Extracellular matrix – structure and function

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The Extracellular Matrix (ECM) is a complex, non-cellular, three-dimensional network of macromolecules and minerals secreted by cells (primarily fibroblasts in most connective tissues). It fills the intercellular space and provides essential structural support, mechanical strength, and biochemical cues to the surrounding cells and tissues. The ECM is the major component of most connective tissues, unlike epithelial, muscle, and nervous tissues, which are largely made up of cells.

Structure and Components

The composition of the ECM varies significantly between different tissue types (e.g., bone, cartilage, tendon, skin), reflecting the specific functional requirements of that tissue. However, it is primarily composed of three major classes of biomolecules: fibrous proteins, ground substance (composed mainly of proteoglycans and GAGs), and adhesive glycoproteins.

1. Fibrous Structural Proteins

These proteins provide tensile strength and elasticity.

• Collagen: The most abundant protein in the human body and the ECM.
  • Structure: It is a fibrous protein that forms a characteristic triple-helical structure.
  • Function: Provides tissues with tremendous tensile strength (resistance to stretching) and structural support.
  • Types: There are over 29 types. Type I is the most common (found in skin, bone, tendons). Type II is found in cartilage. Type III is a major component of reticular fibers and blood vessels. Type IV forms the mesh-like network of the Basement Membrane.
• Elastin:
  • Structure: Forms elastic fibers by being cross-linked into a meshwork, often associated with the glycoprotein fibrillin.
  • Function: Imparts elasticity and resilience to tissues, allowing them to stretch and recoil (return to their original shape) without permanent deformation. Essential in blood vessel walls, skin, and lungs.

2. Ground Substance

This amorphous, hydrated, gel-like material resists compressive forces and acts as a medium for nutrient and waste diffusion.

• Glycosaminoglycans (GAGs): Long, unbranched, linear polysaccharides composed of repeating disaccharide units, typically with a high negative charge due to sulfate and carboxyl groups.
  • Function: The negative charge attracts positively charged ions (like $\text{Na}^{+}$) which, in turn, draws large amounts of water into the matrix via osmosis, creating the turgor or swelling pressure that makes the ECM resistant to compression.
  • Hyaluronic Acid (Hyaluronan): A notable exception among GAGs, as it is extremely long, unsulfated, and generally does not attach to a core protein to form a proteoglycan. It is abundant in load-bearing joints.
• Proteoglycans (PGs): Consist of a core protein covalently attached to one or more GAG chains (e.g., chondroitin sulfate, heparan sulfate).
  • Function: They create the hydrated, gel-like substance of the ground matrix. They can also serve as reservoirs for growth factors and help regulate cellular signaling. Aggrecan is a large, key proteoglycan in cartilage.

3. Adhesive Glycoproteins

These molecules help anchor the cells to the matrix and organize the ECM components.

• Fibronectin: A large glycoprotein present in the interstitial matrix.
  • Function: Acts as a 'bridge,' facilitating the adhesion of cells to the matrix by binding to both collagen and cell surface receptors (like integrins). It also helps organize the matrix itself.
• Laminin: A major component of the Basement Membrane (BM).
  • Function: Binds cell receptors on the basal side of epithelial cells to the collagen Type IV and proteoglycans of the BM, playing a crucial role in establishing and maintaining tissue structure and filtering functions (e.g., in the kidney).

Functions of the Extracellular Matrix

The ECM is a dynamic and active environment, not just an inert scaffold. Its roles are both mechanical (structural) and instructive (biochemical).

Category	Specific Functions	Explanation/Mechanism
Structural Support	Tensile Strength and Elasticity	Provided by collagen (strength) and elastin (recoil). Determines tissue mechanics.
Mechanical Resistance	Resistance to Compression	Achieved by the highly hydrated, gel-like ground substance (GAGs/Proteoglycans).
Cell Adhesion & Migration	Anchorage and Motility	Adhesive glycoproteins (Fibronectin, Laminin) bind cells to the matrix via integrins, guiding cell movement during development and wound healing.
Signaling and Regulation	Growth Factor Reservoir	Proteoglycans can bind and sequester growth factors, releasing them in a controlled manner to regulate cell proliferation, differentiation, and gene expression.
Tissue Architecture	Polarity and Organization	The basement membrane, a specialized ECM, is critical for organizing epithelial cells and providing a physical barrier and filtering function.

Clinical Significance

Alterations in ECM composition or remodeling are fundamental to many disease states:

• Marfan Syndrome: A genetic defect in the fibrillin-1 protein (a component of elastic fibers), leading to weakened elastic tissues, particularly in the aorta, eyes, and skeletal system.
• Scurvy: A deficiency in Vitamin C (ascorbic acid), which is a required cofactor for enzymes that hydroxylate proline and lysine residues in collagen. This prevents the formation of a stable collagen triple helix, leading to weak connective tissue and symptoms like bleeding gums and poor wound healing.
• Ehlers-Danlos Syndrome (EDS): A group of genetic disorders, often related to defects in collagen synthesis, processing, or structure, resulting in overly flexible joints and fragile, stretchy skin.
• Fibrosis and Cancer: Excessive or disordered deposition of ECM components (e.g., collagen) leads to organ fibrosis (scarring). In cancer, the ECM microenvironment is often remodeled to be stiff, which promotes tumor cell growth, migration, and metastasis.