence in Hip Disorders, Scottish Rite for Children, Dallas, TX, USA
| | - Naga Suresh Adapala
- Center for Excellence in Hip Disorders, Scottish Rite for Children, Dallas, TX, USA
| | - Nobuhiro Kamiya
- Center for Excellence in Hip Disorders, Scottish Rite for Children, Dallas, TX, USA
| | - Yousef Abu-Amer
- Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
| | - Harry Kw Kim
- Center for Excellence in Hip Disorders, Scottish Rite for Children, Dallas, TX, USA.,Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Wiegertjes R, van de Loo FAJ, Blaney Davidson EN. A roadmap to target interleukin-6 in osteoarthritis. Rheumatology (Oxford) 2021; 59:2681-2694. [PMID: 32691066 PMCID: PMC7516110 DOI: 10.1093/rheumatology/keaa248] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/26/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023] Open
Abstract
Joint inflammation is present in the majority of OA patients and pro-inflammatory mediators, such as IL-6, are actively involved in disease progression. Increased levels of IL-6 in serum or synovial fluid from OA patients correlate with disease incidence and severity, with IL-6 playing a pivotal role in the development of cartilage pathology, e.g. via induction of matrix-degrading enzymes. However, IL-6 also increases expression of anti-catabolic factors, suggesting a protective role. Until now, this dual role of IL-6 is incompletely understood and may be caused by differential effects of IL-6 classic vs trans-signalling. Here, we review current evidence regarding the role of IL-6 classic- and trans-signalling in local joint pathology of cartilage, synovium and bone. Furthermore, we discuss targeting of IL-6 in experimental OA models and provide future perspective for OA treatment by evaluating currently available IL-6 targeting strategies.
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Affiliation(s)
- Renske Wiegertjes
- Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fons A J van de Loo
- Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Esmeralda N Blaney Davidson
- Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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35
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Influence of body fat in patients with dental implant rehabilitation treated with adjunctive photodynamic therapy. Photodiagnosis Photodyn Ther 2020; 31:101831. [DOI: 10.1016/j.pdpdt.2020.101831] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 12/28/2022]
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Sims NA. The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology. Exp Mol Med 2020; 52:1185-1197. [PMID: 32788655 PMCID: PMC8080635 DOI: 10.1038/s12276-020-0445-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/03/2020] [Accepted: 04/20/2020] [Indexed: 12/15/2022] Open
Abstract
Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone. Maintaining normal bone structure and strength depends on a group of signaling proteins called cytokines that bind to receptor molecules on cell surfaces. Natalie Sims at St. Vincent’s Institute of Medical Research and The University of Melbourne in Australia reviews the role of cytokines in a specific signaling pathway in bone development and disease. Two of the proteins in this pathway respond to cytokine activity, whereas the third inhibits the cytokines’ effects. Studies in mice and humans have identified links between specific bone defects and spontaneous or experimentally induced mutations in the genes that code for the three proteins. The review covers the significance of recent findings to several types of cells that form new bone, degrade bone as part of normal bone turnover, and sustain the structure of bone and cartilage.
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Affiliation(s)
- Natalie A Sims
- St. Vincent's Institute of Medical Research, and Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Parkville, VIC, Australia.
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37
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Kantor A, Krawczenko A, Bielawska-Pohl A, Duś D, Grillon C, Kieda C, Charkiewicz K, Paprocka M. Activity of the human immortalized endothelial progenitor cell line HEPC-CB.1 supporting in vitro angiogenesis. Mol Biol Rep 2020; 47:5911-5925. [PMID: 32705508 PMCID: PMC7455590 DOI: 10.1007/s11033-020-05662-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 07/11/2020] [Indexed: 12/03/2022]
Abstract
The human HEPC-CB.1 cell line with many characteristics of endothelial progenitor cells (EPC) was tested for its proangiogenic properties as a potentially therapeutic compound. HEPC-CB.1 cells’ potential to differentiate into endothelial cells was revealed after treating the cells with a mixture of ATRA, cAMP and VEGF, as shown by the reduced expression levels of CD133, CD271 and CD90 antigens, augmentation of CD146 and CD31, and a decrease in cell clonogenicity. The cooperation of HEPC-CB.1 with the endothelial cell line HSkMEC.2 resulted in the formation of a common network. Tube formation was significantly more effective when resulting from HEPC-CB.1 and HSkMEC.2 cell co-culture as compared to a monoculture of each cell line. The exocrine mechanism of HEPC-CB.1 and HSkMEC.2 cross talk by secreted factors was evidenced using the HEPC-CB.1 supernatant to increase the efficacy of HSkMEC.2 tube formation. The proangiogenic factors produced by HEPC-CB.1 were identified using cytokine antibody array. Out of 120 examined factors, the HEPC-CB.1 cell line produced 63, some with known angiogenic activity. As in vivo the angiogenic process occurs at low oxygen tension, it was observed that in hypoxia, the production of defined factors was augmented. The presented results demonstrate that HEPC-CB.1 cells are able to both cooperate and integrate in a newly formed network and produce factors that help the network formation. The results suggest that HEPC-CB.1 cells are indeed endothelial progenitors and may prove to be an effective tool in regenerative medicine.
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Affiliation(s)
- Aneta Kantor
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wroclaw, Poland.
| | - Agnieszka Krawczenko
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wroclaw, Poland
| | - Aleksandra Bielawska-Pohl
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wroclaw, Poland
| | - Danuta Duś
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wroclaw, Poland
| | - Catherine Grillon
- Centre de Biophysique Moléculaire, CNRS UPR 4301, Rue Charles Sadron, 45071, Orléans, France
| | - Claudine Kieda
- Centre de Biophysique Moléculaire, CNRS UPR 4301, Rue Charles Sadron, 45071, Orléans, France
| | - Karol Charkiewicz
- Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276, Bialystok, Poland
| | - Maria Paprocka
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114, Wroclaw, Poland
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38
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Metcalfe RD, Putoczki TL, Griffin MDW. Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11. Front Immunol 2020; 11:1424. [PMID: 32765502 PMCID: PMC7378365 DOI: 10.3389/fimmu.2020.01424] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.
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Affiliation(s)
- Riley D Metcalfe
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Technology Institute, The University of Melbourne, Parkville, VIC, Australia
| | - Tracy L Putoczki
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Michael D W Griffin
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Technology Institute, The University of Melbourne, Parkville, VIC, Australia
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Schwerd T, Krause F, Twigg SRF, Aschenbrenner D, Chen YH, Borgmeyer U, Müller M, Manrique S, Schumacher N, Wall SA, Jung J, Damm T, Glüer CC, Scheller J, Rose-John S, Jones EY, Laurence A, Wilkie AOM, Schmidt-Arras D, Uhlig HH. A variant in IL6ST with a selective IL-11 signaling defect in human and mouse. Bone Res 2020; 8:24. [PMID: 32566365 PMCID: PMC7289831 DOI: 10.1038/s41413-020-0098-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 03/11/2020] [Accepted: 03/30/2020] [Indexed: 12/14/2022] Open
Abstract
The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.
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Affiliation(s)
- Tobias Schwerd
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK
- Department of Pediatrics, Dr von Hauner Children’s Hospital, LMU Munich, Munich, Germany
| | - Freia Krause
- Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany
| | - Stephen R. F. Twigg
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Dominik Aschenbrenner
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Yin-Huai Chen
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Uwe Borgmeyer
- Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Miryam Müller
- Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany
- Present Address: The Beatson Institute for Cancer Research, Glasgow, UK
| | - Santiago Manrique
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Neele Schumacher
- Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany
| | - Steven A. Wall
- Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Jonathan Jung
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK
- Present Address: School of Medicine, University of Glasgow, Glasgow, UK
| | - Timo Damm
- Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Claus-Christian Glüer
- Section Biomedical Imaging, Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Stefan Rose-John
- Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany
| | - E. Yvonne Jones
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Arian Laurence
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Andrew O. M. Wilkie
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Dirk Schmidt-Arras
- Christian-Albrechts-University Kiel, Institute of Biochemistry, Kiel, Germany
| | - Holm H. Uhlig
- Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK
- Department of Paediatrics, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
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40
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Walker EC, Truong K, McGregor NE, Poulton IJ, Isojima T, Gooi JH, Martin TJ, Sims NA. Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes. eLife 2020; 9:e56666. [PMID: 32458800 PMCID: PMC7253175 DOI: 10.7554/elife.56666] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 05/01/2020] [Indexed: 12/23/2022] Open
Abstract
Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre:Socs3f/f mice. SOCS3 (suppressor of cytokine signalling 3) inhibits signalling by leptin, G-CSF, and IL-6 family cytokines (gp130). In Dmp1Cre:Socs3f/f bone, STAT3 phosphorylation was prolonged in response to gp130-signalling cytokines, but not G-CSF or leptin. Deletion of gp130 in Dmp1Cre:Socs3f/f mice suppressed STAT3 phosphorylation in osteocytes and osteoclastic resorption within cortical bone, leading to rescue of the corticalisation defect, and restoration of compromised bone strength. We conclude that cortical bone development includes both pore closure and accumulation of high density bone, and that these processes require suppression of gp130-STAT3 signalling in osteocytes.
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Affiliation(s)
- Emma C Walker
- St. Vincent’s Institute of Medical ResearchFitzroyAustralia
| | - Kim Truong
- St. Vincent’s Institute of Medical ResearchFitzroyAustralia
- University of Melbourne, Department of Medicine at St. Vincent’s HospitalFitzroyAustralia
| | | | | | - Tsuyoshi Isojima
- St. Vincent’s Institute of Medical ResearchFitzroyAustralia
- Department of Pediatrics, Teikyo University School of MedicineTokyoJapan
| | - Jonathan H Gooi
- St. Vincent’s Institute of Medical ResearchFitzroyAustralia
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of MelbourneParkvilleAustralia
| | - T John Martin
- St. Vincent’s Institute of Medical ResearchFitzroyAustralia
- University of Melbourne, Department of Medicine at St. Vincent’s HospitalFitzroyAustralia
| | - Natalie A Sims
- St. Vincent’s Institute of Medical ResearchFitzroyAustralia
- University of Melbourne, Department of Medicine at St. Vincent’s HospitalFitzroyAustralia
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Abstract
Osteosarcoma is an often highly malignant mesenchymal tumor. By definition, osteosarcoma cells are able to form osteoid, which can mature into tumor bone. Osteosarcoma metastasizes preferentially to the lung. In Europe, the incidence is between 2 and 5 new diagnoses per 1,000,000 people per year. The underlying mechanisms for osteosarcoma formation are not well understood. However, previous radiotherapy or exposition to nuclear radiation increase the risk of osteosarcoma. Patients are usually treated with a neoadjuvant chemotherapy, followed by complete surgical resection of the tumor and post-surgical chemotherapy, which leads to a five-year survival rate of approximately 70% for all stages. Scientific publications in recent years have shown that expression of the cell surface protein interleukin-11 receptor (IL-11R) correlates with a worse prognosis for patients. The IL-11R is activated by its ligand, the cytokine IL-11. IL-11 activates several intracellular signaling cascades within its target cells and is known to be an important regulator of bone homeostasis. Patients with dysfunctional IL-11 signaling display different forms of craniosynostosis. IL-11 induces proliferation of osteosarcoma cell lines in vitro, and the IL-11 signaling cascade was further used to reduce tumor growth and lung metastasis in preclinical mouse models of primary intratibial osteosarcoma. This article gives a comprehensive overview of the frequency, classification, and etiology of osteosarcoma and describes the basic biology of the cytokine IL-11. Furthermore, it summarizes current knowledge about the functional role of IL-11 in osteosarcoma and lists possible therapeutic opportunities.
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42
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Omokehinde T, Johnson RW. GP130 Cytokines in Breast Cancer and Bone. Cancers (Basel) 2020; 12:cancers12020326. [PMID: 32023849 PMCID: PMC7072680 DOI: 10.3390/cancers12020326] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer cells have a high predilection for skeletal homing, where they may either induce osteolytic bone destruction or enter a latency period in which they remain quiescent. Breast cancer cells produce and encounter autocrine and paracrine cytokine signals in the bone microenvironment, which can influence their behavior in multiple ways. For example, these signals can promote the survival and dormancy of bone-disseminated cancer cells or stimulate proliferation. The interleukin-6 (IL-6) cytokine family, defined by its use of the glycoprotein 130 (gp130) co-receptor, includes interleukin-11 (IL-11), leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1), among others. These cytokines are known to have overlapping pleiotropic functions in different cell types and are important for cross-talk between bone-resident cells. IL-6 cytokines have also been implicated in the progression and metastasis of breast, prostate, lung, and cervical cancer, highlighting the importance of these cytokines in the tumor–bone microenvironment. This review will describe the role of these cytokines in skeletal remodeling and cancer progression both within and outside of the bone microenvironment.
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Affiliation(s)
- Tolu Omokehinde
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Rachelle W. Johnson
- Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA
- Vanderbilt Center for Bone Biology, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Correspondence: ; Tel.: +1-615-875-8965
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43
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Abstract
Cytokines and hematopoietic growth factors have traditionally been thought of as regulators of the development and function of immune and blood cells. However, an ever-expanding number of these factors have been discovered to have major effects on bone cells and the development of the skeleton in health and disease (Table 1). In addition, several cytokines have been directly linked to the development of osteoporosis in both animal models and in patients. In order to understand the mechanisms regulating bone cells and how this may be dysregulated in disease states, it is necessary to appreciate the diverse effects that cytokines and inflammation have on osteoblasts, osteoclasts, and bone mass. This chapter provides a broad overview of this topic with extensive references so that, if desired, readers can access specific references to delve into individual topics in greater detail.
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Affiliation(s)
- Joseph Lorenzo
- Departments of Medicine and Orthopaedic Surgery, UConn Health, Farmington, CT, USA.
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44
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Boutin A, Gershengorn MC, Neumann S. β-Arrestin 1 in Thyrotropin Receptor Signaling in Bone: Studies in Osteoblast-Like Cells. Front Endocrinol (Lausanne) 2020; 11:312. [PMID: 32508750 PMCID: PMC7251030 DOI: 10.3389/fendo.2020.00312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/24/2020] [Indexed: 12/20/2022] Open
Abstract
A direct action of thyrotropin (TSH, thyroid-stimulating hormone) on bone precursors in humans is controversial. Studies in rodent models have provided conflicting findings. We used cells derived from a moderately differentiated osteosarcoma stably overexpressing human TSH receptors (TSHRs) as a model of osteoblast precursors (U2OS-TSHR cells) to investigate TSHR-mediated effects in bone differentiation in human cells. We review our findings that (1) TSHR couples to several different G proteins to induce upregulation of genes associated with osteoblast activity-interleukin 11 (IL-11), osteopontin (OPN), and alkaline phosphatase (ALPL) and that the kinetics of the induction and the G protein-mediated signaling pathways involved were different for these genes; (2) TSH can stimulate β-arrestin-mediated signal transduction and that β-arrestin 1 in part mediates TSH-induced pre-osteoblast differentiation; and (3) TSHR/insulin-like growth factor 1 (IGF1) receptor (IGF1R) synergistically increased OPN secretion by TSH and IGF1 and that this crosstalk was mediated by physical association of these receptors in a signaling complex that uses β-arrestin 1 as a scaffold. These findings were complemented using a novel β-arrestin 1-biased agonist of TSHR. We conclude that TSHR can signal via several transduction pathways leading to differentiation of this model system of human pre-osteoblast cells and, therefore, that TSH can directly regulate these bone cells.
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45
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Banerjee A, Bhattacharya S, Dasgupta R, Ray S. Mutational, functional and evolutionary analysis of interleukin-11 in Homo sapiens: A detailed in silico exploration for platelet recovery due to chemotherapy induced thrombocytopenia. Meta Gene 2019. [DOI: 10.1016/j.mgene.2019.100591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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McGregor NE, Murat M, Elango J, Poulton IJ, Walker EC, Crimeen-Irwin B, Ho PWM, Gooi JH, Martin TJ, Sims NA. IL-6 exhibits both cis- and trans-signaling in osteocytes and osteoblasts, but only trans-signaling promotes bone formation and osteoclastogenesis. J Biol Chem 2019; 294:7850-7863. [PMID: 30923130 DOI: 10.1074/jbc.ra119.008074] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 03/25/2019] [Indexed: 11/06/2022] Open
Abstract
Interleukin 6 (IL-6) supports development of bone-resorbing osteoclasts by acting early in the osteoblast lineage via membrane-bound (cis) or soluble (trans) receptors. Here, we investigated how IL-6 signals and modifies gene expression in differentiated osteoblasts and osteocytes and determined whether these activities can promote bone formation or support osteoclastogenesis. Moreover, we used a genetically altered mouse with circulating levels of the pharmacological IL-6 trans-signaling inhibitor sgp130-Fc to determine whether IL-6 trans-signaling is required for normal bone growth and remodeling. We found that IL-6 increases suppressor of cytokine signaling 3 (Socs3) and CCAAT enhancer-binding protein δ (Cebpd) mRNA levels and promotes signal transducer and activator of transcription 3 (STAT3) phosphorylation by both cis- and trans-signaling in cultured osteocytes. In contrast, RANKL (Tnfsf11) mRNA levels were elevated only by trans-signaling. Furthermore, we observed soluble IL-6 receptor release and ADAM metallopeptidase domain 17 (ADAM17) sheddase expression by osteocytes. Despite the observation that IL-6 cis-signaling occurs, IL-6 stimulated bone formation in vivo only via trans-signaling. Although IL-6 stimulated RANKL (Tnfsf11) mRNA in osteocytes, these cells did not support osteoclast formation in response to IL-6 alone; binucleated TRAP+ cells formed, and only in response to trans-signaling. Finally, pharmacological, sgp130-Fc-mediated inhibition of IL-6 trans-signaling did not impair bone growth or remodeling unless mice had circulating sgp130-Fc levels > 10 μg/ml. At those levels, osteopenia and impaired bone growth occurred, reducing bone strength. We conclude that high sgp130-Fc levels may have detrimental off-target effects on the skeleton.
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Affiliation(s)
- Narelle E McGregor
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia
| | - Melissa Murat
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.,the Department of Physiology, Anatomy, and Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia
| | - Jeevithan Elango
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.,the Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Ingrid J Poulton
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia
| | - Emma C Walker
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia
| | - Blessing Crimeen-Irwin
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia
| | - Patricia W M Ho
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia
| | - Jonathan H Gooi
- the Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia, and.,the Structural Biology Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia
| | - T John Martin
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia.,the Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia, and
| | - Natalie A Sims
- From the Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia, .,the Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia, and
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47
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Tachmazidou I, Hatzikotoulas K, Southam L, Esparza-Gordillo J, Haberland V, Zheng J, Johnson T, Koprulu M, Zengini E, Steinberg J, Wilkinson JM, Bhatnagar S, Hoffman JD, Buchan N, Süveges D, Yerges-Armstrong L, Smith GD, Gaunt TR, Scott RA, McCarthy LC, Zeggini E. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet 2019; 51:230-236. [PMID: 30664745 PMCID: PMC6400267 DOI: 10.1038/s41588-018-0327-1] [Citation(s) in RCA: 347] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 12/04/2018] [Indexed: 12/18/2022]
Abstract
Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we perform a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analysing 4 phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discover 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine map to a single variant. We identify putative effector genes by integrating eQTL colocalization, fine-mapping, human rare disease, animal model, and osteoarthritis tissue expression data. We find enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organisation biological pathways. Ten of the likely effector genes, including TGFB1, FGF18, CTSK and IL11 have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.
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Affiliation(s)
| | - Konstantinos Hatzikotoulas
- Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK.,Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Lorraine Southam
- Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK.,Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | | | - Valeriia Haberland
- MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
| | - Jie Zheng
- MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
| | - Toby Johnson
- Target Sciences-R&D, GSK Medicines Research Centre, Stevenage, UK
| | - Mine Koprulu
- Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK.,Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Eleni Zengini
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.,5th Psychiatric Department, Dromokaiteio Psychiatric Hospital, Haidari, Athens, Greece
| | - Julia Steinberg
- Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK.,Cancer Research Division, Cancer Council NSW, Woolloomooloo, New South Wales, Australia
| | - Jeremy M Wilkinson
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Sahir Bhatnagar
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
| | | | - Natalie Buchan
- Target Sciences-R&D, GSK Medicines Research Centre, Stevenage, UK
| | - Dániel Süveges
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, UK
| | | | | | - George Davey Smith
- MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
| | - Tom R Gaunt
- MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK
| | - Robert A Scott
- Target Sciences-R&D, GSK Medicines Research Centre, Stevenage, UK
| | - Linda C McCarthy
- Target Sciences-R&D, GSK Medicines Research Centre, Stevenage, UK
| | - Eleftheria Zeggini
- Human Genetics, Wellcome Genome Campus, Wellcome Sanger Institute, Cambridge, UK. .,Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
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48
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Wu X, Gu Y. Signaling Mechanisms Underlying Genetic Pathophysiology of Craniosynostosis. Int J Biol Sci 2019; 15:298-311. [PMID: 30745822 PMCID: PMC6367540 DOI: 10.7150/ijbs.29183] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 11/30/2018] [Indexed: 12/14/2022] Open
Abstract
Craniosynostosis, is the premature fusion of one or more cranial sutures which is the second most common cranial facial anomalies. The premature cranial sutures leads to deformity of skull shape and restricts the growth of brain, which might elicit severe neurologic damage. Craniosynostosis exhibit close correlations with a varieties of syndromes. During the past two decades, as the appliance of high throughput DNA sequencing techniques, steady progresses has been made in identifying gene mutations in both syndromic and nonsyndromic cases, which allow researchers to better understanding the genetic roles in the development of cranial vault. As the enrichment of known mutations involved in the pathogenic of premature sutures fusion, multiple signaling pathways have been investigated to dissect the underlying mechanisms beneath the disease. In addition to genetic etiology, environment factors, especially mechanics, have also been proposed to have vital roles during the pathophysiological of craniosynostosis. However, the influence of mechanics factors in the cranial development remains largely unknown. In this review, we present a brief overview of the updated genetic mutations and environmental factors identified in both syndromic and nonsyndromic craniosynostosis. Furthermore, potential molecular signaling pathways and its relations have been described.
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Affiliation(s)
- Xiaowei Wu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, No. 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, PR. China
- National Engineering Laboratory for Digital and Material Technology of Stomatology,Beijing Key Laboratory of Digital Stomatology, No. 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, PR. China
| | - Yan Gu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, No. 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, PR. China
- National Engineering Laboratory for Digital and Material Technology of Stomatology,Beijing Key Laboratory of Digital Stomatology, No. 22 Zhongguancun Avenue South, Haidian District, Beijing, 100081, PR. China
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49
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Kuroyanagi G, Adapala NS, Yamaguchi R, Kamiya N, Deng Z, Aruwajoye O, Kutschke M, Chen E, Jo C, Ren Y, Kim HKW. Interleukin-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis in a murine model. Bone 2018; 116:221-231. [PMID: 30125727 DOI: 10.1016/j.bone.2018.08.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 08/11/2018] [Accepted: 08/14/2018] [Indexed: 12/28/2022]
Abstract
Legg-Calvé-Perthes disease (LCPD) is a childhood form of ischemic osteonecrosis of the femoral head which can produce a permanent femoral head deformity and early osteoarthritis. The femoral head deformity results from increased bone resorption and decreased bone formation during repair and remodeling of the necrotic femoral head. A recent study showed that a pro-inflammatory cytokine, interleukin-6 (IL-6), is significantly elevated in the synovial fluid of patients with LCPD. We hypothesized that IL-6 elevation decreases bone formation during the repair process following ischemic osteonecrosis and that IL-6 depletion will increase new bone formation. To test this hypothesis, we surgically induced ischemic osteonecrosis in the wild-type (n = 29) and IL-6 knockout (KO) mice (n = 25). The animals were assessed at 48 h, 2 weeks and 4 weeks following the induction of ischemic osteonecrosis using histologic, histomorphometric and micro-CT methods. IL-6 immunohistochemistry showed high expression of IL-6 in the osteonecrotic side of the wild-type mice at 48 h and 4 weeks following ischemic osteonecrosis, but not in the IL-6 KO mice. We also confirmed an undetectable level of IL-6 expression in the primary osteoblasts of the IL-6 KO mice compared to the readily detectable level in the wild-type mice. Furthermore, we confirmed that IL-6 deletion did not affect the extent of bone necrosis in the IL-6 KO mice compared to the wild-type mice by performing histologic and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) assessments at 2 weeks following the induction of ischemia. Both groups had the same extent of ischemic osteonecrosis and absence of repair at 2 weeks. At 4 weeks, the necrotic epiphyses showed a significant increase in the extent of revascularization in the IL-6 KO mice compared to the wild-type mice (p = 0.001). In addition, a significantly greater recovery of the hematopoietic bone marrow was observed in the osteonecrotic side of the IL-6 KO mice compared to the wild-type mice (p < 0.01). Vascular endothelial growth factor (VEGF) immunohistochemistry showed regionally increased staining in the areas of repair in the osteonecrosis side of IL-6 KO mice compared to the wild-type mice at 4 weeks following ischemic osteonecrosis. Micro-CT assessment of the wild-type mice at 4 weeks showed a significant decrease in the percent bone volume (p < 0.01) in the osteonecrotic side compared to the control side. In contrast, IL-6 KO mice showed significantly increased bone volume in the osteonecrotic side compared to the osteonecrotic side of WT mice (p < 0.001). No significant difference in the bone volume percentage was found between the control side of the wild-type and the IL-6 KO mice. Histomorphometric analysis at 4 weeks revealed increased osteoblast number/bone surface (p < 0.001), bone formation rate (BFR) (p = 0.0001), and mineral apposition rate (MAR) (p < 0.0001) in the osteonecrotic side of the IL-6 KO mice compared to the wild-type mice. The number of osteoclast/bone surface was also increased in the IL-6 KO mice compared to the wild-type mice (p < 0.0001). No significant difference was observed between the control side of the wild-type and IL-6 KO mice with regards to the number of osteoblast or osteoclast/bone surface, BFR, and MAR. We next obtained primary osteoblasts from IL-6 KO mice and showed they expressed a significantly higher level of RANKL/OPG than wild-type mice (p = 0.001) in hypoxia culture condition. Taken together, the findings indicate that IL-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis. This study provides new evidence that therapeutic strategies to block IL-6 may be beneficial for bone healing following ischemic osteonecrosis.
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Affiliation(s)
- Gen Kuroyanagi
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Naga Suresh Adapala
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Ryosuke Yamaguchi
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Orthopaedic and Spine Surgery, Fukuoka Children's Hospital, Fukuoka 813-0017, Japan
| | - Nobuhiro Kamiya
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Sports Medicine, Tenri University, Tenri 632-0071, Japan
| | - Zhuo Deng
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Olumide Aruwajoye
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Michael Kutschke
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Elena Chen
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Chanhee Jo
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Yinshi Ren
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA
| | - Harry K W Kim
- Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-8883, USA.
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50
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GT-repeat extension in the IL11 promoter is associated with Hirschsprung's disease (HSCR). Gene 2018; 677:163-168. [DOI: 10.1016/j.gene.2018.07.054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/18/2018] [Accepted: 07/19/2018] [Indexed: 11/20/2022]
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