Contents
Extracellular Matrix 1
Introduction
This lecture introduces the materials lying outside the cell, known collectively as the extracellular matrix (ECM). There is no one matrix though, with different tissues having their own specific ECM, which may be dynamic or static in structure. In particular the ECM has significant roles in normal tissue development, function and disease. This matrix is manufactured by cells, secreted and modified outside the cell by several different enzymes.
This first lecture introduces the ECM and describes the major fiber (fibre) and matrix components, the second lecture will cover the major ECM glycoproteins and experimental studies of ECM function.
- Spelling - UK sulphate, US sulfate ; UK fibre, US fiber
Lecture Audio
The University has a system for automated recording of lectures called Lectopia. Lectopia requires login using your student number and unipass. I will be adding the link to each iLecture Audio following the Lecture. Due to the automated recording method, most lectures begin 4-5 minutes into MP3 recordings and occasionally stop before the end of the lecture. 2009 All Audio Files
- Lecture 13: Extracellular Matrix 1 Lecture Date: 28-04-2009 Lecture Time: 13:00 Venue: BioMed F Speaker: Mark Hill
Archive
MH - note that content listed below will not match exactly current lecture structure but has been selected as having similar content
- 2008 ANAT3231 Lecture 12/13 Extracellular matrix 1 slide/page (view only) 55 pages, 1.5 Mb | 4 slides/page 14 pages, 740 Kb | 6 slides/page 7 pages, 711 Kb) | slides text 7 pages, 132 Kb
ECM Function
- Support for cells
- Pattern of ECM regulates
- polarity
- cell division
- adhesion
- motility
- Development
- migration
- differentiation
- growth factors
ECM Features
- stable and able to be reorganised?
- different for different tissues
ECM Structure
- Glycoproteins
- Fibers
- Collagen- main fibers
- Elastin
- Hydrated Matrix
- Proteoglycans
- high carbohydrate
- Adhesive
- Laminin
- Fibronectin
Shapes and Sizes ECM molecules
- Note the relative size and differential contribution of protein (green) and glycosaminoglycan (red)
Collagen
- tensile strength and elasticity
- Tendons
- Cartilage
- Bone
- half total body proteins (by weight)
Collagen Components
- Insoluble glycoprotein
- protein + carbohydrate
Protein
- high glycine and 2 modified amino acids
- hydroxylysine
- hydroxyproline
- (gly-X-Y)n
Carbohydrate
- glucose
- galactose
Collagen Structure
Collagen Protein
- 3 polypeptide (a) chains
- left hand helix, forms fibers
- many different (vertebrate) collagens by different combinations of a-chains
- Type I, II, III
- main fibers, flexible
- Type I
- bone, skin, tendons
- 90% of all collagen
- Type II
- cartilage
Collagen Fibers
- Type I, II, III cross striated
- e.g. tendons - type I fibrils, have a 67-nm period striations and are oriented longitudinally (direction of the stress)
- showing overlapping packing of individual collagen molecules
- reticular fibres type III, support individual cells
- Type IV fine unstriated
- sheet-like supportive meshwork
- mature basal laminae
- tracks for embryonic migration
- barriers for cell migration
- Type V-XII
- smaller diameter fibers than I-III
- no striations
Collagen Fibers
Collagen Non-striated
Collage Interactions
Collagen fibril types can interact with a variety of non-fibrous collagen types (microfiber)
- fibrous collagens—types I, II, III, and V
- Cartilage - types II (fiber) and IX collagen microfibrils
- Tendons - type I fibrils bound and linked by type VI microfibrils.
MCB - Interactions of fibrous and nonfibrous collagens
Collagen Type Functions
- Collagen Type I - skin, tendon, vascular, ligature, organs, bone (main component of bone)
- Collagen Type II - cartilage (main component of cartilage)
- Collagen Type III - reticular fibers with type I.
- Collagen Type IV - forms bases of cell basement membrane
MH - You do not need to know the protein table below in detail, just the major type/functions show above.
Collagen Proteins
| Collagen type | Organization in tissues (where known) | References | |
| I | Fibrils in tendon, bone, skin, cornea and blood vessel walls | Chu et al., 1982 | |
| Myers et al., 1981 | |||
| II | Fibrils in cartilage | Miller and Matukas, 1969 | |
| III | Forms heterotypic fibrils with type I collagen | Cameron et al., 2002 | |
| IV | Network in basement membrane | Timpl and Brown, 1996; Timpl et al., 1981 | |
| V | Forms heterotypic fibrils with type I | Birk, 2001 | |
| VI | Fine microfibrils with ubiquitous distribution (distinct from fibrillin- | Kielty et al., 1992 | |
| containing microfibrils | |||
| VII | Forms anchoring fibrils in skin at the dermal/epidermal junction | Keene et al., 1987 | |
| (basement membrane) | |||
| VIII | 3D hexagonal lattice in Descemet's membrane in the eye | Kapoor et al., 1986; Kapoor et al., 1988; | |
| Stephan et al., 2004 | |||
| IX | Associated with type II collagen fibrils | Olsen, 1997; Shimokomaki et al., 1990 | |
| X | Mat-like structure/hexagonal lattice in the hypertrophic zone of the growth plate | Kwan et al., 1991 | |
| XI | Forms heterotypic fibrils with type II | Mendler et al., 1989 | |
| XII | Associated with type I fibrils | Keene et al., 1991; Nishiyama et al., 1994; | |
| Zhang et al., 2003 | |||
| XIII | Transmembrane and possibly involved in cell adhesion | Latvanlehto et al., 2003 | |
| XIV | Associated with type I fibrils | Young et al., 2000b; Young et al., 2002 | |
| XV | Specialized basement membranes, cleaved to produce antiangiogenic | Myers et al., 1996; Ramchandran et al., | |
| fragment (restin) | 1999 | ||
| XVI | Component of specialized fibrillin-rich microfibrils in skin and type II | Kassner et al., 2003 | |
| collagen fibrils in cartilage | |||
| XVII | Transmembrane component of hemidesmosomes (cell-cell junctions), which | Hopkinson et al., 1998 | |
| attach epidermis to basement membrane in skin | |||
| XVIII | Cleaved to produce antiangiogenic fragment (endostatin) | Sasaki et al., 1998 | |
| XIX | Radially distributed aggregates formed by association at one end in vitro | Myers et al., 2003 | |
| XX | May be associated with type I collagen fibrils | Koch et al., 2001 | |
| XXI | May be fibril associated, widespread expression pattern | Fitzgerald and Bateman, 2001 | |
| XXII | Located in specific tissue junctions and may be associated with microfbrils | Koch et al., 2004 | |
| XXIII | Transmembrane collagen identified in cell culture | Banyard et al., 2003 | |
| XXIV | Expressed in tissues containing type I collagen | Koch et al., 2003 | |
| XXV | Transmembrane collagen, cleaved form present in Alzheimer‚ amyloid plaques in neurons | Hashimoto et al., 2002 | |
- Table modified from Canty EG, Kadler KE. Procollagen trafficking, processing and fibrillogenesis. J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53. Review. PMID: 15788652 | JCS Link
Collagen Synthesis
Link: MBoC - The intracellular and extracellular events in the formation of a collagen fibril | MCB - Collagen synthesis |
|
Collagen Diseases
Collagen Diseases - Excess
- fibrosis
- lung- pulmonary fibrosis
- overproduction of collagen I
- liver- over consumption of alcohol
- arteries- atherosclerosis
Collagen Diseases - Insufficient
- Ehlers-Danlos syndrome
- rubber-man
- skin and tendons easily stretched
- contortionists often suffer from this disease
- Osteogenesis imperfecta
- brittle-bone syndrome
- mutation in Type I procollagen
- fail to assemble triple helix
- degrade imperfect collagen
- Leads to fragile bones
- Scurvy
- dietary Vitamin C deficiency
- needed for hydroxylation
- Proline -> Hydroxyproline
- form too few hydrogen bonds in collagen
- skin, bone, teeth weakness and malformation
- blood vessels weakened, bleeding
- Atopic dermatitis (AD)
- chronic inflammatory skin disorder and a major manifestation of allergic disease
- mutation in collagen XXIX (COL29A1) gene
Elastin
- elastin and elastic fibres
- uncoils into an extended conformation when the fiber is stretched
- recoils spontaneously as soon as the stretching force is relaxed
Elastic fibers are composed of a core of cross-linked elastin embedded within a peripheral mantle of microfibrils.
Microfibrils
- may regulate assembly and organization of elastic fibers by acting as a scaffold
- guiding tropoelastin deposition
- aggregates of threadlike filaments
- periodically spaced globular domains (beads) connected by multiple linear arms
- beaded structure is parallel fibrillin monomers aligned head-to-tail
- fibulin-5 induces elastic fiber assembly and maturation by organizing tropoelastin and cross-linking enzymes onto microfibrils PMID: 17371835
Links: MBoC - Collagen and elastin
Elastin Structure
- protein Mr 64 to 66 kDa
- composed of the amino acids glycine, valine, alanine, and proline
- cross-linked tropoelastin monomers
- first secreted as soluble precursors (tropoelastin)
- assembly and crosslinking of tropoelastin monomers
- form insoluble elastin matrix into functional fibres
- lysine residues in the cross-linking domain of secreted tropoelastin rapidly cross-linked (both inter- and intra-molecularly by lysyl oxidase)
- hydrophobic segments - elastic properties
- α-helical segments (alanine- and lysine-rich) - form cross-links between adjacent molecules
Links: Nature - Fibulin-5 is an elastin-binding protein
Elastin Function
- structural integrity and function of tissues
- requiring reversible extensibility or deformability
- high levels in tissues that require elasticity
- lung, skin, major blood vessels
Elastin Disorders
Proteoglycans
MBoC - Proteoglycans in the extracellular matrix of rat cartilage MBoC - Examples of a small (decorin) and a large (aggrecan) proteoglycan found in the extracellular matrix
- consist of protein (~5%) and polysaccharide chain (~95%)
- form a gel to embed the fibril network
- Golgi apparatus - GAG disaccharides are added to protein cores to form proteoglycans
- 10% by weight but fill most of space
- unbranched polysaccharide chains
- disaccharide subunits
- amino sugar
Glycosaminoglycans (Gags)
Five types
- Hyaluronan (or hyaluronic acid) main glycosaminoglycan in connective tissue
- high molecular weight (~ MW 1,000,000 )
- length of about 2.5 µm hyaluronan i
- "backbone" for the assembly of other glycosaminoglycans
- Hyaluronan is also a major component of the synovial fluid, which fills joint cavities, and the vitreous body of the eye.
- Other 4 major glycosaminoglycans
- chondroitin sulphate, dermatan sulphate, keratan sulphate and heparan sulphate (UK sulphate, US sulfate)
- attach through core and link proteins to hyaluronic acid backbone
Proteoglycan Function
- trap water
- resistant to compression
- return to original shape
- occupy space
- link to collagen fibers
- form network
- in bone combined with calcium hydroxyapatite, calcium carbonate
Development
- produce a “cell-free” space
- for cell proliferation and migration into
- heart, cornea
Adult
- in areas of compression
- tissues, joints
Hyaluronan Synthesis
- differs from other GAG synthesis
- synthesized at plasma membranes
- nascent chains directly extruded into ECM
Cell adhesion
embryonic migration
Proteoglycan- Disease
- Mucopolysaccharidosis type I (MPS I) - Hurler disease
- lysosomal storage disease, is associated with an altered elastic matrix
- excess heparan sulphate and dermatan sulphate
- Cancer development
- altered types and kinds of proteoglycans formed by cells
- normal cells -> malignant
- Arthritis
- Cartilage breakdown (cartilage erosion)
- chondrocytes elicit a catabolic response which exceeds anabolism of new matrix molecules
- Degrade proteoglycan (aggrecan)
- Also a mouse model generates antibodies to proteogycan
History
Below are some example historical research finding related to cell junctions from the JCB Archive.
1978 Basal lamina instructs innervation Joshua Sanes and Jack McMahan show that regenerating nerve axons take their cues for new synapse formation from the extracellular matrix (ECM) of muscle cells and not from the muscle cells themselves.
References
Textbooks
Essential Cell Biology
- Essential Cell Biology Chapter 19 p594-604
Molecular Biology of the Cell
Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002
- Molecular Biology of the Cell 4th ed. - V. Cells in Their Social Context Chapter 19. Cell Junctions, Cell Adhesion, and the Extracellular Matrix
- The Extracellular Matrix of Animals
Molecular Cell Biology
Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999
- Molecular Cell Biology - Chapter 22. Integrating Cells into Tissues
- Cell-Matrix Adhesion
The Cell- A Molecular Approach
Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
- The Cell- A Molecular Approach
- The Cell - A Molecular Approach - III. Cell Structure and Function Chapter 12. The Cell Surface
- The Extracellular Matrix
Essentials of Glycobiology, 2nd ed.
Varki, A.; Cummings, R.D.; Esko, J.D.; Freeze, H.H.; Stanley, P.; Bertozzi, C.R.; Hart, G.W.; Etzler, M.E., editors Plainview (NY): Cold Spring Harbor Laboratory Press; 2008
Search Online Textbooks
- "extracellular matrix" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf
- "collagen" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf
- "elastin" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf
- "glycosaminoglycan" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf
Books
PubMed
- PubMed is a service of the U.S. National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals for biomedical articles back to 1948. PubMed includes links to full text articles and other related resources. PubMed
- PubMed Central (PMC) is a free digital archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health (NIH) in the National Library of Medicine (NLM) allowing all users free access to the material in PubMed Central. PMC
- Online Mendelian Inheritance in Man (OMIM) is a comprehensive compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM
- Entrez is the integrated, text-based search and retrieval system used at NCBI for the major databases, including PubMed, Nucleotide and Protein Sequences, Protein Structures, Complete Genomes, Taxonomy, and others Entrez
Search Pubmed
- "extracellular matrix" Entrez all databases
- "collagen" Entrez all databases
- "elastin" Entrez all databases
- "glycosaminoglycan" Entrez all databases
- "proteoglycan" Entrez all databases
- note the spelling differences when carrying out other related ECM searches: UK sulphate, US sulfate ; UK fibre, US fiber
Reviews
Canty EG, Kadler KE. Procollagen trafficking, processing and fibrillogenesis. J Cell Sci. 2005 Apr 1;118(Pt 7):1341-53. Review. PMID: 15788652 JCS Link
- Hay ED. The extracellular matrix in development and regeneration. An interview with Elizabeth D. Hay. Int J Dev Biol. 2004;48(8-9):687-94. No abstract available. PMID: 15558460
- Hay ED. Extracellular matrix. J Cell Biol. 1981 Dec;91(3 Pt 2):205s-223s. Review. No abstract available. PMID: 6172429
- Sandberg LB, Soskel NT, Leslie JG. Elastin structure, biosynthesis, and relation to disease states. N Engl J Med. 1981 Mar 5;304(10):566-79. Review. PMID: 7005671
- Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007 Dec;81(4):229-40. Review. PMID: 18228265
Articles
- Sandberg LB, Soskel NT, Leslie JG. Elastin structure, biosynthesis, and relation to disease states. N Engl J Med. 1981 Mar 5;304(10):566-79. Review.
Links
- Synthesis animated cartoon
- Marfan syndrome is an autosomal dominant disorder that has been linked to the FBN1 gene on chromosome 15. FBN1 encodes a protein called fibrillin
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