Connective Tissue Flashcards
Dense regular connective tissue is composed of fibroblasts and collagen fibers that are highly organized. The internal structure, and high density of collagen fibers (with relatively few cells), gives this type of connective tissue great tensile strength (defined as the force required to pull something to the point where it breaks).
Examples: tendons, ligaments, deep fascia
Cartilage is a specialized type of connective tissue that contains unique cells (chondrocytes).
The extracellular matrix, known as ground substance, is relatively collagen-poor; instead, it is 75% water, with the rest composed predominantly of proteoglycans and glycoproteins. These components give cartilage its classic basophilic appearance.
There are three major types of cartilage:
- Hyaline cartilage is the most common type, and is the one shown
- Elastic cartilage contains elastic fibers interspersed with the ground substance, and is found at sites where both elasticity and strength are needed, such as the external ear
- Fibrocartilage contains type I collagen fibers in the ground substance that provide added strength, at the expense of flexibility. It is found in the intervertebral disks of the spine
Zinc poisoning
Interferes with Copper’s catalysis and can thus phenocopy Copper deficiency
Zinc competes with copper for the coenzyme site, however it cannot catalyze the lysyl oxidase reaction
Major components of connective tissue
The major cellular component of connective tissue is the fibroblast. They may not be the only cells present within connective tissue, or even make up the majority of the cells. However, they synthesize the extracellular components of the connective tissue: collagen (the primary extracellular matrix component, present in all types of connective tissue in varying types and amounts) as well as elastin, glycosaminoglycans, proteoglycans and glycoproteins.
Loose connective tissue is predominantly cellular and contains relatively little extracellular matrix. The cellular components of loose connective tissue can vary, and may include lymphocytes, plasma cells and mast cells. This structure allows for diffusion of oxygen, nutrients and metabolites, and for supporting immune reactions.
Examples: lamina propria, fat (very little collagen in adipose tissue)
Capillaries are the smallest blood vessels, and are responsible for nutrient exchange between blood and tissue.
The walls of capillaries do not have the layered structure that larger vessels do. Instead, a thin layer of endothelium is present, which may contain fenestrations that promote exchange. (Some capillaries have fenestrated endothelium; others do not.) Surrounding the endothelium are a layer of fibroblast-like cells called pericytes. These cells are poorly understood, but may have contractile function. There is no smooth muscle present, no true media, and no adventitia.
Dense irregular connective tissue has an internal structure that is more random than dense regular connective tissue. In the image attached, note how the eosinophilic collagen bundles travel in many different directions.
Functions to provide resistance to excessive stretch and structural support for epithelia. However, the more haphazard internal organization allows space for other structures to pass through, dense irregular connective tissue typically has numerous blood vessels, nerves, and other elements coursing between the collagen fibers – unlike dense regular CT, which has a limited blood supply.
Examples: dermis, submucosa
Types of connective tissue
The major distinguishing features of the different types are (a) the relative representation of cells and extracellular matrix and (b) the arrangement of collagen bundles
Unique types of connective tissue also include cartilage and bone.
Small, valved lymphatic
Lymphatics drain excess extracellular fluid from tissue and return it to the blood. Although they are not technically blood vessels (they shouldn’t carry blood, unless there has been bleeding into the tissue), they are similar in structure to vessels.
The smallest lymphatic vessels (“lymphatic capillaries”) are similar to blood vessels, but are even more permeable (this makes sense; they have to exchange fluid with surrounding tissue, not just specific nutrients). The endothelium is extremely thin, the basement membrane is attenuated, and there are no pericytes.
Mast cells are another cell type frequently found within connective tissue. They are large (20-30 μm diameter) and contain abundant cytoplasmic granules. The granules contain histamine as well as other substances that play important roles in inflammation and, in particular, in allergic responses (anaphylaxis).
As blood travels further from the heart, elastic arteries give way to muscular arteries. In these vessels, the relative size of the media and adventitia varies, but in general, the adventitia is similar to or larger in thickness than the media (in contrast to elastic arteries). The media consists mostly of smooth muscle (hence the name), with relatively little connective tissue present. While elastin is present, it is organized into two continuous layers: the internal elastic lamina, at the junction of the intima and media, and the external elastic lamina, at the junction of the media and adventitia.
The increased amount of muscle in the vessel wall (relative to elastin) allows these vessels to regulate their diameter, and thus regulate blood flow to the tissue, to a much greater degree than elastic arteries.
Collagen Synthesis
Prolyl hydroxylase and lysyl hydroxylase are responsible for adding the hydroxyl groups post-translationally within the ER.
Both prolyl and lysyl hydroxylase require ascorbate (vitamin C) as a cofactor. If vitamin C becomes deficient, then interchain hydrogen bonds cannot form and chains can’t be crosslinked properly. This causes the clinical syndrome of scurvy, associated with poor wound healing, easy brusing, and in severe cases, connective tissue breakdown.
Fat (also known as adipose tissue) is also a type of loose connective tissue. Although it appears cell-poor, most of the lipid is actually contained within the fat cells (adipocytes), and there is very little collagen present.
Fat is an active tissue, and hormones secreted by adipocytes are important regulators of metabolism
Venous valve
Veins have to return blood to the heart without the benefit of any propulsive force (the “push” provided by the heart has long since petered out by the time blood reaches the venous circulation) and, in the lower half of the body, have to do so against gravity. Valves are delicate filaments of elastic connective tissue, lined by endothelium, that project from the intima of the vessel wall. The free edges project in the direction of blood flow. If blood “tries” to flow backward, the valve leaflets will appose each other and close off the vein.
Elastic arteries
The largest blood vessels, such as the aorta, are known as elastic arteries. The wall of these vessels is mostly media, with relatively little intima or adventitia; it is so thick that diffusion from the lumen isn’t sufficient to provide nutrition, so it has its own blood vessels to ensure a nutrient supply, known as the vasa vasorum, which run in the adventitia.
The walls of large elastic arteries contain numerous elastin fibers, arranged in multiple layers stacked throughout the media. This gives the wall great elasticity, which is necessary for its function – these vessels are located nearest the heart, and absorb the full brunt of its pulsatile flow.
Collagen Crosslinking
Although collagen fibrils assemble spontaneously, they are held together by non-covalent interactions and, therefore, are not very stable. The final step in collagen synthesis is formation of covalent crosslinks between neighboring collagen molecules via their hydroxylysine residues, a step catalyzed by the enzyme lysyl oxidase. The links stabilize the polymers, resulting in the formation of mature collagen fibrils.
Lysyl oxidase is one of several enzymes that require copper as part of their active site, so copper deficiency will also result in impairment of connective tissue synthesis.
Extracellular Assembly of Tropocollagen
In the extracellular matrix, procollagen is cleaved by procollagen peptidases to remove the amino- and carboxy-terminal peptides (which do not form helical structure), leaving only the triple-helical portion (known as tropocollagen).
In the fibril-forming collagens (types I, II and III), tropocollagen monomers spontaneously assemble into fibrils – they form a parallel array, with each molecule overlapping with approximately three-fourths of its neighbor.
Elastin Crosslinking
After being secreted into the extracellular space, elastin forms a complex with other matrix proteins (most notably fibrillin) which create a scaffold. Then, through a reaction catalyzed by lysyl oxidase, four lysine side chains combine to form a ring with three double bonds, known as desmosine. The desmosines crosslink the elastin monomers into fibers, and allow the elastin fiber to stretch under stress and return to its relaxed state when the stress is removed.
Assembly of Collagen Triple Helix Intracellulary
Once post-translationally hydroxylated, three collagen alpha chains assemble into a triple helix, known as procollagen. The triple helix is held together by formation of disulfide bonds between cysteine residues near the C-terminus of the alpha chains.
The procollagen molecule is then packaged into vesicles, and secreted from the fibroblast into the extracellular space.
Larger lymphatics are similar in structure to veins, including the presence of valves. The largest lymphatics have some amount of smooth muscle in the wall (as do large veins). However, unlike veins, the layers are poorly defined.
the largest lymphatics ultimately merge to form the thoracic duct, which drains into the venous circulation and thus returns the lymphatic fluid to the blood.
Plasma cells are immune cells frequently found in connective tissue, particularly within the GI tract.
They can be identified by their eccentric (off-center) nucleus, basophilic cytoplasm (this is unusual – cytoplasm is usually eosinophilic), and area of clearing right next to the nucleus (called a “hof”, from the German for court). The nuclear chromatin is often in a highly condensed “clock-face” pattern, as in the image attached.
Plasma cells have one function and one function only – to secrete antibody
Collagen
It is the most abundant protein in the human body, and is found in all types of connective tissue in varying amounts, and with different subtypes found in different kinds of CT.
Collagen is synthesized by fibroblasts. There are many different types (more than 25), but all have the same fundamental structure of three polypeptides (α chains) wound around each other in a triple helix.
In the major structrural collagens (types I, II and III), collagen proteins further organize into long, rope-like polymers called fibrils. Other types (like type IV, the major collagenous component of the basement membrane) form more of a meshwork.
Tunica intima: The endothelium
Tunica media: Consists of a mixture of dense irregular connective tissue and smooth muscle. The relative amounts of connective tissue versus muscle, and the amount and organization of elastin fibers present (if any), reflects the function of the vessel
Tunica adventitia: Consists of loose connective tissue, in some cases including adipose tissue
Elastin fibers in connective tissue (resorcin fuchsin stain)
Elastin is an extracellular protein that is found in connective tissue with elastic properties, such as the walls of the alveoli in the lung, certain blood vessels, and elastic cartilage. Elastin fibers can be difficult to see on H&E stain, so special stains are often used to visualize them
Molecular Sequence of Collagen
Collagen has a unique amino acid sequence. It is rich in proline and glycine. Specifically, every third residue is glycine, and the residue two amino acids down from the glycine (and immediately before the next glycine) is either a proline or lysine residue which is hydroxylated (a post-translational modification). (The amino acid between the glycine and the hydroxylated residue is frequently proline, but it is not hydroxylated).
The structural properties of collagen stem directly from its amino acid sequence. Glycine, which lacks a side chain, gives the polypeptide chain the flexibility to bend without steric hindrance, and the proline residues create “kinks” in the chain. The hydroxylated proline and lysine residues create inter-chain hydrogen bonds which are essential to stabilizing the triple helix.
Cortical bone
Unlike cartilage, which is avascular and relies on diffusion to provide nutrients to the chondrocytes, bone has a complex internal vascular system. The cells, called osteocytes, are found in lacunae, which are connected by canaliculi
Bone vasculation diagram
Layers of cortical bone are arranged concentrically to form osteons, also known as Haversian systems. At the center of each osteon is a channel, the Haversian canal, through which blood vessels run. Volkmann’s canals run perpendicular to and connect the Haversian canals and also contain blood vessels, forming an extensive vascular network that ensures that the blood supply will not be disrupted if there is local injury.
Veins
Since pressures are lower on the venous side of the circulation than on the arterial side and flow is non-pulsatile, the walls of veins are thinner than those of comparably sized arteries, and contain far less elastic tissue (a poorly developed internal elastic lamina may be seen in the largest veins, but in general you won’t see one)
Veins are usually collapsed in tissue sections, since the wall is too thin to resist the pressure generated by the surrounding tissue fluid, while arteries usually appear open. The adventitia of veins is of variable thickness, and is usually continuous with the connective tissue around it.
Ehlers-Danlos syndrome
Overly flexible and elastic skin and joints caused by poor collagen formation. Numerous genes involved in collagen synthesis and expression may be involved in this disease.
Concerns include torn ligaments, torn tendons, blood vessel rupture, kidney disease, etc.
Smaller muscular arteries (getting even further away from the heart, and closer to the capillary beds) lose their external elastic laminae, although the internal elastic lamina is usually retained.
Otherwise, they are similar in structure to large muscular arteries: the media consists mostly of smooth muscle, while the adventitia is of variable thickness and contains mostly loose connective tissue.
Bone
Its extracellular matrix (called osteoid) is reinforced by addition of an inorganic (mineral) component, calcium hydroxyapatite, which gives it the ability to withstand mechanical stress.
The histologic appearance of bone on H&E stained sections is misleading, since to cut it into sections thin enough to be viewed under a microscope, the bone first has to be decalcified, which removes the mineral component (which is quite basophilic) and leaves behind the eosinophilic collagen-rich matrix
Cortical bone is cylindrical, with a rigid outer shell of bone, while in trabecular bone, the bone is arranged in a three-dimensional lattice with intersecting rods and columns
