The roles of β1 [beta-1] integrin in cartilage development [Elektronische Ressource] / Aurelia Raducanu

Aurelia Raducanu

Sujets

• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2009
• Nombre de lectures: 49
• Langue: Deutsch
• Poids de l'ouvrage: 6 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München







The roles of β1 integrin in cartilage development















Aurelia Raducanu
aus
Bukarest, Rumänien


2009Erklärung
Diese Dissertation wurde im Sinne von § 13 Abs. 3 der Promotionsordnung vom
29. Januar 1998 von Herrn Prof. Dr. Reinhard Fässler betreut.









Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.


München, am 23.04.2009





Aurelia Raducanu













Dissertation eingereicht am 23.04.2009
Erster Gutachter: Prof. Dr. Reinhard Fässler
Zweiter Gutachter: PD Dr. Matthias Schieker
Sondergutacher: Dr. Attila Aszódi
Mündliche Prüfung am 29.05. 2009 To my parents
(pentru parintii mei) Table of contents
1. Table of contents

1. TABLE OF CONTENTS......................................................................................................I
2. LIST OF PUBLICATIONS................................................................................................II
3. ABBREVIATIONS ........................................................................................................... III
4. SUMMARY.......................................................................................................................... V
5. INTRODUCTION................................................................................................................ 1
5.1. THE INTEGRIN FAMILY OF ADHESION RECEPTORS ............................................................. 1
5.1.1. Integrins and their ligands ....................................................................................... 1
5.1.2. Integrin structure...................................................................................................... 3
5.1.3. Integrin signaling ..................................................................................................... 4
5.1.4. Integrins in mouse development............................................................................... 9
5.1.5. β1 Integrin controls orientation of the spindle machinery and cell polarity ......... 10
5.2. SKELETAL DEVELOPMENT .............................................................................................. 13
5.2.1. Endochondral ossification...................................................................................... 13
5.2.2. The growth plate – the functional unit of endochondral ossification .................... 16
5.2.3. Mechanism of column formation............................................................................ 18
5.2.4. Regulation of growth plate morphogenesis............................................................ 19
5.2.4.1. Transcription and diffusible factors ..................................................................................... 19
5.2.4.2. The primary cilium and endochondral bone formation..................................................... 28
5.2.4.3. The impact of ECM proteins on cartilage development ................................................... 30
5.2.4.4. Integrin expression and function during endochondral ossification ............................... 32
5.3. THE ARTICULAR CARTILAGE........................................................................................... 34
5.3.1. Morphology of the normal articular cartilage....................................................... 34
5.3.2. Osteoarthritic articular cartilage........................................................................... 36
5.3.3. The role of β1 integrin in articular cartilage functions......................................... 38
5.4. ATOMIC FORCE MICROSCOPY (AFM) ............................................................................. 40
6. AIM OF THESIS................................................................................................................ 42
7 BRIEF SUMMARIES OF THE PUBLICATIONS ......................................................... 44
7.1 PAPER I............................................................................................................................ 44
7.2 PAPER II .......................................................................................................................... 45
7.3 PAPER III......................................................................................................................... 46
7.4 PAPER IV 47
8. REFERENCES ................................................................................................................... 49
9. ACKNOWLEDGEMENTS............................................................................................... 59
10. CURRICULUM VITAE.................................................................................................. 60
11. SUPPLEMENTS .............................................................................................................. 61

I List of publications
2. List of Publications

This thesis is based on the following publications, which are referred to in the text by their
Roman numerals (I-IV):


I. Aurelia Raducanu and Attila Aszodi. β1 integrin-dependent cell shape governs mitotic spindle
positioning in growth plate chondrocytes. Submitted manuscript



II. Aurelia Raducanu and Attila Aszódi* Knock-Out Mice in Osteoarthritis Research Current
Rheumatology Reviews, 2008, 4, 183-192

III. Aurelia Raducanu, Ernst B. Hunziker, Inga Drosse and Attila Aszódi. β1 integrin-deficiency
results in multiple abnormalities of the knee joint. Submitted manuscript



1 2 2 3 3 4IV. Martin Stolz *, Riccardo Gottardi , Roberto Raiteri , Sylvie Miot , Ivan Martin , Raphaël Imer ,
5 6 7 1,8 9Urs Staufer4 , Aurelia Raducanu , Marcel Düggelin , Werner Baschong , A. U. Daniels ,

10 6 1Niklaus F. Friederich , Attila Aszodi and Ueli Aebi . Early detection of aging cartilage and

osteoarthritis in mice and patient samples using atomic force microscopy. Nat Nanotechnol.
2009 Mar;4(3):186-92.



The following publication was not the focus of my project but I have contributed with tools
which I have made during my PhD

1 1,5 1 1 1 2V. Kanatsu-Shinohara M , Takehashi M , Takashima S , Lee J , Morimoto H , Chuma S ,

3 2 3 1,4Raducanu A , Nakatsuji N , Fässler R , Shinohara T . Homing of Mouse Spermatogonial

Stem Cells to Germline Niche Depends on β1-Integrin Cell Stem Cell. 2008 Nov 6;3(5):533-42.




Reprints were made with permission from the publishers.



II Abbreviations

3. Abbreviations



AC articular cartilage GEF guanine nucleotide exchange
ACTRI activin receptor type I factor
ADAM a disintegrin and GFR growth factor receptor
metalloproteinase Gli glioma-associated oncogene
ADAMTS a disintegrin and homolog roteiwith GPCRs G proteins coupled receptors
trombospondin motifs GSK3 β glycogen synthase kinase 3 β
AdMIDAS adjacent to MIDAS GTP guanosine triphosphate
ADP adenosine diphosphate ICAMs intercellular adhesion
AGEs advanced glycation products molecules
Akt RAC-alpha serine/threonine- IFT intraflagellar transport
protein kinase Ift88 ar transport protein
APC adenomatous polyposis coli 88
Arp2/3 actin related protein 2/3 Ig immunoglobulin
complex IGF-1 insulin growth factor-1
BBS4 Bardet-Biedl Syndrome protein Ihh Indian hedgehog
4 ILK integrin linked kinase
BMP bone morphogenetic protein IPP ILK-PINCH-Parvin
BMPR BMP receptor IP3 inositol triphosphate
BrdU Bromodeoxyuridine IT-AFM indentation type atomic force
CaMKII calmodulin-dependent protein microscopy
kinase CII JAK Janus kinase
Cbfa1 core-binding factor alpha A JNK c-jun N-terminal kinase
CD campomelic dysplasia kDa kiloDaltons
CD44 cluster designation 44 Kif3a kinesin family member 3A
Cdc42 cell division cycle 42 LAP latency-associated peptide
CE convergent extension LEF lymphoid enhancer-binding
Cho chondrodysplasia factor
CILP cartilage intermediate layer LGN leucine, glycine, asparagine
protein LRP lipoprotein receptor-related
Cmd cartilage matrix deficiency proteins
COMP cartilage oligomeric matrix LTBP latent TGF β binding protein
protein MAPK mitogen-activated protein
Cre cyclization recombinase kinase
DAG diacylglycerol MEK MAP kinase-ERK kinase
DGO Diego MFGE8 milk fat globule-EGF factor 8
Dsh/Dvl Dishevelled MIDAS metal-ion-dependent adhesion
EB1 microtubule plus-end binding site
protein 1 mInsc mouse Inscuteable
ECM extracellular matrix MLC myosin light chain
EGF epidermal growth factor MMP matrix