CONNECTIVE TISSUE

4 CONNECTIVE TISSUE




Classification


The connective tissue provides the supportive and connecting framework (or stroma) for all the other tissues of the body. The connective tissue is formed by cells and the extracellular matrix (ECM). The ECM represents a combination of collagens, noncollagenous glycoproteins, and proteoglycans (ground substance) surrounding the cells of connective tissue. The cells of the connective tissue have important roles in the storage of metabolites, immune and inflammatory responses, and tissue repair after injury.


Unlike epithelial cells, which are almost free of intercellular material, connective tissue cells are widely separated by components of the ECM. In addition, epithelial cells lack direct blood and lymphatic supply, whereas connective tissue is directly supplied by blood and lymphatic vessels and nerves.


Connective tissue can be classified into three major groups (Figure 4-1): embryonic connective tissue, adult connective tissue, and special connective tissue.



Embryonic connective tissue is a loose tissue formed during early embryonic development. This type of connective tissue, found primarily in the umbilical cord, consists predominantly of a hydrophilic ECM and therefore has a jellylike consistency. Because of this consistency, it is also called mucoid connective tissue or Wharton’s jelly.


Adult connective tissue has considerable structural diversity because the proportion of cells to fibers and of ground substance varies from tissue to tissue. This variable cell-to-ECM ratio is the basis for the subclassification of adult connective tissue into two types of connective tissue proper




Loose connective tissue contains more cells than collagen fibers and is generally found in the mucosa and submucosa of various organs and surrounding blood vessels, nerves, and muscles. This type of connective tissue facilitates dissection as performed by anatomists, pathologists, and surgeons.


Dense connective tissue contains more collagen fibers than cells. When the collagen fibers are preferentially oriented—as in tendons, ligaments, and the cornea—the tissue is called dense regular connective tissue. When the collagen fibers are randomly oriented—as in the dermis of the skin—the tissue is called dense irregular connective tissue.


In addition, reticular and elastic fibers predominate in irregular connective tissue.


Reticular connective tissue contains reticular fibers, which form the stroma of organs of the lymphoid-immune system (for example, lymph nodes and spleen), the hematopoietic bone marrow, and the liver. This type of connective tissue provides a delicate meshwork to allow passage of cells and fluid.


Elastic connective tissue contains irregularly arranged elastic fibers in ligaments of the vertebral column or concentrically arranged sheets or laminae in the wall of the aorta. This type of connective tissue provides elasticity.


The special connective tissue comprises types of connective tissue with special properties not observed in the embryonic or adult connective tissue proper. There are four types of special connective tissue (Figure 4-2):







Adipose tissue has more cells (called adipose cells or adipocytes) than collagen fibers and ground substance. This type of connective tissue is the most significant energy storage site of the body.


The hematopoietic tissue is found in the marrow of selected bones. This type of connective tissue is discussed in Chapter 6, Blood and Hematopoiesis.


Cartilage and bone are also regarded as special connective tissue but are traditionally placed in separate categories. Essentially, cartilage and bone are dense connective tissues with specialized cells and ground substance. An important difference is that cartilage has a noncalcified ECM, whereas the ECM of bone is calcified. These two types of specialized connective tissue fulfill weight-bearing and mechanical functions that are discussed later (see Cartilage and Bone).



Cell components of connective tissue


The four major cell components of connective tissue are the fibroblast, the macrophage, the mast cell, and the plasma cell.


Under light microscopy, the fibroblast appears as a spindle-shaped cell with an elliptical nucleus. The cytoplasm is very thin and generally not resolved by the light microscope. Under electron microscopy, the fibroblast shows the typical features of a protein-secreting cell: a well-developed rough endoplasmic reticulum and a Golgi apparatus.


The fibroblast synthesizes and continuously secretes mature proteoglycans and glycoproteins and the precursor molecules of various types of collagens and elastin. Different types of collagen proteins and proteoglycans can be recognized as components of the basement membrane. As you may remember, type IV collagen is found in the basal lamina and type III collagen appears in the reticular lamina as a component of reticular fibers (see Boxes 4-A and 4-B). Heparan sulfate proteoglycans and the glycoprotein fibronectin are two additional products of the fibroblast that appear in the basement membrane. The protein collagen is a component of collagen and reticular fibers. However, elastic fibers do not contain collagen.





Collagen: Synthesis, secretion, and assembly


Collagens are generally divided into two categories: fibrillar collagens (forming fibrils with a characteristic banded pattern), and nonfibrillar collagens (see Box 4-C).



The synthesis of collagen starts in the rough endoplasmic reticulum (RER) following the typical pathway of synthesis for export from the cell (Figure 4-3).



Preprocollagen is synthesized with a signal peptide and released as procollagen within the cisterna of the RER. Procollagen consists of three polypeptide a chains, lacking the signal peptide, assembled in a triple helix.


Hydroxyproline and hydroxylysine are typically observed in collagen. Hydroxylation of proline and lysine residues occurs in the RER and requires ascorbic acid (vitamin C) as a cofactor. Inadequate wound healing is characteristic of scurvy, caused by a vitamin C deficiency.


Packaging and secretion of procollagen take place in the Golgi apparatus. Upon secretion of procollagen, the following three events occur in the extracellular space:





Groups of collagen fibers orient along the same axis to form collagen bundles. The formation of collagen bundles is guided by proteoglycans and other glycoproteins, including FACIT (for fibril-associated collagens with interrupted helices) collagens.



Clinical significance: Ehlers-Danlos syndrome


Ehlers-Danlos syndrome is clinically characterized by hyperelasticity of the skin (Figure 4-4) and hypermobility of the joints. The major defect resides in the synthesis, processing, and assembly of collagen. Several clinical subtypes are observed. They are classified by the degree of severity and the mutations in the collagen genes. For example, the vascular type form of Ehlers-Danlos syndrome—caused by a mutation in the COL3A1 gene—is associated with severe vascular alterations leading to the development of varicose veins and spontaneous rupture of major arteries. A deficiency in the synthesis of type III collagen, prevalent in the walls of blood vessels, is the major defect. Arthrochalasia and dermatosparaxsis types of Ehlers-Danlos syndrome display congenital dislocation of the hips and marked joint hypermobility. Mutations in the COL1A1 and COL1A2 genes (Figure 4-5), encoding type I collagen, and procollagen N-peptidase gene disrupt the cleavage site at the N-terminal of the molecule and affect the conversion of procollagen to collagen in some individuals.





Elastic fibers: Synthesis, secretion, and assembly


Like collagen, the synthesis of elastic fibers involves both the RER and the Golgi apparatus (Figure 4-6).



Elastic fibers are synthesized by the fibroblast (in skin and tendons), the chondroblast, the chondrocyte (in elastic cartilage of the auricle of the ear, epiglottis, larynx, and auditory tubes), and smooth muscle cells (in large blood vessels like the aorta and in the respiratory tree).


Proelastin, the precursor of elastin, is cleaved and secreted as tropoelastin. In the extracellular space, tropoelastin interacts with fibrillins and fibulin 1 to organize elastic fibers, which aggregate to form bundles of elastic fibers. Tropoelastin contains a characteristic but uncommon amino acid: desmosine. Two lysine residues of tropoelastin are oxidized by lysyl oxidase to form a desmosine ring that cross-links two tropoelastin molecules. Cross-linking enables the stretching and recoil of tropoelastin, like rubber bands. Elastic fibers do not contain collagen. Elastic fibers are produced during embryonic development and in adolescence but not so much in adults. Although elastic fibers are resilient during human life, many tissues decrease elasticity with age, in particular the skin, which develops wrinkles.


Under the light microscope, elastic fibers stain black or dark blue with orcein, a natural dye obtained from lichens.


Under the electron microscope, a cross section of an elastic fiber shows a dense core of elastin surrounded by microfibrils of fibulin 1 and fibrillins.



Clinical significance: Marfan syndrome


Marfan syndrome is an autosomal dominant disorder in which the elastic tissue is weakened. Defects are predominantly observed in three systems: the ocular, skeletal, and cardiovascular systems. The ocular defects include myopia and detached lens (ectopia lentis). The skeletal defects (Figure 4-7) include long and thin arms and legs (dolichostenomelia), hollow chest (pectus excavatum), scoliosis, and elongated fingers (arachnodactyly).



Cardiovascular abnormalities are life-threatening. Patients with Marfan syndrome display prolapse of the mitral valve and dilation of the ascending aorta. Dilation of the aorta and peripheral arteries may progress to dissecting aneurysm (Greek aneurysma, widening) and rupture. Medical treatment, such as administration of β-adrenergic blockers to reduce the force of systolic contraction in order to diminish stress on the aorta, and limited heavy exercise increase the survival rate of patients with Marfan syndrome.


Defects observed in Marfan syndrome are caused by poor recoiling of the elastic lamellae dissociated by an increase in proteoglycans (see Figure 4-7). In the skeletal system, the periosteum, a relatively rigid layer covering the bone, is abnormally elastic and does not provide an oppositional force during bone development, resulting in skeletal defects.


A mutation of the fibrillin 1 gene on chromosome 15 is responsible for Marfan syndrome. Fibrillin is present in the aorta, suspensory ligaments of the lens (see Chapter 9, Sensory Organs: Vision and Hearing), and the periosteum (see Bone). A homologous fibrillin 2 gene is present on chromosome 5. Mutations in the fibrillin 2 gene cause a disease called congenital contractural arachnodactyly. This disease affects the skeletal system, but ocular and cardiovascular defects are not observed.




Mast cells


Like macrophages, mast cells originate in the bone marrow from precursor cells lacking cytoplasmic granules. When mast cell precursors migrate into the connective tissue or the lamina propria of mucosae, they proliferate and accumulate cytoplasmic granules. Mast cells and basophils circulating in blood derive from the same progenitor in the bone marrow.


The mast cell is the source of vasoactive mediators contained in cytoplasmic granules (Figure 4-9). These granules contain histamine, heparin, and chemotactic mediators to attract monocytes, neutrophils, and eosinophils circulating in blood to the site of mast cell activation.



Leukotrienes are vasoactive products of mast cells. Leukotrienes are not present in granules; instead, they are released from the cell membrane of the mast cells as metabolites of arachidonic acid.


There are two populations of mast cells: mucosal mast cells (found predominantly in the intestine and lungs), and connective tissue mast cells.


Connective tissue mast cells differ from mucosal mast cells in the number and size of metachromatic (see Box 4-D) cytoplasmic granules, which tend to be more abundant in connective tissue mast cells. Although these two cell populations have the same cell precursor, the definitive structural and functional characteristics of mast cells depend on the site of differentiation (mucosa or connective tissue).






Extracellular matrix


The ECM is a combination of collagens, noncollagenous glycoproteins, and proteoglycans surrounding cells and fibers of the connective tissue.


Recall that the basement membrane contains several ECM components such as laminin, fibronectin, various types of collagen, and heparan sulfate proteoglycan. In addition, epithelial and nonepithelial cells have receptors for ECM constituents. An example is the family of integrins with binding affinity for laminin and fibronectin. Integrins interact with the cytoskeleton, strengthening cell interactions with the ECM by establishing focal contacts or modifying cell shape or adhesion.


Several noncollagenous glycoproteins of the ECM mediate interactions with cells and regulate the assembly of ECM components. Noncollagenous glycoproteins have a widespread distribution in several connective tissues, although cartilage and bone contain specific types of noncollagenous glycoproteins. We study them later when we discuss the processes of chondrogenesis (formation of cartilage) and osteogenesis (bone formation).


Proteoglycan aggregates (Figure 4-11) are the major components of the ECM. Each proteoglycan consists of glycosaminoglycans (GAGs), proteins complexed with polysaccharides. GAGs are linear polymers of disaccharides with sulfate residues. GAGs control the biological functions of proteoglycans by establishing links with cell surface components, growth factors, and other ECM constituents.



Different types of GAGs are attached to a core protein to form a proteoglycan. The core protein, in turn, is linked to a hyaluronan molecule by a linker protein. The hyaluronan molecule is the axis of a proteoglycan aggregate. Proteoglycans are named according to the prevalent GAG (for example, proteoglycan chondroitin sulfate, proteoglycan dermatan sulfate, proteoglycan heparan sulfate).


The embryonic connective tissue of the umbilical cord (Wharton’s jelly) is predominantly ECM material surrounding the two umbilical arteries and the single umbilical vein. Proteoglycans have extremely high charge density and, therefore, significant osmotic pressure. These attributes enable a connective tissue bed to resist compression because of the very high swelling capacity of these molecules. The umbilical blood vessels, crucial elements for fetal-maternal fluid, gas, and nutritional exchange, are surrounded by a proteoglycan-enriched type of connective tissue to provide resistance to compression.



Degradation of the extracellular matrix


The ECM can be degraded by matrix metalloproteinases, a family of zinc-dependent proteases secreted as latent precursors (zymogens) proteolytically activated in the ECM. The activity of matrix metalloproteinases in the extracellular space can be specifically inhibited by tissue inhibitors of metalloproteinases (TIMPs).


The expression of matrix metalloproteinase genes is regulated by cytokines, growth factors, and cell contact with the ECM.


The degradation of the ECM occurs normally during the development, growth, and repair of tissues. However, excessive degradation of the ECM is observed in several pathologic conditions such as rheumatoid arthritis, osteoarthritis, and diseases of the skin. Tumor invasion, metastasis, and tumor angiogenesis require the participation of matrix metalloproteinases whose expression increases in association with tumorigenesis.


Members of the family of matrix metalloproteinases include:






Jun 18, 2016 | Posted by in HISTOLOGY | Comments Off on CONNECTIVE TISSUE

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