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 detail in the connective tissue diseases learning card.


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 of the connective tissue

Resident cells

Transient immune cells

Extracellular matrix

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.

Collagen fibers Reticular fibers Elastic fibers
Main molecule
  • Tensile strength
  • Tensile strength with limited elasticity
  • Elasticity
  • Tissues that require high elasticity and the ability to recoil after a transient stretch, e.g., aorta, lung, skin, and vocal folds
Associated proteins
  • Fibrillin
  • Fibulin-5

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


  • Definition: : a family of glycoproteins synthesized by fibroblasts and secreted (as triple-stranded procollagen) into the extracellular space. Collagen is the most ubiquitous 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 (second most common: lysine or hydroxylysine)
    • Position Y: most commonly hydroxyproline (second most common: lysine or hydroxylysine)
  • Types: Out of about 42 genes coding for collagen chains, about 28 types of collagen triple helices can be assembled. Some collagen types form fibrils, e.g., collagen types I, II, III, V, and XI, while others do not, e.g., collagen types IV, VIII, and X.
  • Degradation: enzymatic via specific collagenases
  • Synthesis: Collagens are synthesized at the rough ER (rER).

Collagen types

Collagen types Tissue distribution Related conditions
Type 1 collagen
Type 2 collagen
  • Achondrogenesis (type II)
Type 3 collagen
  • Reticular fibres in skin, blood vessels, granulation tissue, uterus, fetal tissue early embryos and throughout embryogenesis
Type 4 collagen
Type 5 collagen

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

Collagen synthesis

Stages Process Site Intermediate product (precursors of collagen)
1. Translation
  • Synthesis of polypeptide chain (pro-α chain with repeating Gly-X-Y sequence) and further processing
IC (rER) Preprocollagen
2. Hydroxylation
  • Hydroxylation of proline residue to hydroxyproline and of lysine residue to hydroxylysine
IC (rER) Procollagen (pro-α chain)
3. Glycosylation IC (rER)
4. Formation of a triple helix
  • Formation of disulfide bonds and hydrogen bonds between three α-chains to form a triple helix
  • Function: requirement for fibril formation (fibrillogenesis)
IC (rER) Procollagen (triple helix)
5. Exocytosis
  • Exocytosis of the collagen triple helix into the extracellular space
6. Proteolytic processing
  • Cleavage of the procollagen at the C-terminus and N-terminus
  • Function: Collagen molecules become insoluble in water.
EC Tropocollagen
7. Fibrillogenesis (cross-linking)
  • Formation of collagen fibrils: cross-linking of hydroxylysine residues in adjacent tropocollagens
  • Enzyme: copper-dependent lysyl oxidase
  • Function: requirement for subsequent fiber formation
EC Collagen fibrils
8. Formation of fibers EC Collagen fiber (end product)
Abbreviations: IC = intracellular; EC = extracellular; ECM = extracellular matrix; rER = rough endoplasmic reticulum

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.


  • Definition: elastic protein that is a major component of elastic fibers
  • Characteristics
  • Synthesis: several elastin molecules are cross-linked (polymerization) and form bundles as elastic fibers
    • Fibrillin forms the scaffold for laying down tropoelastin
    • Cross-linking between tropoelastin takes place extracellularly with the aid of transglutaminase and lysl oxidase
  • Degradation: enzymatically via elastase (elastase inhibition by α1-antitrypsin)

Defective α1-antitrypsin leads to increased elastase activity, which results in the autosomal recessive disorder α1-antitrypsin deficiency.

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 = a derivative of uronic acid (e.g., glucuronic acid), second sugar = a 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


  • 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 or cell-matrix junction
    • Further signaling and regulatory functions (e.g., by binding signaling molecules)
  • Examples

Glycoproteins of the ECM

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!


Connective tissue types

Type Main components Function Occurrence
Loose connective tissue
  • Structural framework for organs (interstitium)
  • Attaches epithelia to underlying tissue
  • Allows for independent movement
  • Interstitium
  • Most abundant form of connective tissue
Dense connective tissue
  • Provide tensile strength, especially in tissue under mechanical stress
  • Dense regular connective tissue : tendons, ligaments, aponeurosis
  • Dense irregular connective tissue: dermis (stratum reticulare), fascia, dura mater, sclera, cornea, and organ and joint capsules
Reticular connective tissue
Elastic ligaments
  • Provides ligaments with a high level of elasticity
Mucous connective tissue
Stroma of ovary

Clinical significance

  • 1. McKusick VA, Kniffin CL. Achondrogenesis, type II; ACG2. url: Accessed July 16, 2018.
  • 2. Sobreira N, McKusick VA. Ehlers-Danlos Syndrome. Updated May 30, 2018. Accessed July 16, 2018.
  • Alberts B, Johnson A, Lewis J, Morgan D, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. New York: Garland Science; 2014.
last updated 06/18/2019
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