Learning Objectives

  • List the major components of connective tissue and the role each plays in the function of connective tissue.
  • List the major resident cells of connective tissue and the function each plays.
  • Diagram the pathway through which collagen is synthesized and assembled into fibers.
  • List the major immune cells that can localize to connective tissue and the function each plays.
  • Compare the contents of tendon and cartilage and how the differences produce biomaterials with different mechanical properties.

Keywords

  • Type I collagen
  • Type II collagen
  • Type III collagen
  • Type IV collagen
  • Elastic fibers
  • Elastin
  • Fibrillin
  • Proteoglycan
  • Glycosaminoglycans
  • Hyaluronan
  • Cartilage
  • Fibroblasts
  • Chondrocytes
  • Collagen fibril
  • Collagen fiber
  • Lysyl oxidase

Pre-Lecture Reading

Overview

Connective tissue performs a wide range of functions and is composed of a mixture of protein fibers, proteoglycans and hyaluronan. The relative amounts of these components determines the function of the connective tissue. Bone and tendon contain predominantly collagen fibers to provide robust mechanical strength, whereas the connective tissue in most other organs has fewer collagen fibers and more proteoglycans. In addition, the connective tissue of most organs contains blood vessels and cells of the immune system to provide metabolic support and protection against foreign pathogens. In most organs, fibroblasts synthesize most components of the connective tissue. Cartilage is a specialized form of connective tissue that is rich in proteoglycans and hyaluronan. Cartilage resists compression and covers the surfaces of most joints.

Types of Connective Tissue

Loose connective tissue is found in most organs and provides mechanical, metabolic and immune support. Loose connective tissue is highly cellular and rich in proteoglycans; it contains fewer collagen fibers. Loose connective tissue controls the diffusion of metabolites and signaling molecules and contains blood vessels and immune cells.

Dense connective tissue is found in the walls of large arteries, dermal layer of skin, tendon and bone. Dense connective tissue contains fewer cells and more collagen fibers. In tendon and bone, the collagen fibers are arranged in very precise order to provide very robust tensile strength.

Components of Connective Tissue

Collagens are the main structural component of connective tissue and they resist tensile or stretching forces. Collagens comprise a large family of proteins of around 40 types but there are four types that are most common.

  • Type I collagen forms fibers and is found in most connective tissues with bone, ligaments, tendon and skin having the high concentrations of type I collagen.
  • Type II collagen forms fibers but are less well organized than type I fibers. They are found mainly in cartilage.
  • Type III collagen forms fibers but these fibers are much thinner than type I. Type III collagen make up reticulin fibers in organs and help organize cells within organs.
  • Type IV collagens form branched networks and help organize the basement membrane.

Fibrous collagens have three levels of organization: trimer, fibril and fiber. Individual collagen polypeptides self-assemble into trimers in the endoplasmic reticulum. Trimers self-assemble into fibrils outside the cell. Covalent crosslinks between trimers increases mechanical strength of collagen fibrils. Some fibrils self-assemble into fibers.

Elastic fibers allow connective tissue to stretch and recoil. The walls of large arteries contain high concentrations of elastin fibers that allow them to stretch during systole and contract during diastole. Elastin is the main functional component of elastic fibers. Elastin protein has little structure and individual proteins are crosslinked into a network. Tensile forces stretch elastin protein into an extended conformation. When tensile force removed, elastin protein returns to disorganized conformation, generating a recoil force.

Proteoglycans form a porous, gel-like substance that controls diffusion of small molecules and resists compressive forces. Proteoglycans are proteins with long sugar side chains. The sugars are repeated disaccharides called glycosaminoglycans. The negative charge of sugars attract Na+ and water. Proteoglycans also bind specific metabolites and signaling molecules to regulate their exposure to surrounding cells.

Hyaluronan is a special glycosaminoglycan that is composed of a long chain of repeated disaccharide and no protein. Hyaluronan can contain up to 25,000 disaccharides, allowing it to occupy a large volume and retain large amounts of water. Hyaluronan is enriched in cartilage.

Resident Cells

Fibroblasts synthesize most components of connective tissue, including collagen, elastic fibers and proteoglycans. Collagen synthesis has key intracellular and extracellular events that are critical for its assembly and mechanical structure. Collagen is synthesized through constitutive secretory pathway. Collagen trimers assemble in ER and each collagen polypeptide has prodomains on N and C termini that prevent trimers from assembling into fibrils within fibroblasts. After release outside cell, enzymes remove prodomains, allowing trimer to assemble into long fibrils. Lysyl oxidase generates covalent crosslinks between trimers in fibrils. Fibrils can also assemble into large fibers.

Elastic fibers consist of elastin and a long, extended protein called fibrillin. Fibrillin forms a template around which elastin assembles to form a functional elastic fiber. Fibrillin also binds some key signaling molecules that regulate cell growth and function.

Mast cells trigger inflammatory response after exposure to allergens and insect bites. Mast cells contain secretory granules filled with heparin, histamine and proteases. Receptors for IgE antibody on the surface of mast cells trigger fusion of secretory vesicles with plasma membrane. Histamine increases permeability of blood vessels and heparin inhibits blood clotting.

Fat cells (adipocytes) store large amounts of triglycerides in a large lipid droplet.

Mesenchymal stem cells are capable of differentiating into all resident cells of connective tissue.

Transient Immune Cells

Transient cells of connective tissue enter from the circulatory system and consist primarily of immune cells. Neutrophils are first line of defense against bacterial infections. They detect and track bacterial proteins and then phagocytose captured bacteria. Neutrophils contain vesicles with lysozyme, proteases and free radicals that fuse with phagosome to destroy bacteria. Macrophages engulf cellular debris and foreign antigens. They have receptors which recognize antigens complexed with antibodies. Macrophages endocytose the antigen complexes and then destroy the engulfed material in their lysosomes. Macrophages can also present foreign material to T-cells to initiate an immune response. Eosinophils are enriched during parasitic infections and lyse parasites. Basophils contain secretory granules with similar content to mast cells.

Cartilage

Cartilage is a specialized form of connective tissue that is found throughout the body, including joints, ear, nose and trachea. Cartilage is avascular and contains type II collagen fibers that are thinner than type I fibers and are very stable. Cartilage is also rich in glycosaminoglycans. Megacomplexes are prominent in cartilage and consist of the proteoglycan aggregan crosslinked to hyaluronan. Megacomplexes retain large amounts of water and help cartilage resist compression. Chondrocytes are the cells of cartilage and synthesize all components of cartilage.

Questions

  1. How would mutations in lysyl oxidase affect collagen?
  2. Answer: A mutation that reduced the activity of lysyl oxidase would make collagen fibrils weaker. Lysyl oxidase generates covalent crosslinks between adjacent collagen trimers. These crosslinks tether trimers to increase the mechanical strength of fibrils.
  3. Where would you expect to find large amount of elastic fibers?
  4. Answer: Elastic fibers allow tissues to stretch and recoil and are found in structures that are subject to rapid changes in pressure. For example, the aorta must accommodate large changes in blood pressure during systole and diastole. Similarly, the walls of the air spaces in the lung are subjected to to rapid changes in air pressure.
  5. Would a mutation in collagen that produced an abnormal proteins likely be a dominant or recessive mutation?
  6. Answer: The mutation would most likely be dominant. A cell that contains wild-type and mutant collagen genes would produce a mix of normal and mutated protein. Both proteins would be randomly incorporated into collagen fibrils so that every fibril would contain some mutated collagen, weakening the fibril and potentially producing some clinical effect.
  7. Type I collagen is found in large amounts in both tendon and the dermal region of skin. In which would you expect collagen fibers to show more order?
  8. Answer: Collagen fibers would show greater order in tendon. Tendon is usually stretched in one direction and the collagen fibers are aligned in that direction. In contrast, skin is stretched in multiple directions, requiring collagen fibers to be arranged in multiple directions.