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Biochemistry · Biochemistry of the Extracellular Matrix

Extracellular matrix

Intercellular matrix is a highly specialized molecular framework of connective tissue (bones, teeth, cartilage, tendons, basement membranes). It not only provides mechanical support for cells, but also ensures strength, cushioning, and selective filtration of substances.

Test your knowledge on this topicAsk the AI
Two componentsThe matrix is formed by two groups of substances: structural proteins and heteropolysaccharides.
Water dynamicsIn the morning, intervertebral discs contain up to 75% water, losing up to 20% under daily load.
Selective filterIn the kidneys, the basement membrane lies between two layers of cells, filtering plasma.
Anchoring fixationType VII collagen firmly "anchors" the epidermis to the underlying dermis, forming loops.
5 min readFor medical studentsUpdated 09/24/2026
Material prepared by WhiteCoat Pro editorial team based on platform study guidesReviewed by medical editor: Aulov A. A., general practitioner · 09/24/2026

Biochemical composition

The properties of any tissue depend on the proportions and precise organization of the two basic components of the intercellular matrix:

  1. Proteins
  2. Collagen forms the main structural framework.
  3. Elastin is responsible for the stretchability and elasticity of the tissue.
  4. Fibronectin acts as a universal adhesive protein.
  5. Laminin is a crucial adhesive component binding cells to subcellular structures (typical of basement membranes).
  1. Heteropolysaccharides
  2. Glycosaminoglycans (GAGs).
  3. Proteoglycans are complex molecules consisting of a core protein and GAG chains.

Basement membranes

Basement membranes are thin layers of matrix that isolate cells (epithelial, endothelial, fat, muscle, Schwann cells) from the surrounding connective tissue.

Under an electron microscope, a two-layer structure of the membrane is visible:

  • Lamina rara (lamina lucida) lies directly adjacent to the cell membrane.
  • Lamina densa (lamina densa) contacts the underlying connective tissue.

Molecular organization: The structural skeleton is formed by type IV collagen, which creates an elastic three-dimensional network. Laminin and heparan sulfate-containing proteoglycans (HSPGs) attach to this network. The sulfated glycoprotein nidogen plays a crucial role. Its polypeptide chain has three globular domains: one firmly binds laminin, and another binds type IV collagen. As a result, nidogen acts as a "linker", forming the ternary complex "laminin — nidogen — collagen".

Functions of basement membranes:

  • Supportive: attachment and strict orientation of cells.
  • Filtration: in the renal tubules, the membrane acts as a semipermeable filter, preventing plasma macromolecules from entering the primary urine.
  • Electrostatic barrier: proteoglycan chains carry a high negative charge. They physically repel negatively charged molecules (such as plasma proteins) and erythrocytes.
  • Regulatory: participation in regeneration and embryogenesis.
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Organization of subepithelial layers

To prevent the epithelial basement membrane from detaching from the connective tissue (stroma/dermis), an "anchoring" mechanism exists. The main organizing element here is type VII collagen.

Dimers of this protein form bundles (anchoring fibrils). With their C-termini, they attach to the dense layer (lamina densa) of the basement membrane and extend deep into the tissue, forming loops.

In the subepidermis, these loops are fixed in two ways:

  1. They attach to "anchoring discs"—specialized matrix densities consisting of type IV collagen.
  2. They enclose interstitial fibrils (types I and III collagen) passing through them.

Biomechanics of articular cartilage

Cartilage must withstand colossal mechanical loads. Its "endoskeleton" (fibrillar network) is formed by types II, IX, and XI collagens. However, the cushioning function rests entirely on water-retaining macromolecules.

Massive high-molecular-weight aggregates of aggrecan and hyaluronic acid are formed in cartilage. The glycosaminoglycan chains within them act as polyanions: they possess numerous acidic groups and a strong negative charge. Due to this, the matrix attracts water (high hydration).

Mechanism of action:

  • During compression, water is physically squeezed out of the matrix. This continues until the internal swelling pressure balances the load.
  • Upon release of the load, decompression occurs, and water rushes back into the cartilage.

Briefly: answers to topical questions

What are the main classes of glycosaminoglycans (GAGs) in the matrix?

The main classes of glycosaminoglycans (GAGs) in the matrix include hyaluronic acid and sulfated GAGs. The classification includes:

  • Hyaluronic acid is non-sulfated.
  • Chondroitin sulfates are sulfated (usually at C4 or C6).
  • Dermatan sulfates are an epimer of chondroitin sulfate, sulfated at C4.
  • Keratan sulfates are the only GAG without uronic acid, sulfated at C6.
  • Heparin is a sulfated GAG.
  • Heparan sulfates contain N- and O-sulfate groups.

All listed GAGs, except hyaluronic acid, contain a sulfate group and are polyanions.

What are the stages of collagen biosynthesis?

The process of collagen formation is divided into two main stages: intracellular (synthesis and modification) and extracellular (maturation and assembly).

Intracellular stages:

  • Synthesis of preprocollagen; the process begins on the ribosomes of the rough endoplasmic reticulum.
  • Cleavage of the signal peptide.
  • Hydroxylation of proline and lysine.
  • For proline hydroxylation, the enzyme prolyl hydroxylase and the cofactor vitamin C are required.
  • Glycosylation.
  • Formation of the triple helix — procollagen.
  • Secretion into the intercellular matrix.

Extracellular stages:

  • In the intercellular matrix, the terminal propeptides (N- and C-) are cleaved by procollagen peptidases.
  • Tropocollagen is formed.
  • Tropocollagen is capable of self-assembly into collagen fibrils: collagen molecules combine into microfibrils, then into mature fibrils.
  • Cross-links are formed.
  • Fibrils aggregate into large bundles; the end product is a collagen fiber.

Which cell surface receptors does fibronectin bind to?

Fibronectin on the cell surface binds to integrins (cellular receptors on the cell membrane). Specifically, fibronectin is a ligand for the following leukocyte $\alpha\beta$-integrins:

  • VLA-4 ($\alpha_4\beta_1$)
  • VLA-5 ($\alpha_5\beta_1$)
  • LPAM-1 ($\alpha_4\beta_7$)

Which enzymes degrade extracellular matrix proteins?

Extracellular matrix proteins are degraded by proteolytic enzymes, which include:

  • Matrix metalloproteinases (MMPs). Collagenase MMP-1 is a Zn²⁺-dependent extracellular matrix enzyme that performs the primary hydrolysis of the native collagen molecule into two fragments: 1/4 and 3/4 of the total length. It is also involved in the degradation of other matrix proteins, such as laminin and fibronectin.
  • Other proteases, including gelatinases, which subsequently act during collagen catabolism for complete hydrolysis into amino acids.
  • Lysosomal proteases, which cleave the resulting triple-helical collagen fragments.
  • Serine proteases are mentioned alongside MMPs as proteolytic enzymes activated in the pathogenesis of the connective tissue cap weakening in atherosclerotic plaques.
How to memorize

The layers of the basement membrane are easy to remember by density logic: first comes the light and sparse lamina rara (Latin for rare, adjacent to the cell), followed by the dense lamina densa (Latin for thick), which rests on the connective tissue.

Class and exam questions

Why does human height change throughout the day?

This is a clinical example of the hydrated matrix of intervertebral discs at work. During the day, under the influence of body weight, water is squeezed out of the cartilage (a loss of about 20%), and height decreases by 1–2 cm. During sleep without load, the water returns. In zero gravity in space, height can increase by 5 cm.

How does the basement membrane function as an electrostatic barrier?

The barrier is provided by proteoglycans carrying a high negative charge. They physically repel negatively charged molecules and cells, preventing the loss of blood plasma proteins and erythrocytes.

What is nidogen and what is its purpose?

This is a sulfated glycoprotein with three globular domains. It acts as a "linker" (binding bridge): it attaches to laminin with one domain and to type IV collagen with the other.

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What else to study on this topic

  • Minor components of cartilage matrix: small proteoglycans, growth factors, and non-collagenous proteins (anchorin, chondroadherin).
  • Structure and functions of the laminin molecule: cell- and matrix-binding sites.
  • Organization of aggrecan and hyaluronic acid molecules in cartilage.
  • The role of the extracellular matrix in embryonic development and tissue regeneration.

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Other topics in the section "Biochemistry of the Extracellular Matrix"

CollagenScurvyMatrix metalloproteinasesElastinGlycosaminoglycansHyaluronic acidProteoglycansFibronectinLaminin
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