Case 23- Cartilage Flashcards
Connective tissue
- Connective tissue (CT) arises from mesoderm. Mesoderm forms mesenchyme which is embryonic connective tissue
- Consists of cells positioned far apart and surrounded by the extracellular matrix (ECM)
- Fibroblasts are major cell type of CT
- Cell type and ECM components depend on type of CT. All CT has the same basic structure
- Types of connective tissue- cartilage and bone, blood, adipose and lymph. Blood and lymph are a type of specialised connective tissue
What causes the functional differences in connective tissue
Depends on the specific organisation of its constituents:
• Extracellular matrix components= fibre types: Collagen and elastin (produced by fibroblasts). Also have ground substance (water and glycosaminoglycans), this is the liquid part of the extracellular matrix
• Cells: Fibroblasts, osteocytes (bones), chondrocytes (cartilage), adipocytes (fat). Immune cells- mast cells, plasma cells and macrophages
Ending blast and cyte
- blast= immature cell type
- cyte- mature cell type
Function of connective tissue- overview
Function can be protective and structural as well as connective. For example, tendon and ligament are connective but bone is structural. CT components depend on location and function.
Typical connective tissue structure
- Epithelium
- Basement membrane
- Fibroblasts
- Elastin
- Macrophage- immune cell which contributes to connective tissue
- Adipocyte
- Reticulin (type III collagen)
- Ground substance- surrounds the cells and fibres
- Plasma cell
- Mast cell
- Collagen- produced by fibroblasts, beneath the epithelium and basement
Typical connective tissue structure
- Epithelium
- Basement membrane
- Fibroblasts
- Elastin
- Macrophage- immune cell which contributes to connective tissue
- Adipocyte
- Reticulin (type III collagen)
- Ground substance- surrounds the cells and fibres
- Plasma cell
- Mast cell
- Collagen- produced by fibroblasts, beneath the epithelium and basement
Connective tissue cell types
- Fibroblasts- Synthesise extracellular matrix, collagen, elastin
- Osteoblasts (immature form of osteocyte)- Synthesise bone matrix, the osteoblast mature into osteocytes and get trapped within the bone
- Chondrocytes- Synthesise cartilage matrix
- Mesenchymal cell- Undifferentiated stem cells, found in the embryo and adults
- Adipocytes- White/brown
- Immune cells- Mast cells, macrophages, plasma cells
Fibroblasts
- Immature cells
- Produce extracellular matrix, collagen and elastic fibres
- Mobile and undifferentiated
- Proliferate in response to injury
Fibrocytes- inactive fibroblast
Mature cell, maintains tissue
Collagen fibre
- Fibres of extracellular matrix
- Produced by fibroblasts
- 28 types including 5 common types (I-V)
- Type I: Triple helix– tropocollagen. High tensile strength so found in tendons
Elastic fibres
- Elastin is an extensible protein
- It allows body tissues to spring back into shape i.e. lungs, skin, bladder
- Low turnover as we age- wrinkles
Two components of Elastic fibres
- Central core- loosely cross linked elastin fibres
* Glycoprotein outer coat- Microfibrils (fibrillin)
Types of soft connective tissue
- Loose (low collagen)- areolar, adipose (unilocular/multilocular), reticular (liver/endocrine/glands/ spleen/ lymph nodes), synovial
- Dense (high collagen)- regular i.e. tendon/ ligaments/ joint/ capsule. Irregular i.e. dermis
Skeletal connective tissue
- Cartilage- hyaline (smooth, on the articular surface of bones), elastic, fibrocartilage
- Bone (calcified ECM- solidified by osteoblasts)- woven (immature), haversian (mature)
- Dental (mineralised)- dentine, enamel
Specialised/Mesenchyme CT
Specialised CT- blood/lymphoid
Mesenchyme (embryonic)
Soft connective tissue- loose aereolar connective tissue
- Areolar = “small open space”
- Subcutaneous CT
- Areolar CT can be described as packing material
- Also transports gases from blood vessels to tissues
- Lots of ground substance and fibroblasts- causes lots of open spaces
Categories of adipose tissue
Can define the type of adipose tissue by the number of locules (small compartments) per cell. White adipose is unilocular so only has one compartment (fat droplet) per cell whilst brown adipose is multilocular so there are multiple fat droplets per cell.
Adipose connective tissue (loose)- White adipose (unilocular)
- Contains CT fibres (e.g. reticulin)
- Subcutaneous
- Each cell contains one fat droplet
Adipose connective tissue (loose)- Brown adipose (multilocular)
- Multiple fat droplets
- Contains many mitochondria
- Energy release - heat
- High levels in neonates, infants
Synovial membrane- soft CT
- Loose soft connective tissue
- Lines non-articular surfaces in joints
- A form of connective tissue which is made of other types of connective tissue
- Secretes synovial fluid (blood plasma, hyaloronan and glycoproteins)
- Thin outerlayer (intima)- composed of macrophages or fibroblasts
- Vacularised inner layer (subintima)- composed of loose areolar, loose fibrous or adipose.
Reticular connective tissue- soft CT
- Loose connective tissue
- Found in liver endocrine glands, lymph nodes, spleen
- Made of a network of fine collagen III fibres (reticulin)
Dense regular connective tissue
- e.g tendon, ligament
- Tendons have a lot of type 1 collagen, high tensile strength. Type of Soft, dense, regular connective tissue
- Found in fibrous joint capsule and the gums
- Lots of collagen
- Ordered, linear structure
- Formation requires vitamin C
Scurvy
Lack of vitamin C, reduced collagen in the gums. Teeth fall out
Dense irregular connective tissue
- Collagen Fibres arranged in irregular pattern
- Fibroblasts
- Small amount of ECM
- E.g deep dermis
Types of skeletal connective tissue
• Dental- dentine, enamel
• Bone- woven (immature), Haversian (mature)
• Cartilage - Hyaline (Articular, respiratory, growth plates)
- Fibrocartilage (joints, intervertebral discs)
- Elastic (Epiglottis, Ear, Larynx)
Structure of cartilage
- Cell types- Chondroblasts, immature cells which synthesise the matrix
- Perichondrium- outer layer of cartilage
- Matrix
- Chondrocytes- mature form of the chondroblasts which are stuck in the matrix
- Lipid droplets
Hyaline cartilage
- Location- Articular surfaces. Supporting rings in the respiratory system (cricoid cartilage around the trachea), Nasal cartilage and Developing bones (epiphyseal/growth plates). The long bones grow from epiphyseal/growth plates
- Articular cartilage, found on the surface of joints
- High level of water in the ground substance
- Smooth surface (Glassy)
- Function- Rigid but flexible, resistant to compression (contains water)
Elastic cartilage
- Epiglottis, Ear, Larynx
- Composition- Chondrocytes are the cell type. Collagen fibres are in the perichondrium on the outer surface of the cartilage, bundles of elastic fibres (elastin) in the matrix which is within the elastic fibres. Surrounded by extracellular matrix
- Lots of elastin fibres
Elastic cartilage
- Epiglottis, Ear, Larynx
- Composition- Chondrocytes are the cell type. Collagen fibres are in the perichondrium on the outer surface of the cartilage, bundles of elastic fibres (elastin) in the matrix which is within the elastic fibres. Surrounded by extracellular matrix
- Lots of elastin fibres
Fibrocartilage- joints
- Acetabular labrum (hip joint)
- Glenoid labrum (shoulder joint)
- Menisci (knee joint)- on proximal surface of the tibia, allowing it to articulate with the fibula
- Pubic symphysis
- Intervertebral discs
Cartilage
A modified form of connective tissue. There are three types hyaline, elastic and fibrocartilage
Cartilage is composed of
- Cells- chondrocytes, that produce a large amount of collagenous ECM
- ECM (extracellular matrix)- mainly proteoglycan and collagen/elastic fibres
The 2 main extracellular components of cartilage
- Fibrous proteins- predominantly type II collagen which confers mechanical stability
- GAG- which resists deformation by compressive forces
Cartilage structure
- Collagen fibres are thin and arranged in an interwoven lattice
- This merges with ECM of adjacent support tissues
- Major GAG are: hyaluronic acid, chondroitin sulphate, keratin sulphate bound to a core protein called AGGRECAN forming a large proteoglycan.
Proteoglycans and Collagen fibres
Proteoglycans= GAG’s attached to core proteins. Flexibility or resilience to compressive forces. Major component is chondroitin sulphate
Collagen fibres- provide rigidity and tensile strength. Composed of type II, IX, X and XI collagen
Cartilage- percentages
- Unusual protein – 30% glycine, 30% proline/hydroxyproline; also contains hydroxylysine
- Adult articular cartilage consists of 2/3 by dry weight collagen
- Made up of many tropocollagen molecules aggregated together = insoluble
Hyaline cartilage summary
- Contains type II collagen only.
- In fetal development it forms the temporary skeleton until replaced by bone
- In childhood it forms the growing points of long bones, the articular surface in joints and in the respiratory system acts as a support tissue
Fibrocartilage
- Contains both type II and type I collagen
* Component of intervertebral discs, tendon attachments to bones + junctions between flat bones of the pelvis
Elastic cartilage
- Contains elastic fibres in addition to type II collagen
* Located in the auricle of the ear, walls of external auditory canal, Eustachian tubes and epiglottis of the larynx
What is a proteoglycan
- A protein core heavily glycosylated with multiple glycosaminoglycan (GAG) subunits (instead of simple sugar units)
- A subclass of glycosylated proteins which are found primarily in the extracellular matrix, particularly as part of the cartilage
- GAG: long chain unbranched polysaccharide of repeating disaccharide subunits
- Contains one Amino sugar (N-acetylglucosamine or N-acetylgalactosamine) which is known as an aminoglycan along with a uronic sugar or galactose. The aminoglycan contains an N atom instead of an OH molecule.
- Key component of the ECM including the cartilage
Basic structure of proteoglycans
- Protein core- contains a number of serine residues, contains many hundreds of GAG subunits, has a ‘brush’ like structure. Linear protein. The majority of the protein is the carbohydrate protrusions
- Tetrasaccharide linkage- a sugar linkage unit
- Glycosaminoglycan- disaccharide subunit containing an N-acetylated sugar and a Uronic acid. The disaccharide subunit is repeated multiple times and is the main component of the Proteoglycan
Functions of Proteoglycans
- In cartilage they provide some of the shock absorbent features
- Structural features within the eye
Proteoglycans
- GAG is attached to a core protein via an O linkage (i.e. serine)
- Made primarily in the ER/Golgi
- There extension occurs extracellularly but they start off as most glycoproteins
- May be sulfonated- addition of heparin/heparan sulphate
- Highly polar (-ve charge)- due to additions
- Attracts water, swelling to +30 volume of dry weight… important in function. By adjusting the amount of proteoglycan you adjust the amount of water in the tissue. In cartilage the water is trapped within a cellular matrix of collagen
- Forms a gel like substance
- Water can move in/out with compression/decompression of the joint. Provides protection from compression events
Hyaluronic acid (Hyaluronan)
- Unique GAG, synthesised on the plasma membrane. A large chain carbohydrate. Made up of repeating disaccharide subunits
- Secreted into the extracellular environment, at this stage it is not associated with proteins (not a glycoprotein)
- V.large
- Found throughout connective, epithelial and neural tissues
- Major component of synovial fluid (lubricant)
- Proteoglycan associate with Hyaluronan, forms the matrix of the gel like substance found within the cartilage. Many hundreds of proteoglycans attach
- HAPLN1 (hyaluronanic acid and proteoglycans link protein 1)- the protein associated with the attachment of proteoglycan and Hyaluronan
Articular cartilage
- Function of the cartilage reflects composition
- The cartilage between spinal disks
- The main proteoglycan in cartilage is AGGRECAN (core protein)
- Aggregates with Hyaluronan and collagen to form the ECM which is found within the cartilage
- The collagen net constrains the aggrecan/Hyaluronan gel, prevents the gel from expanding beyond the cartilage disk
- Acts against compressive force (shock absorbing)
Function of articular cartilage
- Each proteoglycan attracts water around it to form a hydration shell
- The hydration shell is a result of the GAG subunits, the hydration shell expands beyond the protein
- Hydration shells repel each other- preventing excessive compression damaging the cartilage
- Swelling function is limited by cartilagous mesh
Compression- articular cartilage
- Compressive forces ‘squeeze’ cartilage and water moves out. The wait at which the water moves out determines the degree of force that counteracts the compression.
- The degree of porosity determines the rate at which water moves out into surrounding tissue
- The degree of porosity= % of proteoglycans
- Results in moving into the surrounding tissue slowly
- Cartilage deforms slowly- due to the control in the movement of water
- ‘dampening effect’ of the compressive forces
How cartilage composition affects function
Different types of cartilage are made up of differing percentage of collagen, proteoglycan and water. The centre of cartilage is the most resistant to compression as it has the most amount of water and the outside is the least resistant as it has the least amount of water
Aggrecan function in cartilage
- The load bearing properties of cartilage are provided by the tensile properties of the collagen fibre network and the osmotic swelling pressure of the high concentration of aggrecan. The collagen holds the gel together
- The aggrecan is immobilised within the matrix by forming supramolecular aggregates with hyaluronan and link proteins
Proteoglycan functionality and composition
- Can vary with type of glycosylation (change type of sugar)/sulfanation (affects charge)
- The core protein can vary
- Degree of saturation i.e. the amount of water which is absorbed which is affected by the number of proteoglycans and the degree of glycosylation
- Age- less proteoglycan, degree of degradation
Proteoglycan functionality and composition: core protein
- Aggrecan: cartilage
- Brevican: CNS role
- Neurocan: Cell adhesion, implicated in bipolar disorders
- Versican: cell adhesion, migration and proliferation
- All these proteins are members of the lectican protein family with a chondroitin sulfate chain which is a type of GAG chain which is heavily sulfonated
Other functions of proteoglycans
- Cell adhesion
- DNA regulation
- Nervous system
- Lipid metabolism
- Cell growth
- Basement membrane permeability
- Killer T lymphocytes
- Platelet adhesion to endothelial surfaces
- Dentinogenesis- Ca reservoir
- Tumour suppression
- Amyloid plaque formation- role in dementia
- Embryo implantation
GAG- Hyaluronate
Location- Synovial fluid, articular cartilage, skin, vitreous humour, ECM of loose connective tissue
Comments- Large polymers; molecular weight can reach 1 million Daltons; high shock absorbing character; average person has 15 gm in body; 30% turned over every day; synthesized in plasma membrane by three hyaluronan synthases: HAS1, HAS2, and HAS3
GAG- Chondroitin sulfate
Location- cartilage, bone, heart valves
Function- Most abundant GAG; principally associated with protein to form proteoglycans; the sulfation of chondroitin sulfates occurs on the C-2 position of the uronic acid residues and the C-4 and/or C-6 positions of GalNAc residues; the chondroitin sulfate proteoglycans form a family of molecules called lecticans and includes aggrecan, versican, brevican, and neurcan; major component of the ECM; loss of chondroitin sulfate from cartilage is a major cause of osteoarthritis
GAG- Heparin sulfate
Location- basement membrane, components of cell surfaces
Role- Contains higher acetylated glucosamine than heparin; found associated with protein forming heparan sulfate proteoglycans (HSPG);; HSPG binds numerous ligands such as fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF); HSPG also binds chylomicron remnants at the surface of hepatocytes; HSPG derived from endothelial cells act as anti-coagulant molecules
GAG- Heparin
Location- component of the intracellular granules of mast cells, lines the arteries of the lungs, liver and skin
Role- More sulfated than heparan sulfates; clinically useful as an injectable anticoagulant although the precise role in vivo is likely defence against invading bacteria and foreign substances
GAG- Dermatan sulfate
Location- skin, blood vessels, heart valves, tendons, lung
Role- Sulfation of dermatan sulfates occurs on the C-2 position of the uronic acid residues and the C-4 and/or C-6 positions of GalNAc residues; may function in coagulation, wound repair, fibrosis, and infection; excess accumulation in the mitral valve can result in mitral valve prolapse
GAG- Keratan sulfate
Location- cornea, bone, cartilage aggregated with chondroitin sulfates
Role- Usually associated with protein forming proteoglycans; keratan sulfate proteoglycans include lumican, keratocan, fibromodulin, aggrecan, osteoadherin, and prolargi
Proteoglycan- Aggrecan
Belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); protein core encoded by the ACAN gene; ACAN found on chromosome 15q26.1; forms a complex with hyaluronan; major component of articular cartilage
Proteoglycan- Brevican
Belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); protein core encoded by the BCAN gene; predominantly expressed in the central nervous system; brevican protein devoid of glycosaminoglycan chains is also found within the brain
Proteoglycan- Decorin
Is a member of the small leucine-rich proteoglycan (SLRP) family; protein core encoded by the DCN gene; binds to type I collagen fibrils; also interacts with fibronectin, thrombospondin, the epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-β); may play a role in epithelial/mesenchymal interactions during organ development
Proteoglycan- Keratocan
A keratan sulfate proteoglycan (KSPG); protein core encoded by the KERA gene; is a member of the small leucine-rich proteoglycan (SLRP) family; important to the transparency of the cornea
Proteoglycan- Lumicran
Major keratan sulfate proteoglycan (KSPG); the protein core encoded by the LUM gene; is a member of the small leucine-rich proteoglycan (SLRP) family, also referred to as the small interstitial proteoglycan gene (SIPG) family; present in large quantities in the corneal stroma and in interstitial collagenous matrices of the heart, aorta, skeletal muscle, skin, and intervertebral discs; interacts with collagen fibrils; may regulate collagen fibril organization, corneal transparency, and epithelial cell migration and tissue repair
Proteoglycan- Neurocan
Belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); a nervous system proteoglycan; protein core encoded by the NCAN gene; is a susceptibility factor for bipolar disorder, absence of the NANC gene in mice results in a variety of manic-like behaviors which can be normalized by administration of lithium
Proteoglycan- Perlecan
More commonly called heparan sulfate proteoglycan (HSPG) of basement membrane; protein core encoded by the HSPG2 gene; possesses angiogenic and growth-promoting properties primarily by acting as a coreceptor for fibroblast growth factor 2 (FGF2)
Proteoglycan- Syndecans
A family of cell surface heparan sulfate proteoglycans (HSPGs) that act as transmembrane cell surface receptors; consists of four members: syndecan-1, -2, -3, and -4; aberrant syndecan regulation plays a critical role postnatal tissue repair, inflammation and tumour progression; syndecan-1 expression is prevalent in differentiating plasma cells and its expression can serve as a marker for cells that are secreting immunoglobulin;
Proteoglycan- Versican
Belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); protein core encoded by the VCAN gene alternative splicing generates three versican species designated V0, V1, and V2 that differ in the length of the attached glycosaminoglycans; one of the main components of the ECM; significant proteoglycan in vitreous body of the eye; participates in cell adhesion, proliferation, migration, and angiogenesis; contributes to the development of atherosclerotic vascular diseases, cancer, tendon remodeling, hair follicle cycling, central nervous system injury, and neurite outgrowth; Wagner syndrome is caused by mutation in the VCAN gene, causes vitroeretinal degeneration
