PROGRESS IN HERITABLE SOFT CONNECTIVE TISSUE DISEASES

Contents
Editor and Contributors
	About the Editor
	Contributors
1: Introduction
	References
2: Basic Structure, Physiology, and Biochemistry of Connective Tissues and Extracellular Matrix Collagens
	2.1	 Introduction
	2.2	 Collagens
	2.3	 Fibril-Forming Collagens
	2.4	 Fibril-Associated Collagens with Interrupted Triple Helices
	2.5	 Basement Membrane Collagen
	2.6	 Beaded Filament-Forming Collagen
	2.7	 Hexagonal Network-Forming Collagen
	2.8	 Transmembrane Collagens
	2.9	 Procollagen Synthesis, Collagen Fibril Assembly, Growth and Maturation
	2.10	 Triple Helix Assembly and the Impact of Primary Structure on Secondary, Tertiary, and Quaternary Structures
	2.11	 Collagen Fibril Assembly
	2.12	 Assembly and Growth of Mature Tendon Fibrils
	2.13	 Regulation of Collagen Fibril Assembly and Growth
	2.14	 Effects of Composition and Structure on Function for Tendons and Ligaments
	2.15	 Effect of Anatomical Location on Tendons and Ligaments
	2.16	 Roles of Collagens in Transition from Midsubstance to Enthesis in Tendons and Ligaments
	2.17	 Collagen in Repair
	2.18	 Summary
	References
3: Tendon Extracellular Matrix Assembly, Maintenance and Dysregulation Throughout Life
	3.1	 Introduction
		3.1.1	 Tendon Composition, Structure, and Function
		3.1.2	 Function-Based Variations in Tendon Composition and Structure
		3.1.3	 Tendon Cell Populations
	3.2	 Postnatal Development
		3.2.1	 Collagen Fibril Formation
		3.2.2	 Post-formation Assembly
		3.2.3	 Regulators of Matrix Growth and Development
			3.2.3.1	 Water Structures
			3.2.3.2	 Surface-Associated Proteoglycans
			3.2.3.3	 pN-Collagen
			3.2.3.4	 Minor Collagens
			3.2.3.5	 Elastin, Fibrillins, and Fibulins
			3.2.3.6	 Thrombospondins
	3.3	 Maintenance of the Matrix During Adulthood
		3.3.1	 Matrix Turnover
			3.3.1.1	 Collagenous Matrix
			3.3.1.2	 Non-collagenous Matrix
		3.3.2	 Mechanical Stimulation for Matrix Remodeling
			3.3.2.1	 Exercise
			3.3.2.2	 Disuse or Stress Deprivation
			3.3.2.3	 Sub-failure Microdamage
		3.3.3	 Biochemical Disruption of Matrix Homeostasis
		3.3.4	 Circadian Regulation
	3.4	 Dysregulation of ECM Structure and Function During Aging
		3.4.1	 Changes to Matrix Structure and Function with Age
		3.4.2	 Matrix Turnover in Aged Tendons
		3.4.3	 Aging-Associated Changes in Cell Function Affecting Matrix Homeostasis
			3.4.3.1	 DNA Damage and Matrix Turnover
			3.4.3.2	 Mitochondrial Dysfunction and Oxidative Stress
			3.4.3.3	 Cellular Senescence and SASP in Matrix Degradation
			3.4.3.4	 Tendon Stem Cell Exhaustion and Matrix Repair
			3.4.3.5	 Altered Intercellular Communication and Mechanosensing
	3.5	 Novel Systems and Tools to Study ECM Maintenance and Regulation
		3.5.1	 In Vitro Model Systems
		3.5.2	 In Vivo Model Systems
		3.5.3	 Tools for Labelling Collagen Turnover
			3.5.3.1	 Collagen-Binding Protein Labels
			3.5.3.2	 Bio-orthogonal Labels
			3.5.3.3	 ECM Proteins Conjugated to Labels
			3.5.3.4	 Endogenous Labels
			3.5.3.5	 Collagen Hybridizing Peptide
	3.6	 Conclusions and Avenues for Future Work
	References
4: Basic Components of Connective Tissues and Extracellular Matrix: Fibronectin, Fibrinogen, Laminin, Elastin, Fibrillins, Fibulins, Matrilins, Tenascins and Thrombospondins
	4.1	 Fibronectin
	4.2	 Fibrinogen
	4.3	 Laminins
	4.4	 Elastin
	4.5	 Fibrillins
	4.6	 Latent-TGFβ-Binding Proteins (LTBPs)
	4.7	 Fibulins
	4.8	 Matrilins
	4.9	 Tenascins
		4.9.1	 Tenascin-X
		4.9.2	 Tenascin-C
	4.10	 Thrombospondins
		4.10.1	 Cartilage Oligomeric Matrix Protein (COMP) or Thrombospondin-5
	References
5: Proteoglycans and Diseases of Soft Tissues
	References
6: Growth Factor Roles in Soft Tissue Physiology and Pathophysiology
	6.1	 Basics of Tendon Repair
	6.2	 Transforming Growth Factor β (TGFβ) Family
	6.3	 Fibroblast Growth Factors
	6.4	 Role of IGF-I in Tendon Healing
	6.5	 PDGF
	6.6	 VEGF
	6.7	 Other Modalities
	6.8	 Epilogue
	References
7: Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-β Signaling
	7.1	 Introduction
	7.2	 TGF-β, Signaling Pathways, and Physiological Effects
		7.2.1	 “Canonical” TGF-β Signaling
		7.2.2	 Alternate “Noncanonical” TGF-β Signaling
		7.2.3	 Cellular Responses to TGF-β Signaling
	7.3	 TGF-β Signaling and Connective Tissue Disorders
		7.3.1	 Ehlers-Danlos Syndrome
		7.3.2	 Familial Thoracic Aortic Aneurysm and Dissection Syndrome (FTAAD)
		7.3.3	 Shprintzen-Goldberg Syndrome (SGS)
		7.3.4	 Hereditary Hemorrhagic Telangiectasia (HHT)
		7.3.5	 Other Connective Tissue Disorders with TGF-β Involvement
	7.4	 TGF-β-Directed Therapy as a Prime Target for Connective Tissue Disorders
	7.5	 Genetic Testing
		7.5.1	 Genetic Testing for FTAAD
		7.5.2	 Genetic Testing for SGS
		7.5.3	 Genetic Testing for HHT
	7.6	 Summary
	References
8: Pathophysiology and Pathogenesis of Marfan Syndrome
	8.1	 Introduction
		8.1.1	 History and Overview
		8.1.2	 Identification of the Primary Genetic Defect
	8.2	 Diagnosis and Clinical Presentation
		8.2.1	 Diagnostic Criteria
		8.2.2	 Clinical Presentation of MFS
			8.2.2.1	 Musculoskeletal Manifestations
			8.2.2.2	 Ocular and Craniofacial Manifestations
			8.2.2.3	 Neurologic Manifestations
			8.2.2.4	 Pulmonary Manifestations
			8.2.2.5	 Cutaneous Findings
			8.2.2.6	 Cardiovascular Manifestations
	8.3	 Molecular Pathogenesis
		8.3.1	 Mouse Models of MFS
		8.3.2	 Identification of Disease Mechanisms
	8.4	 Genetic Testing and Patient Management
		8.4.1	 Genetic Testing
		8.4.2	 Management and Treatment of MFS in the Pediatric Population
		8.4.3	 Management and Treatment of MFS in the Adult Population
		8.4.4	 Cardiovascular Management
			8.4.4.1	 Imaging Surveillance
			8.4.4.2	 Surgical Management
			8.4.4.3	 Mitral Valve Repair
			8.4.4.4	 Treatment of MFS in Pregnancy
	8.5	 Clinical Trials
	8.6	 Conclusions
	References
9: Ehlers-Danlos Syndromes, Joint Hypermobility and Hypermobility Spectrum Disorders
	9.1	 Introduction
	9.2	 Historical Overview
		9.2.1	 Original Description and the Berlin Nosology (1986)
		9.2.2	 Villefranche Nosology (1997)
		9.2.3	 The Beginning of the Twenty-First Century
		9.2.4	 International Classification (2017)
		9.2.5	 The Present
	9.3	 Joint Hypermobility
		9.3.1	 Definition
		9.3.2	 Epidemiology
		9.3.3	 Patterns
		9.3.4	 Clinical Measurements
		9.3.5	 Secondary Musculoskeletal Manifestations
	9.4	 The “Spectrum” and Hypermobility Spectrum Disorders
	9.5	 Joint Hypermobility-Related Co-Morbidities
	9.6	 Molecular Pathogenesis of Ehlers-Danlos Syndromes
		9.6.1	 Collagen Biogenesis
		9.6.2	 Other Constituents of the Extracellular Matrix
	9.7	 Diagnosis
	9.8	 Structure of the TNXB-Surrounding Genomic Region and TNXB Analysis
	9.9	 Principles of Management
		9.9.1	 Mucocutaneous Manifestations and Tissue Fragility
		9.9.2	 Secondary Musculoskeletal Manifestations
		9.9.3	 Cardiovascular Manifestations
		9.9.4	 Reduced Bone Mass
		9.9.5	 Pregnancy and Anesthesiology
		9.9.6	 Joint Hypermobility-Related Co-Morbidities
	References
10: Ehlers Danlos Syndrome with Glycosaminoglycan Abnormalities
	10.1	 Introduction
	10.2	 Background
	10.3	 Spondylodysplastic EDS (spEDS)
		10.3.1	 EDS, Spondylodysplastic Type 1 (EDSSPD1, spEDS-B4GALT7, MIM#130070)
			10.3.1.1	 Clinical Manifestations
			10.3.1.2	 Genetic Information
			10.3.1.3	 Biochemical Characteristics
		10.3.2	 EDS, Spondylodysplastic Type 2 (EDSSPD2, spEDS-B3GALT6, MIM#615349)
			10.3.2.1	 Clinical Manifestations
			10.3.2.2	 Genetic Information
			10.3.2.3	 Biochemical Characteristics
			10.3.2.4	 Pathology
	10.4	 Musculocontractural EDS (mcEDS)
		10.4.1	 EDS, Musculocontractural Type 1 (mcEDS-CHST14, MIM#601776)
			10.4.1.1	 Clinical Manifestations
			10.4.1.2	 Genetic Information
			10.4.1.3	 Biochemical Information
			10.4.1.4	 Pathophysiology
		10.4.2	 EDS, Musculocontractural Type 2 (mcEDS-DSE, MIM#615539)
			10.4.2.1	 Clinical Manifestations
			10.4.2.2	 Genetic Information
			10.4.2.3	 Biochemical Information
	References
11: Loeys-Dietz Syndrome
	11.1	 Introduction
	11.2	 Inheritance and Mutational Spectrum
	11.3	 Signs and Symptoms
		11.3.1	 Cardiovascular Manifestations
		11.3.2	 Skeletal Manifestations
		11.3.3	 (Cranio)Facial Manifestations
		11.3.4	 Cutaneous Manifestations
		11.3.5	 Other Findings
	11.4	 The Expanding Spectrum of LDS and Closely Related Disease
	11.5	 Diagnostic Criteria for LDS
	11.6	 Differential Diagnosis
		11.6.1	 Syndromic Differential Diagnosis
			11.6.1.1	 Ehlers-Danlos Syndrome
			11.6.1.2	 Arterial Tortuosity Syndrome and Autosomal Recessive Cutis Laxa Type 1
			11.6.1.3	 Meester-Loeys Syndrome
		11.6.2	 Non-syndromic Differential Diagnosis
	11.7	 Pathology
	11.8	 Biochemical Defects and Pathogenesis
	11.9	 Treatment and Management
		11.9.1	 Natural History
		11.9.2	 Medical Treatment
		11.9.3	 Surgical Treatment
	11.10	 Genetic Counselling
	References
12: Meester-Loeys Syndrome
	12.1	 Introduction
	12.2	 Genetics
	12.3	 Clinical Features
		12.3.1	 Cardiovascular Manifestations
		12.3.2	 Skeletal Manifestations
		12.3.3	 Craniofacial Manifestations
		12.3.4	 Cutaneous Manifestations
		12.3.5	 Neurological Manifestations
	12.4	 Diagnostic Criteria for MRLS
	12.5	 Differential Diagnosis
	12.6	 Biglycan
	12.7	 Pathogenesis
	12.8	 Treatment and Management
	12.9	 Genetic Counseling
	12.10	 SEMDX
	References
13: Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis
	13.1	 Introduction
	13.2	 Clinical Delineation of Cutis Laxa Syndromes
		13.2.1	 CL Entities Due to Defects in Extracellular Matrix Proteins
			13.2.1.1	 ELN-related Autosomal Dominant Cutis Laxa
			13.2.1.2	 FBLN4/EFEMP2 -related Cutis Laxa
			13.2.1.3	 Arterial Tortuosity Syndrome
			13.2.1.4	 FBLN5-related Cutis Laxa
			13.2.1.5	 LTBP4-related Cutis Laxa (Urban-Rifkin-Davis Syndrome)
		13.2.2	 Neurometabolic Cutis Laxa Syndromes
			13.2.2.1	 CL Entities Due to Defects in Cellular Trafficking
			13.2.2.2	 Mitochondrial CL Disorders
		13.2.3	 Acquired Cutis Laxa
	13.3	 Diagnosis of Cutis Laxa Syndromes
		13.3.1	 Histological and Ultrastructural Findings in Cutis Laxa Syndromes
		13.3.2	 Differential Diagnosis of Related Entities Presenting with CL-like Features (Table 13.2)
			13.3.2.1	 Related Entities
			13.3.2.2	 Congenital Malformation Syndromes Associated with Cutis Laxa
	13.4	 Animal Models for Cutis Laxa Syndromes
		13.4.1	 Mouse Models for CL Syndromes Caused by Defects in Extracellular matrix Proteins
		13.4.2	 Zebrafish: An Emerging Model System for CL Syndromes
	13.5	 Pathophysiology of Cutis Laxa Syndromes: State of the Art
		13.5.1	 Mutations in Extracellular Matrix Proteins
		13.5.2	 Mutations Affecting Intracellular Trafficking
		13.5.3	 Mutations Affecting Metabolism and Mitochondrial Functioning
	13.6	 Avenues in Cutis Laxa Research
	References
14: Collagen VI Muscle Disorders: Mutation Types, Pathogenic Mechanisms and Approaches to Therapy
	14.1	 Introduction
	14.2	 Collagen VI Structure and Assembly
		14.2.1	 Clinical Features
	14.3	 Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy
		14.3.1	 Clinical Features
		14.3.2	 Mouse Models Suggest Broader Tissue Involvement
	14.4	 Collagen VI Mutations: An Overview and Update
		14.4.1	 Premature Stop Codons and Haploinsufficiency
		14.4.2	 Triple Helical Glycine Substitutions
		14.4.3	 In-Frame Deletions in the Triple Helix
		14.4.4	 Mutations in the N- and C-terminal Globular Regions
		14.4.5	 A Common Deep Intronic Mutation Causes UCMD
	14.5	 Pathogenic Mechanisms and Potential Targeted Therapies
		14.5.1	 Genetic Approaches
		14.5.2	 Targeting Mitochondrial Abnormalities, Apoptosis and Autophagy
	14.6	 Endotrophin: A Bioactive Collagen VI Peptide
	14.7	 Conclusions
	References
15: Connective Tissue Disorders in Domestic Animals
	References
Index