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The Roles of Extracellular Matrix Molecules Matrilins and Aggrecan in Bone Development and Articular Cartilage Functions

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The Roles of Extracellular Matrix Molecules Matrilins and Aggrecan in Bone Development and Articular Cartilage Functions Aus der Klinik für Allgemeine, Unfall- und Wiederherstellungschirurgie Klinik der Universität München Vorstand/Direktor: Wolfgang Böcker The Roles of Extracellular Matrix Molecules Matrilins and Aggrecan in Bone Development and Articular Cartilage Functions Dissertation zum Erwerb des Doktorgrades der Humanbiologie an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Ping Li aus (Geburtsort) Hebei, China Jahr 2020 Mit Genehmigung der Medizinischen Fakultät der Universität München Berichterstatter: PD Dr. Attila Aszodi Mitberichterstatter: PD Dr. Jesus Buija Prof Dr. Susanne Mayer Prof Dr. Mohammad-Mehdi Shakibaei Mitbetreuung durch den Promovierten Mitarbeiter: Dr. hum,biol. Paolo Alberton Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: ______14.09.2020______________________ Dean’s Office Medical Faculty Faculty of Medicine Affidavit Li, Ping Surname, first name I hereby declare, that the submitted thesis entitled The Roles of Extracellular Matrix Molecules Matrilins and Aggrecan in Bone Development and Articular Cartilage Functions is my own work. I have only used the sources indicated and have not made unauthorised use of services of a third party. Where the work of others has been quoted or reproduced, the source is always given. I further declare that the submitted thesis or parts thereof have not been presented as part of an examination degree to any other university. München, 16.03.2020 Ping Li Place, Date Signature doctoral candidate Affidavit Human Biology Date: 15.09.2020 I TABLE OF CONTENTS TABLE OF CONTENTS ........................................................................................... I ABBREVATIONS .................................................................................................. II LIST OF PUBLICATIONS ...................................................................................... IV CONFIRMATION OF THE CO-AUTHORS..................................................................V 1. INTRODUCTION .............................................................................................. 1 1.1. Bone and cartilage .............................................................................................2 1.1.1. Endochondral ossification .................................................................................................... 2 1.1.2. Articular cartilage..................................................................................................................5 1.2. Extracellular matrix ............................................................................................7 1.2.1. Collagens .............................................................................................................................8 1.2.2. Proteoglycans .......................................................................................................................9 1.2.3. Perifibrillar adapter proteins ..............................................................................................10 1.2.4. Matrilin family .................................................................................................................10 1.2.4.1. Expression pattern and functions of matrilins ............................................................11 1.3. Diseases related to matrilins and aggrecan in the skeletal system ...................................13 1.3.1. Chondrodysplasia ........................................................................................13 1.3.2. Osteoarthritis .......................................................................................................................14 1.4. Aim of thesis .....................................................................................................16 1.5. Own contributions.............................. ................................................................17 2. SUMMARY ........................................................................................................18 3. ZUSAMMENFASSUNG ........................................................................................18 PAPER I ............................................................................................................................................. 23 PAPER II ..............................................................................................................50 REFERENCES .......................................................................................................70 ACKNOWLEDGMENT............................................................................................80 CURRICULUM VITAE ..........................................................................................81 II ABBREVATIONS AC Articular cartilage ADAMTS A disintegrin and metalloproteinase with thrombospondin motifs AFM Atomic force microscopy BHMED Bilateral hereditary micro-epiphyseal dysplasia CS Chondroitin sulphate EO Endochondral ossification COMP Cartilage oligomeric matrix protein ECM Extracellular matrix ER Endoplasmic reticulum FACIT Fibril-associated collagens with interrupted triple helix GAGs Glycosaminoglycans GP Growth plate HA Hyaluronan H&E Haematoxylin and Eosin HSCs Hematopoietic stem cells HZ Hypertrophic zone IGD Interglobular domains IGF-1 Insulin-like growth factor 1 ITM Interterritorial matrix IO Intramembranous ossification kDa Kilodalton KS Keratan sulphate Leucine-rich repeat LRR LP Link protein III MED Multiple epiphyseal dysplasia MMPs Matrix metalloproteinases OA Osteoarthritis Osteochondritis dissecans OCD PCM Pericellular matrix PG Proteoglycan POC Primary ossification center Ptc-1 Patched-1 PTHrP Parathyroid hormone related peptide PRG4 Proteoglycan 4 PSACH Pseudoachondroplasia PZ Proliferative zone rER Rough endoplasmic reticulum RZ Resting zone SEMD Spondyloepimetaphyseal dysplasia Small leucine-rich repeat proteoglycans SLRPs Smoothened Smo SOC Secondary ossification center TM Territorial matrix TSP Thrombospondin UPR Unfolded protein response VEGF Vascular endothelial growth factors vWFA von Willebrand factor A IV LIST OF PUBLICATIONS This thesis is based on the following publications I. Mice lacking the Matrilin Family of Extracellular Matrix Proteins Develop Normal Skeleton but are More Susceptible for Age-associated Osteoarthritis Ping Li, Lutz Fleischhauer, Claudia Nicolae, Carina Prein, Zsuzsanna Farkas，Maximilian Michael Saller, Wolf Christian Prall, Raimund Wagener, Juliane Heilig, Anja Niehoff, Hauke Clausen- Schaumann, Paolo Alberton, Attila Aszodi* International Journal of Molecular Sciences. 2020 Jan 19; 21(2). pii: E666. II. Aggrecan Hypomorphism Compromises Articular Cartilage Biomechanical Properties and Is Associated with Increased Incidence of Spontaneous Osteoarthritis. Alberton Paolo, Dugonitsch HC, Hartmann B, Li Ping, Farkas Z, Saller MM, Clausen-Schaumann H, Aszodi Attila. International Journal of Molecular Sciences. 2019 Feb 26; 20(5). pii: E1008. 1 1. Introduction Bones are important constituents of the organ systems of the vertebrates providing body support, physical protection for inner organs, movement facilitation, mineral storage and a niche for hematopoiesis [1, 2]. In human, there are more than 200 bones, which derive through two developmental pathways: 1) flat bones of the skull form directly from the condensation of the skeletogenic mesenchymal cells in the process of intramembranous ossification (IO); 2) while long bones of the appendicular and axial skeleton arise from intermediates of cartilaginous templates in the process of endochondral ossification (EO) [3]. EO starts with the condensation of the skeletogenic mesenchymal cells at the sites of the future bones, and the progenitor cells in these aggregates, under the guidance of various factors, differentiate into chondrocytes forming the cartilage template. Chondrocytes within the cartilage anlage begin to proliferate and synthesize cartilage-specific extracellular matrix, which is rich in collagen II and aggrecan [3]. The cartilage templates subsequently undergo maturation, hypertrophy, vascular invasion and mineralization, and the bones grow both laterally and longitudinally [4, 5]. As a result of the morphogenetic processes, embryonic cartilage is largely replaced by bone (transient cartilage), except the ends of long bones where it remains intact and forms the permanent articular cartilage [6, 7]. Articular cartilage (AC) is a highly hydrated, strong, resilient, avascular, alymphatic and aneural tissue. Covering the ends of long bones, AC is not only providing a lubricating, frictionless surface for the synovial, diarthrodial joints, but is also essential to distribute the mechanical loading generated during movement [8]. AC is composed of a relatively small number of chondrocytes, which lay down a specialized extracellular matrix (ECM). The major constituents of the ECM are the organic components (about 40%) and water (about 60%) [9, 10]. AC is characterized by a unique zonal structure with varying structural and biochemical properties. Generally, the AC is divided into four vertical layers: the superficial zone, the middle zone, the deep zone and the calcified cartilage zones[11]. All these zones have characteristic mechanical behavior for loading stimuli [12]. The ECM of both the transient and permanent cartilage provides physical support for chondrocytes, and acts as a sponge reserving growth factors and other cytokines, which in turn could modulate cell proliferation and differentiation. The ECM is predominantly
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