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CONNECTIVE TISSUE - Coggle Diagram

- - - - Lamina Lucida:
        Clear zone; rich in integrins, glycoproteins, and integral membrane proteins produced by epithelial cells
      - Lamina Densa:
        Darker zone; rich in Type IV collagen filaments
    - - Variable thickness;
        
        composed of reticular fibers (Type III collagen) and Type VII collagen anchoring fibrils (which link to Lamina Densa)
  - - - type IV collagen + lamin bind entactin + perlecan
      - integrins of epithelial cells bind basal lamina
- - - - Forces nutrient- and oxygen-rich fluid out of the permeable capillary wall into the surrounding connective tissue and epithelia.
    - - As fluid exits at the arterial end, large blood proteins like albumin cannot diffuse out and become highly concentrated inside the capillary.
        
        This concentration creates oncotic pressure (colloid osmotic pressure due to non-diffusible blood proteins).
        
        Mechanism: The high oncotic pressure draws waste-laden interstitial fluid back into the venous capillaries and venules, returning it to the general venous circulation.
  - - - Removal via Lymphatics:
        This remaining fluid, containing various cellular waste elements, is collected by lymphatic capillaries (blind-end capillaries present in the extracellular matrix).
        
        Final Destination:
        The lymphatic system processes this fluid and returns it to the bloodstream, where waste products are ultimately distributed to the lungs and liver for final clearance.
- - - - Composition:
        
        Glycosaminoglycans (GAGs)
        
        Long, unbranched heteropolysaccharides with repeating disaccharide units (Uronic acid + N-acetylated amino sugar)
        
        Properties:
        High negative charge density (from sulfur & carboxyl groups) --> extended rod-like helical conformation --> highly hydrophilic (attracts Na+ and H2O) --> viscous, gelatinous consistency
        
        Hyaluronic Acid (Non-sulfated GAG)
        
        Heaviest and most widespread; exists in monomeric form (not bound to a protein core)
        
        Forms proteoglycan aggregates via link proteins
        
        Synthesized at the cytosolic face of fibroblast plasma membranes
        
        Found in: Dermis, synovial fluid, vitreous humor, umbilical cord (prevents vessel bending), cartilage
        
        Sulfated GAGs (Bound to proteins)
        
        Keratan Sulfates: Type I (cornea), Type II (skeleton, cartilage, bone, intervertebral discs); lacks uronic acid
        
        Chondroitin Sulfates: Present in cartilage, bone, ligaments, tendons, aorta walls
        
        Dermatan Sulfate: Present in dermis, heart valves, blood vessel walls
        
        Heparan Sulfate: Found within basement membranes
        
        Heparin: Found in mast cells (anticoagulant function)
        
        Proteoglycans:
        Core protein axis ("bottle-brush" structure) linked to multiple GAGs via O-glycosidic bonds (at serine/threonine residues via a saccharide bridge)
        
        Key Types:
        
        Aggrecan:
        Typical of cartilage; binds non-covalently to hyaluronic acid to form massive water-retaining aggregates
        
        Versican:
        Widespread in developing tissues and osteoid (bone matrix mineralization)
        
        Syndecan:
        Transmembrane protein on B lymphocytes; helps bone marrow anchoring during differentiation, lost in circulation, re-expressed in plasma cells
        
        Decorin:
        Smallest proteoglycan; regulates type I collagen fibrillogenesis (essential for proper fiber deposition)
        
        Multi-adhesive Glycoproteins:
        
        Predominantly protein core with oligosaccharide chain
        
        facilitates cell-to-matrix anchoring
        
        Key Types:
        
        Laminin:
        
        Found in basal laminae;
        
        anchors epithelial cells via integrins, collagen IV/XVII, and heparan sulfate
        
        Fibronectin:
        
        Dimer linked by disulfide bonds;
        
        most abundant in connective tissue proper;
        
        binds fibroblasts/osteocytes to collagen and integrins
        
        Tenascin:
        
        Involved in embryogenesis and wound healing/repair (absent in normal mature tissues)
        
        Osteopontin:
        
        Located in bone matrix; anchors osteoclasts
        
        Bone serum protein
    - - collagen fibers
        
        Most abundant structural component of connective tissue
        
        Properties: Inelastic and inextensible, but provides high resistance to traction/tensile strength
        
        Capacity: Every mm^2 of collagen can support a weight of about 5 kg
        
        Staining: Eosinophilic (stains pink under optical microscope); appears as wavy structures of variable thickness and undetermined length
        
        Collagen hierarchy:
        
        alpha-chains
        
        Individual left-handed polypeptide chains synthesized inside the cell
        
        Tropocollagen (Triple Helix)
        
        3 alpha-chains twist together into a right-handed triple helix molecule.
        
        arranged head-to-tail in parallel rows with a staggered alignment; this staggering leaves a gap where a tropocollagen subunit is missing, creating "holes" where osmium accumulates in TEM (visible as a depression in SEM)
        
        Diameter of about ~1.5 nm and a length of about 300 nm
        
        Amino Acid Sequence Requirements
        
        Modified Amino Acids: High presence of proline, hydroxyproline, and hydroxylysine
        
        1 more item...
        
        Nature of the Molecule: Properly described as a glycoprotein due to the presence of carbohydrate residues (galactose and glucose) associated with hydroxyproline
        
        Glycine Triplet: Characterized by the repeating sequence Glycine-X-Y (a residue of glycine every three amino acids)
        
        1 more item...
        
        Stabilization Forces:
        
        Secondary/Tertiary structure: Stabilized by intrachain hydrogen bonds between amino acids in peptide bonds
        
        Quaternary structure: Stabilized by interchain hydrogen bonds, covalent bonds, and weak interactions (hydrophobic interactions and Van der Waals forces)
        
        Collagen Fibrils
        
        Secreted tropocollagen units self-assemble outside the cell in a staggered
        
        head-to-tail pattern with axial periodicity (creating the alternating light/dark 67-68 nm striation bands).
        
        Strenght is driven by covalent bonds established between the tropocollagen units of adjacent rows
        
        Collagen Fibers
        
        Multiple collagen fibrils pack tightly together side-by-side to form a classic, wavy collagen fiber (visible under a standard light microscope; stains pink with eosin).
        
        1 more item...
        
        Chain Genetic Diversity:
        
        42 different types of alpha-chains have been identified --> encoded by different genes located on different chromosomes
        
        Homotrimers:
        3 identical alpha-chains
        (e.g., Type II collagen made up of three identical alpha1 chains)
        
        Heterotrimers:
        2/3 genetically distinct alpha-chains
        (e.g., Type I collagen consists of two chains identified as alpha1 and one distinct chain identified as alpha2)
        
        Conformation: Each individual $\alpha$-chain has a left-handed helical winding, but overall they wrap around each other forming a right-handed triple helix
        
        COLLAGEN BIOSYNTHESIS (SYNTHESIS)
        
        Intracellular Phase (Inside the Fibroblast):
        
        Translation: Starts with the translation of the mRNA portion on the ribosomes of the rough endoplasmic reticulum (RER) to form pro-$\alpha$ chains
        .
        
        Propeptides (Registration Peptides): The newly formed chain is not the final $\alpha$-chain, but a prochain $\alpha$ which possesses extra non-helical extensions at both ends ($\text{N-}$ and $\text{C-}$ terminal) containing cysteine residues to form disulfide bridges; their function is to prevent premature intracellular assembly into fibrils
        .
        
        Hydroxylation: Proline and lysine residues undergo hydroxylation inside the cell via prolyl hydroxylase and lysyl hydroxylase enzymes
        .
        
        Glycosylation: Hydroxylysine residues are glycosylated with glucose and galactose
        .
        
        Triple Helix Formation: Disulfide bridges at the terminal ends assist the alignment, allowing the three chains to fold into a triple helix molecule called Procollagen
        .
        
        Exocytosis: Procollagen is packaged and secreted out of the cell into the extracellular matrix
        
        (3) Mandatory Cofactor: Vitamin C (ascorbic acid) acts as an essential antioxidant against these enzymes; lack of Vitamin C blocks the process (causing scurvy)
        
        Extracellular Phase (Outside the Cell)
        
        Cleavage: Specific extracellular enzymes called procollagen peptidases cut the non-helical peptide bonds at the amino-terminal and carboxy-terminal ends
        .
        
        Tropocollagen: The removal of the registration peptides turns the molecule into official tropocollagen
        .
        
        Fibrillogenesis: Cleaved tropocollagen molecules spontaneously self-assemble into staggered rows to form fibrils, which in turn associate to form collagen fibers and fiber bundles
        
        CLASSIFICATION OF COLLAGEN TYPES
        Approximately 29 types of collagen have been identified, each specific to certain connective tissues
        
        Fibrillar Collagens (Types I, II, III, V, XI)
        Molecules aggregate to form distinct structural fibrils with a 68 nm banding pattern
        
        Type I Collagen:
        
        Most common;
        
        poorly glycosylated (only 1% of its residues are glycosylated with galactose);
        
        forms thick fibers and bundles; does not react to PAS reaction
        
        Type II Collagen:
        
        Located in cartilage; associated with Type IX collagen which bridges and anchors separate Type II fibrils to form networks; does not associate into large fibers
        
        Type III Collagen (Reticular Fibers):
        
        Highly glycosylated (~10%);
        
        strongly highlighted by the PAS reaction;
        
        forms delicate meshworks
        
        2. Hexagonal Network-Forming Collagens
        
        Includes Type VIII and Type X collagen
        
        3. Fibril-Associated Collagens (FACITs)
        
        Includes Type IX collagen (acts as a bridging component for Type II fibril networks)
        
        4. Basement Membrane Collagens
        
        Includes Type IV, Type VI, and Type VII collagen;
        found mostly forming non-fibrillar structural meshworks supporting tissue boundaries
        
        5. Unusual Transmembrane Collagens
        
        Type XVII Collagen:
        Transmembrane protein that interacts directly with integrins to stabilize the structure of hemidesmosomes (cell-to-matrix junctions in epithelial basal layers)
        
        Clinical: Bullous Pemphigoid:
        An autoimmune disease characterized by circulating autoantibodies attacking Type XVII collagen in the epidermal basement membrane $\rightarrow$ causes detachment of the epidermis from the underlying dermis, generating bullous lesions
        
        Type XIII Collagen:
        Found localized at the level of focal adhesions
        
        PROTEOLYTIC DEGRADATION
        
        Matrix Renewal:
        All proteins in the body undergo a constant cycle of degradation and resynthesis, allowing for the growth, remodeling, and renewal of tissues; collagen fibers undergo a slow but constant renewal
        
        Matrix Metalloproteinases (MMPs):
        
        A family of zinc-dependent enzymes found in the connective tissue numbered from 1 to 9 that handle proteolytic degradation of the ECM
        
        Collagenase: Degrades native structural collagen types I, II, III, and X
        
        Gelatinase: Degrades previously denatured collagen fragments
        
        Tissue Inhibitors of Metalloproteinases (TIMPs)
        
        A family of proteins that specifically inhibit MMP activity to prevent uncontrolled destruction of the matrix
        
        Regulation during Inflammation:
        TIMPs can be inhibited by specific substances produced by macrophages $\rightarrow$ this allows MMPs to start "digesting" the extracellular matrix fibers, making the matrix looser and more penetrable for immune/allergic cells migrating from the blood
      - reticular fibers
        
        They are actually collagen fibrils (Type III) that detach from a main fiber to attach to another fiber, creating an interconnected system.
        
        Their individual dimensions are below the resolving power of the standard optical microscope.
        
        Network & Tissue
        
        Cytoreticulum: They branch out to form a fine, supporting, three-dimensional meshwork/network.
        
        Stroma:
        the supportive connective tissue framework of an organ or gland
        .
        Parenchyma:
        the functional cellular part of the organ
        
        Highly abundant in hematopoietic and lymphoid organs (such as lymph nodes, spleen, and bone marrow) where they form a soft supporting network.
        .
        in the thymus (though the thymus does not contain proper reticular fibers itself, its supporting network is provided by a cytoreticulum).
        .
        They provide a soft matrix in organs like the liver and kidney.
      - elatic fibers
        
        Great Elasticity --> stretched up to 120% of their initial length.
        
        Deformation: deform like a rubber band when subjected to compressive or tensile forces, and instantly snap back to their original shape and size as soon as the stress stops.
        
        Two Main Components
        
        central Elastin Core
        
        Composed of elastin:
        
        protein rich in proline and glycine
        
        lacking hydroxylysine.
        
        random distribution of hydrophobic glycine molecules causes the elastin chains to coil randomly, allowing the fibers to slide smoothly over each other or stretch.
        
        Desmosine / Isodesmosine:
        
        rare, unique modified amino acid present only in elastin
        
        responsible for creating stable cross-covalent bonds that link 4 separate elastin molecules together (formed between 3 allysine residues and 1 lysine).
        
        Fibrillin Microfibrils Network
        
        outer, surrounding scaffolding made of a fibrillin (protein)
        
        not extensible;
        
        primary function is to guide, anchor, and tightly manage the expansion of the internal elastin core to prevent the fiber from over-stretching and tearing.
        
        Biosynthesis Pathway
        
        Synthesized by fibroblasts and smooth muscle cells.
        .
        Step 1: The cells first produce and deposit the fibrillin microfibrils in series outside the cell, forming a rosary-shaped structural track.
        .
        Step 2: Next, elastin is secreted and deposited directly inside the pre-existing fibrillin microfibril tracks, allowing well-deposited elastic fibers to fully form.
        
        Genetic Defects:
        If a mutation blocks the proper formation of fibrillin microfibrils, the elastin molecules deposit in a completely disorderly fashion, resulting in no efficient elastic fibers.
        
        Morphological Typologies
        
        Elastic Fibers:
        Long, thin branching strands prevalent in elastic ligaments.
        
        Elastin Networks:
        Very thin, delicate webs found close to basement membranes, notably connecting the epidermis to the underlying dermis.
        
        Elastic Sheets / Laminae:
        
        Concentric layers or sheets containing gaps/openings (fenestrated appearance) located inside the walls of blood vessels (especially large elastic arteries like the aorta).
        
        The fenestrations are crucial as they allow the free passage of nutrients and water through the dense wall. These sheets are produced by smooth muscle cells.
        
        CONNECTIVE TISSUE PATHOLOGIES
        
        Marfan Syndrome
        
        Target:
        Alteration of the elastic fibers due to a genetic defect in the synthesis of their structural components (specifically mutating the fibrillin framework).
        
        Clinical Manifestations:
        
        high height
        
        tapered and elongated fingers (arachnodactyly)
        
        severe heart disease (high vulnerability to aortic aneurysms or tears due to the weakening of the elastic laminae).
        
        Ehlers-Danlos Syndrome
        
        Target:
        Caused by an autosomal dominant mutation in one of the genes encoding collagen chains.
        
        Mechanism:
        
        incorrect, flawed aggregation of collagen fiber bundles.
        
        collagen is poorly aggregated, the tissue becomes mechanically fragile, weak, and hyper-delicate.
        
        Clinical Manifestations:
        
        Extreme joint hyperlaxity (e.g., swan-neck thumbs)
        
        severe skin hyperextensibility, and a tendency to manifest abnormal scars.
        
        Lesions can easily occur on the walls of arteries, frequently causing severe internal hemorrhages and death.
        
        Scurvy
        
        Target:
        Nutritional deficiency of Vitamin C (ascorbic acid).
        
        Mechanism:
        Collagen synthesis strictly requires specific enzymes (prolyl hydroxylase and lysyl hydroxylase) to hydroxylate lysines and prolines. These enzymes cannot function without Vitamin C acting as an active antioxidant cofactor. Without hydroxylation, the triple helix of tropocollagen cannot establish stable interchain covalent bonds and completely falls apart.
        
        Clinical Manifestations:
        
        heavily impacts tissues with a rapid collagen turnover rate.
        
        periodontal ligaments (which anchor teeth into the jaw bone) are the very first tissues to suffer from this pathology, rapidly leading to bleeding gums and severe tooth loss.
        
        Historically common among sailors on long ocean crossings lacking fresh fruit