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Molecular Mechanisms in Calvarial Bone and Suture Development

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Molecular Mechanisms in Calvarial Bone and Suture Development Molecular Mechanisms in Calvarial Bone and Suture Development David Rice Department of Orthodontics and Pedodontics, Institute of Dentistry, and, Developmental Biology Programme, Institute of Biotechnology, University of Helsinki, Finland. Academic Dissertation To be discussed publicly with the permission of the Faculty of Medicine of the University of Helsinki, in auditorium 1041, Viikki Biocenter 2 on 5th November 1999, at 12 noon. Helsinki 1999 Supervised by: Professor Irma Thesleff, University of Helsinki, Finland. Reviewed by: Professor Seppo Vainio, University of Oulu, Finland. and Professor Kalervo Väänänen, University of Turku, Finland. Opponent: Assistant Professor Lynne Opperman, Baylor School of Dentistry, Texas A & M University, U.S.A. ISBN 951-45-8960-2 (PDF version) Helsinki 1999 Helsingin yliopiston verkkojulkaisut http://ethesis.helsinki.fi/ 2 CONTENTS 3DJH /LVW RI 2ULJLQDO 3XEOLFDWLRQV 5 $EEUHYLDWLRQV 6 6XPPDU\ 7 5HYLHZ RI WKH /LWHUDWXUH 9 %RQH 'HYHORSPHQW DQG *URZWK 9 Origin and patterning of the craniofacial skeleton 9 Mesenchymal condensations 9 Intramembraneous ossification 10 Endochondral ossification 11 &HOOXODU %LRORJ\ RI %RQH 11 Osteoblasts, stromal cells and osteocytes 13 Osteoclasts 18 Proliferation of bone cells 22 Proliferation during calvarial bone and suture development 22 Apoptosis during embryogenesis 23 Apoptosis during bone and suture development 24 'HYHORSPHQW RI WKH &DOYDULD 24 Developmental anatomy 24 Sutures and fontanelles 25 Suture morphology 26 Suture closure 27 Suture position 27 Sutural growth 28 Role of the dura 28 Biomechanical forces 30 3DWKRELRORJ\ RI &DOYDULDO 'LVRUGHUV 30 Premature suture fusion, craniosynostosis 30 Delayed suture formation, cleidocranial dysplasia 32 Other conditions 33 $QLPDO 0RGHOV ZLWK D &DOYDULDO 3KHQRW\SH 34 5HJXODWLRQ RI (PEU\RQLF 'HYHORSPHQW 44 )LEUREODVW JURZWK IDFWRUV )*)V DQG WKHLU 5HFHSWRUV 45 FGFs and their receptors in embryogenesis 45 FGFs in bone and suture development 46 FGF receptors in bone and suture development 47 3 +HOL[/RRS+HOL[ SURWHLQV 48 TWIST and Inhibitors of differentiation (IDs) in embryogenesis 48 TWIST and IDs in bone and suture development 48 +HGJHKRJV 49 Hedgehogs in embryogenesis 49 Hedgehogs in bone development 49 06;V 50 MSX1 and 2 in embryogenesis 50 MSX1 and 2 in bone and suture development 51 7KH 7UDQVIRUPLQJ *URZWK )DFWRU β 7*)β 6XSHUIDPLO\ 51 The TGFβ superfamily in embryogenesis 51 The TGFβs in bone and suture development 52 1HOO 53 $LPV 54 0DWHULDOV DQG 0HWKRGV 55 5HVXOWV DQG 'LVFXVVLRQ 63 &RQFOXGLQJ 5HPDUNV 74 $FNQRZOHGJHPHQWV 75 5HIHUHQFHV 76 2ULJLQDO 3XEOLFDWLRQV ,,9 93 4 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original articles, which are referred to in the text by their Roman numerals. In addition, some unpublished data are also presented. I Rice, D.P.C., Kim, H.J., and Thesleff, I. (1997). Detection of gelatinase B expression reveals osteoclastic bone resorption as a feature of early calvarial bone development. Bone 21, 479-486. http://www-east.elsevier.com:80/bone II Rice, D.P.C., Kim, H-J., and Thesleff, I. (1999). Apoptosis in calvarial bone and suture development. Eur. Oral Sci. 106, 1-10. http://www.munksgaard.dk III Kim, H-J.*, Rice, D.P.C.*, Kettunen, P.J., and Thesleff, I. (1998). FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125, 1241-1251. * Equal contribution. http://www.biologists.com/Development/125/07/dev1213.html IV Rice, D.P.C., Åberg, T., Chan, C., Tang, Z., Kettunen, P.J., Pakarinen, L., Maxson, R.E.Jr., and Thesleff, I. (1999). Integration of FGF and TWIST signalling in calvarial bone and suture development. Submitted to Development. http://www.biologists.com 5 ABBREVIATIONS bHLH Basic helix-loop-helix IHH Indian hedgehog BMP Bone morphogenetic protein LIF Leukaemia inhibitory factor BSA Bovine serum albumin OMIM Online Mendelian Inheritance BSP Bone sialoprotein in Man BrdU 5’-bromo-2’-deoxyuridine mRNA Messenger ribonucleic acid CAM Cell adhesion molecule MSX Vertebrate homologue of CBFA1 Core binding factor alpha 1 'URVRSKLOD muscle segment CCD Cleidocranial dysplasia (0VK) gene cDNA Complementary MMP Matrix metalloproteinase deoxyribonucleic acid OC Osteocalcin Col Collagen OPG Osteoprotegerin CSF Colony stimulating factor OSF2 Osteoblast specific factor 2 DEPC Diethylpyrocarbonate P Post natal day DIG Digoxigenin PBS Phosphate buffered saline DNA Deoxyribonucleic acid PDGF Platelet derived growth factor DTT Dithiothreitol PFA Paraformaldehyde E Embryonic day PTC Patched EGF Epidermal growth factor PTHrP Parathyroid hormone related FGF Fibroblast growth factor peptide FGFR Fibroblast growth factor RNA Ribonucleic acid receptor SHH Sonic hedgehog Gel B Gelatinase B TGF Transforming growth factor GDF Growth and differentiation TNAP Tissue non-specific alkaline factor phosphatase GLI Vertebrate homologue of the TRAP Tartrate resistant acid 'URVRSKLOD segment polarity phosphatase gene cubitus interruptus TUNEL Terminal deoxynucleotidyl HH Hedgehog transferase mediated nick end HLH Helix-loop-helix labelling HSPG Heparan sulphate UTP Uridine triphosphate proteoglycan WNT Vertebrate homologue of the ID Inhibitor of differentiation 'URVRSKLOD segment polarity IG Immunoglobulin gene wingless Upper case letters refer to Humans. Lower case letters refer to other animals. Italics are used for genes. Non italics are used for proteins In this thesis, unless it is specifically stated otherwise, I shall refer to the mouse as a model for discussion. 6 SUMMARY The development and growth of the skull is a highly co-ordinated process involving many different tissues that interact to form a complex end result. When this normal development is disrupted debilitating pathological conditions, such as craniosynostosis and cleidocranial dysplasia, can result. The bones of the vault of the skull, or calvaria, are connected by joints called sutures and fontanelles. These joints normally close in a synchronized manner, allowing the underlying brain and the rest of the skull to reach its full size and shape. Craniosynostosis is a condition where the bones of the calvaria fuse prematurely, and as the brain and head continue to develop, so growth between the calvarial bones is restricted and deformity results. In contrast, cleidocranial dysplasia is characterised by a delay in suture closure. It is known that mutations in the Fibroblast growth factor receptors 1, 2 and 3 (FGFR1, 2 and 3), as well as the transcription factors MSX2 and TWIST cause craniosynostosis and that mutations in the transcription factor Core binding factor alpha 1 (CBFA1) causes cleidocranial dysplasia. However, relatively little is known about the development of the calvaria; about where and when these genes are active during normal calvarial development; how these genes may interact in the developing calvaria and the disturbances that may occur to cause these disorders. In this work we have attempted to address some of these questions from a basic biological perspective. We have put forward the developing mouse calvaria as a model system, in which one can study not only the processes of suture development but also the processes of intramembraneous bone formation and its subsequent modelling and remodelling. In comparison to the long bone, in which a cartilage framework is laid down prior to osteoblasts differentiating and finally forming bone, in the calvaria the majority of bone is formed intramembraneously. Here, osteoblasts differentiate directly form neighbouring mesenchymal or stromal cells and lay down matrix, which is subsequently mineralised without the formation of a cartilage substructure. This provides us with a relatively simplified model for studying osteoblast differentiation. By using both in-situ hybridisation and enzyme histochemical techniques we have described the distribution of osteoblasts and osteoclasts in the developing calvaria, and noted that the processes of bone deposition and resorption are highly integrated during calvarial bone and suture development and modelling. In addition, we have endeavoured to study bone cell turnover with regard to proliferation and cell death. we have found that cell death does indeed occur in both osteoblasts and osteoclasts and hypothesise that this may be one mechanism by which bone formation and resorption is regulated. Thus, the co-ordination of osteoblast and osteoclast differentiation, cell function and cell death appear to be central in maintaining suture patency, and hence the normal harmonized development of the calvaria. Consequently, when this co-ordination is disrupted craniosynostosis or cleidocranial dysplasia may result. In an effort to discover where and when some of the genes, either known or proposed the be involved in bone formation, as well as genes known to cause pathological conditions of the calvaria, are active during normal calvarial development; we have performed a detailed survey using in-situ hybridisation. This was in both sectional and 7 for the first time whole-mount mouse calvarial tissue. Rather than being expressed in a random fashion, we found that many of these genes were distributed in a unique spatio- temporal manner. From this baseline, we have attempted to investigate how these genes may interact. To this end, we have adapted a culture system, in which embryonic mouse calvarial development can be successfully monitored and manipulated in-vitro. Using a system of beads impregnated with a variety of different growth factors
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