Connective tissue

Connective tissue is the most abundant type of tissue in the body. It serves to connect and support other tissues and also has regulatory and immunologic functions. Connective tissue consists of cells, mainly fibroblasts, and an extracellular matrix (ECM). The specific composition of the ECM determines the biochemical properties of the connective tissue. There are many different types of connective tissue, with loose and dense connective tissue being the most common.

Disorders of connective tissue are discussed in “Connective tissue diseases”

Connective tissue consists of specialized cells that are embedded in the extracellular matrix (ECM). Connective tissue is classified as loose or dense connective tissue depending on the ratio and structure of its components.

• Cells
  • Resident cells (e.g., fibroblasts, fibrocytes): synthesize extracellular matrix
  • Transient cells (e.g., macrophages, neutrophils)
• Extracellular matrix (ECM)
  • Three types of fibers
    • Collagen fibers
    • Reticular fibers
    • Elastic fibers
  • Glycosaminoglycans
  • Proteoglycans
  • Glycoproteins
  • Water

Resident cells

• Fibroblasts (the most common cell type in connective tissue)
  • Origin: derived from mesenchymal stem cells
  • Function: synthesis and organization of the ECM
  • Histological features: spindle-shaped cells arranged in a branching pattern
• Fibrocytes: a fibroblast with low metabolic activity
• Myofibroblasts: contractile hybrid cells with features of both fibroblasts and smooth muscle cells
  • Function: synthesize ECM components and are involved in the proliferative phase of wound healing
  • Histological features: indistinguishable from fibroblasts under the light microscope without immunohistochemical staining for, e.g., actin or desmin
• Chondroblasts and chondrocytes
  • Function: produce and maintain the ECM in cartilage
  • See “Cartilage.”

Transient immune cells

• Immune cells: lymphocytes, plasma cells, macrophages, and mast cells

The extracellular matrix (ECM) is composed of various macromolecules arranged in a three-dimensional structure. Its specific composition determines the biochemical properties of the connective tissue.

Extracellular matrix fibers (connective tissue fibers)

Collagen molecules are the basis of collagen fibers and reticular fibers. They account for the majority of proteins in the ECM, which makes them the most abundant proteins in the human body. Elastic fibers are composed of elastin molecules and can be found together with collagen fibers in tissues that require elasticity in addition to tensile strength, e.g., the lung.

Marfan syndrome is caused by a mutation in the fibrillin gene (FBN1).

Collagen

• Definition
  • A family of glycoproteins synthesized by fibroblasts and secreted (as triple-stranded procollagen) into the extracellular space
  • Collagen is the most ubiquitous and abundant protein in humans.
• Structure: A collagen molecule is a protein with a repeating amino acid sequence (Gly-X-Y)_n.
  • The first amino acid of this triplet is glycine (collagen is comprised of ⅓ glycine).
  • Position X: most commonly proline; (also common: lysine, hydroxylysine)
  • Position Y: most commonly hydroxyproline; (also common: hydroxylysine, lysine)
• Function: organize, strengthen, and provide elasticity to the extracellular matrix
• Types
  • Of the 42 genes coding for collagen chains, 28 types of collagen triple helices can be assembled. ^[1]
  • Some collagen types (e.g., collagen type I, II, III, V, XI) form fibrils while others do not (e.g., collagen type IV, VIII, X).

• Degradation: enzymatic via specific collagenases (zinc-dependent proteinases that belong to the matrix metalloproteinases family)
• Synthesis: Collagens are synthesized at the rough ER (rER) and undergo extensive post-translational modifications.

Type ONE collagen is in bONE.
Type TWO collagen: carTWOlage
Type THREE collagen is deficient in the vascular type of Ehlers-Danlos syndrome (3D = ThreE D).
Type FOUR collagen is under the FLOOR (part of basement membrane).

Vitamin C deficiency leads to scurvy because it impairs hydroxylation of procollagen chains.

Impaired triple helix formation during collagen synthesis is the pathophysiological mechanism of osteogenesis imperfecta.

Ehlers-Danlos syndrome is caused by defective cleavage of procollagen molecules.

Menkes disease occurs as a result of defective cross-linking of tropocollagen.

Elastin

• Definition: : an elastic protein that is a major component of elastic fibers
• Characteristics
  • Rich in the nonhydroxylated amino acids glycine, proline, and lysine, in contrast with the hydroxylated proline and lysine residues (hydroxyproline, hydroxylysine) present in collagen.
  • Provides tissue with elasticity (via alternating α-helices and hydrophobic domains)
  • Elastin has a spontaneous, disorganized spatial structure (relaxed conformation) that temporarily adopts an orderly arrangement only when stretched.
• Occurrence: tissues requiring high elasticity and the ability to recoil after a transient stretch
  • Large arteries (e.g., aorta)
  • Lungs
  • Skin
  • Vocal folds
  • Elastic ligaments (e.g., the ligamenta flava, which connect the vertebrae and can adopt both relaxed and stretched conformations).
• Synthesis: Several elastin molecules are crosslinked (polymerization) and form bundles as elastic fibers.
  • Fibrillin forms the scaffold for laying down tropoelastin.
  • Desmosine, a pyridinium ring formed by the condensation of four lysine residues, forms the crosslink between tropoelastin molecules.
    • Cross-linking between tropoelastin occurs extracellularly
    • Formed with the aid of transglutaminase and lysyl oxidase.
• Degradation: enzymatically via elastase (elastase inhibition by α₁-antitrypsin)

Defective α1-antitrypsin leads to increased elastase activity, resulting in the autosomal codominant disorder α1-antitrypsin deficiency, which is characterized by panacinar emphysema and cirrhosis.

Normal aging involves decreased levels of dermal collagen and elastin as well as decreased synthesis of collagen fibrils. Crosslinking is not affected by aging.

Glycosaminoglycans (GAGs)

• Definition: a family of unbranched polysaccharide chains of repeating disaccharide units with multiple negative charges that constitute a large volume fraction of the ECM
• Structure: polymer of repeating disaccharide units
  • First sugar: derivative of uronic acid (e.g., glucuronic acid)
  • Second sugar: hexosamine (e.g., the amino sugar N-acetylglucosamine)
• Four main groups
  • Hyaluronic acid
  • Chondroitin sulfate and dermatan sulfate
  • Heparan sulfate
  • Keratan sulfate
• Function
  • Bind H₂O in connective tissue due to its negative charges: act as a cushion
  • Component of proteoglycans

Proteoglycans

• Definition: proteins with numerous covalently linked GAG side chains
• Function
  • Bind H₂O → shock absorption and a supportive function (e.g., in cartilage → resistance to compression of articular cartilage)
  • Formation of cell-cell junction or cell-matrix junction
  • Further signaling and regulatory functions (e.g., by binding signaling molecules)
• Examples
  • Aggrecan: large proteoglycan found in cartilage as an aggregate with hyaluronic acid → shock absorption withstands compression
  • Decorin: small proteoglycan that binds collagen fibrils → regulates fibril assembly

Glycoproteins of the ECM

• Definition: proteins with short carbohydrate side chains that contribute to the organization of the extracellular matrix by offering specific binding sites for cells and other matrix molecules
• Examples
  • Fibronectin
    • Glycoprotein important for cell-matrix interactions
    • Function: binds to collagen and integrins and plays an important role in embryogenesis (regulates cell migration) and hemostasis (cross-linking of fibrin molecules with thrombocytes and fibroblasts)
  • Laminin
    • Major component and organizer of the basal lamina (besides type IV collagen)
    • Function: binds to collagens, integrins, and proteoglycans

Proteoglycans are primarily composed of carbohydrates that are attached to the side of a small core protein. In contrast, glycoproteins are mainly composed of a protein that is attached to the side chain of a short carbohydrate.

This section describes additional structures surrounding skeletal muscles that minimize friction during movement and maximize the transfer of force.

Ligaments

• See “Synovial joints” in “Joints.”

Tendon

• See “Tendon” in “Muscle tissue.”

Synovial bursa

• See “Synovial joints” in “Joints.”

Fascia

• Definition: a thin layer of connective tissue that separates muscles and organs from other body structures
• Function
  • Supports and protects muscles and internal organs
  • Reduces friction between muscles and is well-innervated to facilitate proprioception and nociception
• Types
  • Deep fascia: surrounds individual muscles and forms fascial compartments
  • Visceral fascia: holds organs in their cavities and encloses organs in layers of connective tissue
  • Superficial fascia: thin layer of loose connective tissue that lies directly beneath the skin

Muscle tissue

• See “Muscle tissue.”

Cartilage

• See “Cartilage.”

Bone tissue

• See “Bone tissue.”

• Fibrosis: the proliferation of fibroblasts and deposition of collagen in tissues
  • Can be a result of a reparative process (e.g., following injury, inflammation, and/or necrosis): e.g., cirrhosis, retroperitoneal fibrosis
    OR
  • Can be a result of a reaction to chronic irritants (e.g., pneumoconiosis, chronic lymphedema)
• Marfan syndrome
• Ehlers-Danlos syndrome
• Menkes disease
• Osteogenesis imperfecta
• Scurvy
• Connective tissue diseases
• Wound healing
• Fibroma