Connective tissues encompass the major structural constituents of the body. Although seemingly diverse, structurally and functionally they possess

many shared qualities; therefore, they are considered in a single category. Most connective tissues are derived from mesoderm, which form the multipotential mesenchyme from which bone, cartilage, tendons, ligaments, capsules, blood and hematopoietic cells,and lymphoid cells develop. Functionally, connective tissues serve in support, defense, transport, storage, and repair, among others. Connective tissues, unlike epithelia, are composed mainly of

•extracellular elements and

•a limited number of cells.

They are classified mostly on the basis of their nonliving components rather than on their cellular constituents. Although the precise ordering of the various subtypes differs from author to author, the following categories are generally accepted:

•Embryonic connective tissues

Mesenchymal

Mucous

•Adult connective tissues

Connective tissue proper

Loose (areolar)

Reticular

Adipose

Dense irregular

Dense regular

-Collagenous

-Elastic

•Specialized connective tissues

Supporting tissues

Cartilage

Bone

Blood

EXTRACELLULAR MATRIX

The extracellular matrix of connective tissue proper may be subdivided into fibers, amorphous ground substance, and extracellular fluid.

Fibers

Three types of fibers are recognized histologically: collagen, reticular, and elastic.

•Collagen, the most abundant of the fibers, is inelastic

and is composed of a staggered array of the protein tropocollagen, composed of three α chains. Interestingly, every third amino acid is glycine, and a significant amount of proline, hydroxyproline, lysine, and hydroxylysine constitutes much of the tropocollagen subunit.

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Since glycine is a very small amino acid, the three α chains can form a tight helix as they wrap around each other.

The hydrogen bonds of hydroxyproline residues of individual α chains hold the three chains together to maintain the stability of the tropocollagen molecule.

Hydroxylysine residues hold the tropocollagen molecules to each other to form collagen fibrils.

Currently, there are at least 25 different types of collagens that are known, depending on the amino acid composition of their α chains. The most common collagens are

type I (dermis, bone, capsules of organs, fibrocartilage, dentin, cementum),

type II (hyaline and elastic cartilages),

type III (reticular fibers),

type IV (lamina densa of the basal lamina),

type V (placenta), and

type VII (anchoring fibrils of the basal lamina).

With the exception of type IV, all collagen fibers display a 67-nm periodicity as the result of the specific arrangement of the tropocollagen molecules.

Synthesis of collagen occurs on the rough endoplasmic reticulum (RER), where polysomes possess different mRNAs coding for the three α chains (preprocollagens).

Within the RER cisternae, specific proline and lysine residues are hydroxylated, and hydroxylysine residues are glycosylated.

Each α chain possesses propeptides (telopeptides) located at both amino and carboxyl ends. These propeptides are responsible for the precise alignment of the α chains, resulting in the formation of the triple helical procollagen molecule.

Coatomer-coated transfer vesicles convey the procollagen molecules to the Golgi apparatus for modification, mostly the addition of carbohydrate side chains. Subsequent to transfer to the trans-Golgi network, the procollagen molecule is exocytosed (via non–clathrin- coated vesicles), and the propeptides are cleaved by the enzyme procollagen peptidase, resulting in the formation of tropocollagen.

Tropocollagen molecules self-assemble, forming fibrils with 67-nm characteristic banding (see Graphic 3-1). Type IV collagen is composed of procollagen rather than tropocollagen subunits, hence the absence of periodicity and fibril formation in this type of collagen.

•Reticular fibers (once believed to have different composition) are thin, branching, carbohydrate-coated fibers composed of type III collagen that form delicate networks around smooth muscle cells, certain epithelial cells, adipocytes, nerve fibers, and blood vessels.

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They also constitute the structural framework of certain organs, such as the liver and the spleen.

As a result of the carbohydrate coat, when stained with silver stain, the silver preferentially deposits on these fibers giving them a brown to black appearance in the light microscope.

•Elastic fibers, as their name implies, are highly elastic and may be stretched to about 150% of their resting length without breaking.

They are composed of an amorphous protein, elastin, surrounded by a microfibrillar component, consisting of fibrillin.

The elasticity of elastin is due to its lysine content in that four lysine molecules, each belonging to a different elastin chain, form covalent desmosine crosslinks with one another.

These links are highly deformable and can stretch as tensile forces are applied to them. Once the tensile force ceases, the elastic fibers return to their resting length.

Elastic fibers do not display a periodicity and are found in regions of the body that require considerable flexibility and elasticity.

Amorphous Ground Substance

The amorphous ground substance constitutes the gellike matrix in which the fibers and cells are embedded and through which extracellular fluid diffuses. Ground substance is composed of glycosaminoglycans (GAGs), proteoglycans, and glycoproteins.

• Glycosaminoglycans (GAGs) are linear polymers of repeating disaccharides, one of which is always a hexosamine and the other is a hexuronic acid. All of the GAGs, with the exception of hyaluronic acid, are sulfated and, thus, possess a predominantly negative charge. The major GAGs constituents are hyaluronic acid, chondroitin 4-sulfate, chondroitin 6-sulfate, dermatan sulfate, and heparan sulfate (see Table 3-1).

•Proteoglycans are composed of a protein core to which GAGs are covalently bound. Many of these proteoglycan molecules are also linked to hyaluronic acid, forming massive molecules, such as aggregans aggregate, of enormous electrochemical domains that attract osmotically active cations (e.g., Na+), forming hydrated molecules that provide a gel-like consistency to connective tissue proper and function in resisting