Connective Tissue

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I. INTRODUCTION. Types of connective tissue include loose connective tissue (e.g., fascia, lamina propria), dense connective tissue (e.g., tendons), adipose tissue, cartilage, and bone. The common features of all connective tissues are the ground substance, fibers, and cells, as described below.

II. GROUND SUBSTANCE contains the following components:

A. Proteoglycans consist of a core protein, which binds many side chains of gly-coaminoglycans (GAGs), and a link protein, which binds hyaluronic acid. GAGs are highly sulfated (SO^~) and consist of repeating disaccharide units of a hexosamine (e.g., N-acetylglucosamine, N-acetylgalactosamine) and a uronic acid (e.g., glucuronic acid). Specific GAGs include the following.

1. Hyaluronic acid is found in most connective tissues and binds to the link protein of a large number of proteoglycans to form a proteoglycan aggregate.

2. Chondroitin sulfate is found in cartilage and bone.

3. Keratan sulfate is found in cartilage and bone, cornea, and intervertebral disk.

4. Dermatan sulfate is found in dermis of skin, blood vessels, and heart valves.

5. Heparan sulfate is found in the basal lamina, lung, and liver.

B. Glycoproteins

1. Fibronectin is a component of the basal lamina.

2. Laminin is a component of the basal lamina.

3. Chondronectin is found in cartilage.

4. Osteocalcin, osteopontin, and bone sialoprotein are found in bone.

C. The mineral (inorganic) component varies depending on the type of connective tissue.

D. Water (tissue fluid). The high concentration of negative charges due to sulfation (SO|~) and carboxylation (COO-) of GAGs attracts water into the ground substance.

III. FIBERS

A. Collagen contains two characteristic amino acids, hydroxyproline and hydroxyly-sine.

1. Synthesis of collagen involves intracellular and extracellular events.

a. Intracellular events include:

(1) Synthesis of preprocollagen within rough endoplasmic reticulum (rER)

(2) Hydroxylation of proline and lysine within rER catalyzed by peptidyl proline hydroxylase and peptidyl lysine hydroxylase (Vitamin C is essential in this step. When vitamin C deficiency [i.e., scurvy] occurs, wounds fail to heal, bone formation is impaired, and teeth become loose.)

(3) Glycosylation of hydroxylysine within rER

(4) Formation of triple helix procollagen within rER (involves registration peptides)

(5) Addition of carbohydrates within Golgi complex

(6) Secretion of procollagen b. Extracellular events include:

(1) Cleavage of procollagen to form tropocollagen by extracellular peptidases

(2) Self-assembly of tropocollagen into fibrils (67-nm periodicity)

(3) Cross-linking of adjacent tropocollagen molecules catalyzed by lysyl oxidase

2. Types of collagen (Table 3-1)

B. Elastic fibers consist of an amorphous core of the elastin protein surrounded by microfibrils of the fibrillin protein. Elastic fibers contain two unique amino acids called desmosine and isodesmosine, which are involved in cross-linking.

IV. CELLS

A. Resident or fixed cells are a stable population of cells that remain in the connective tissue. These include the following types of cells.

1. Fibroblasts/fibrocytes are fixed cells that are involved in the secretion of collagen and ground substance.

2. Macrophages (histiocytes)

a. Macrophages arise from monocytes within the circulating blood and bone marrow.

b. They have a phagocytic function.

Table 3-1

Distribution of Collagen Types in the Body

Type Location in Body

Fibrocartilage, bone, dermis of skin, tendons

In wound healing, type I replaces the initial type III collagen.

Most ubiquitous type of collagen

Hyaline cartilage Elastic cartilage

Liver, spleen, tunica media of blood vessels, muscularis externa of gastrointestinal tract

In wound healing, type III is laid down first.

In keloid formation, increased amounts of type III are laid down.

Traditionally called reticular fibers

Basal lamina

(1) Fc antibody receptors on the macrophage cell membrane bind antibody-coated foreign material and subsequently phagocytose the material for lysosomal digestion.

(2) C3 (a component of complement) receptors on the macrophage ccll membrane bind bacteria and subsequently phagocytose the bacteria (called opsonization) for lysosomal digestion.

(3) Certain phagocytosed material (e.g., bacilli of tuberculosis and leprosy, Trypanosoma cruzi, Toxoplasma, Leishmania, asbestos) cannot undergo lysosomal digestion, so macrophages will fuse to form foreign body giant cells.

(4) In sites of chronic inflammation, macrophages may assemble into epithelial-like sheets called epithelioid cells of granulomas.

C. Macrophages have an antigen-presenting function.

(1) Exogenous antigens circulating in the bloodstream are phagocytosed by macrophages and undergo degradation in endosomal acid vesicles.

(2) Antigen proteins are degraded into antigen peptide fragments, which are presented on the macrophage cell surface in conjunction with class II major histocompatibility complex (MHC).

(3) CD4+ helper T cells with antigen-specific T cell receptor (TcR) on its cell surface recognize the antigen peptide fragment.

d. Macrophages are activated by lipopolysaccharides (a surface component of gram-negative bacteria) and interferon-7

e. They secrete interleukin-1 (IL-1 ; stimulates mitosis of T lymphocytes), in-terleukin-6 (IL-6; stimulates differentiation of B lymphocytes into plasma cells), pyrogens (mediate fever), tumor necrosis factor-«, and granulocyte-macrophage colony-stimulating factor

3. Mast cells a. Mast cells arise from stem cells in the bone marrow.

b. They have a function in immediate (type 1 ) hypersensitivity reactions (anaphylactic reactions).

C. They have immunoglobulin E (IgE) antibody receptors on their cell membranes that bind IgE produced by plasma cells upon first exposure to an allergen (e.g., plant pollen, snake venom, foreign serum), which sensitizes the mast cells.

d. Mast cells secrete the following substances upon second exposure to the same allergen, causing the classic wheal-and-flare reaction in the skin:

(1) Heparin, an anticoagulant

(2) Histamine, which increases vascular permeability and causes smooth muscle contraction of bronchi

(3) Leukotriene C4 and D4, which increase vascular permeability, cause vasodilation, and cause smooth muscle contraction of bronchi

(4) Eosinophil chemotactic factor, which attracts eosinophils to the inflammation site

4. Adipocytes a. Adipocytes in multilocular (brown) adipose tissue contain numerous fat droplets and numerous mitochondria that lack elementary particles on the inner membrane. The energy produced by these mirochondria is dissipated as heat instead of being stored as ATP. Brown adipose tissue is present in human infants after birth to assist in regulation of body temperature but disappears within a few years. Multilocular adipose tissue has a brown color due to the numerous mitochondria that contain cytochromes, which have a color similar to hemoglobin.

b. Adipocytes in unilocular (white) adipose tissue contain a large, single fat droplet surrounded by a thin rim of cytoplasm. This tissue accounts for all of the stored fat in humans and has a yellow color due to the presence of carotene.

(1) In general, adipocytes synthesize and store triacylglycerols (also called triglycerides, fats, or neutral fats), which are composed of three fatty acids in ester linkage with glycerol.

(2) In the fed state, an increased insulin:glucagon ratio stimulates adipocytes to produce the following reactions.

(a) Adipocytes secrete lipoprotein lipase (LPL) into the capillaries of white adipose tissue. Lipoprotein lipase catalyzes the digestion of triacylglycerols [carried by very tow density lipoproteins (VLDL) and chylomicrons] into fatty acids and glycerol. The fatty acids enter the adipocyte to be stored as triacylglycerols. The glycerol travels to the liver.

(b) Adipocytes uptake and metabolize glucose and use it for energy (via glycolysis) and as a source of the glycerol moiety of the stored triacylglycerols.

(3) In the fasted state, a decreased insulimglucagon ratio and epinephrine stimulate adipocytes to begin lipolysis due to increased levels of cyclic adenosine monophosphate (cAMP), which activate hormone-sensitive lipase. Hormone-sensitive lipase catalyzes the cleavage of fatty acids from triacylglycerol. The fatty acids become the major fuel of the body because they are used by muscle and kidney for production of energy (i.e., ATP) and converted in the liver to ketone bodies. The glycerol is used as a source of carbon by the liver for gluconeogenesis.

(4) Adipocytes secrete a hormone called leptin that has an anorexic action in that leptin decreases appetite and decreases body weight (due exclusively to a reduction of fat stores). The action of leptin is mediated through satiety centers in the hypothalamus (i.e., paraventricular and arcuate nuclei) where leptin receptors are found. The gene for leptin has been cloned and is called the LEP gene in humans.

5. Chondroblasts and chondrocytes are discussed in Chapter 4.

6. Osteoblasts and osteocytes are discussed in Chapter 5.

B. Transient or free cells enter connective tissue from blood, usually during inflammation. These cells include neutrophils, eosinophils, basophils, monocytes, B lymphocytes, plasma cells, and T lymphocytes, which are discussed in Chapter 9.

V. CLINICAL CONSIDERATIONS

A. Ehlers-Danlos syndrome is a genetic defect involving peptidyl lysine hydroxylase that affects type I and type III collagen synthesis, resulting in hypermobile joints, excessive stretchability of the skin, and rupture of large bowel and/or large arteries.

B. Marfan syndrome is a genetic defect involving fibrillin (a component of elastic fibers), resulting in weakened tunica media of aorta (aortic dissection) and ectopia lentis.

C. Homocystinuria is a genetic defect involving the enzyme cystathionine synthetase, resulting in abnormal cross-linking of collagen.

0. Osteogenesis imperfecta is a genetic defect involving type I collagen, resulting in spontaneous fractures of bone and blue sclera of the eye.

E. Alport syndrome (hereditary nephritis) is a genetic defect involving type IV collagen, resulting in renal failure and deafness.

F. Keloid formation is a deviation in normal wound healing whereby an excessive accumulation of collagen occurs, resulting in a raised, tumorous scar.

G. Amyloidosis is a group of diseases that have in common the deposition of amyloid (a proteinaceous substance) in the intercellular space of various organs.

1. By light microscopy, amyloid is an eosinophilic, amorphous substance. By electron microscopy, amyloid is composed of nonbranching fibrillar proteins (95%) and a glycoprotein called P component, which is pentagonal in shape (5%).

2. A number of different nonbranching fibrillar proteins have been identified, which include:

a. Amyloid light chain, an immunoglobulin protein secreted by plasma cells b. Amyloid-associated protein, synthesized by the liver

C. Beta2-microglobulin, a component of the major histocompatibility complex class 1 proteins d. Beta2-amyloid, a 4000-d peptide e. Islet amyloid polypeptide (amylin), which is increased within pancreatic islets of Langerhans in patients with type 2 diabetes

3. Types of amyloidosis include the following.

a. Immunocyte dyscrasias with amyloidosis (primary amyloidosis) is the most common form of amyloidosis and is associated with the amyloid light chain protein. Some patients with multiple myeloma (a plasma cell neoplasia) demonstrate amyloidosis along with the presence of light chains (Bence Jones proteins) in the serum and urine.

b. Reactive systemic amyloidosis (secondary amyloidosis) occurs as a secondary complication to chronic inflammation (e.g., rheumatoid arthritis, regional enteritis, ulcerative colitis) and is associated with the amyloid-associated protein.

C. Hemodialysis-associated amyloidosis occurs in patients on long-term hemodialysis and is associated with the beta2-microglobulin protein.

d. Senile cerebral amyloidosis occurs in patients with Alzheimer disease and is associated with beta2-amyloid protein deposition in cerebral plaques.

e. Endocrine amyloid occurs in patients with type 2 diabetes and is associated with islet amyloid polypeptide deposition in the pancreatic islets.

VI. SELECTED PHOTOMICROGRAPHS

A. Proteoglycan aggregate (Figure 3-1; see 11 A)

Proteoglycan Clinical Diseases

Figure 3-1. (A) Electron micrograph of a proteoglycan aggregate. A proteoglycan aggregate consists of a large number of proteoglycans (clotted box indicates one proteoglycan) bound to hyaluronic acid (boxed area). The rhick, fuzzy areas {arrows) indicate the side chains of glycosaminoglycans (GAGs). (Reproduced with permission from Buckwalter J A, Rosenberg L: Structural changes during development in bovine letal epiphyseal cartilage. Collagen Relat Res 3:489, 1983.) (B) A diagram of a proteoglycan showing the core protein, which binds many side chains of GAGs, and a link protein, which binds hyaluronic acid.

Figure 3-1. (A) Electron micrograph of a proteoglycan aggregate. A proteoglycan aggregate consists of a large number of proteoglycans (clotted box indicates one proteoglycan) bound to hyaluronic acid (boxed area). The rhick, fuzzy areas {arrows) indicate the side chains of glycosaminoglycans (GAGs). (Reproduced with permission from Buckwalter J A, Rosenberg L: Structural changes during development in bovine letal epiphyseal cartilage. Collagen Relat Res 3:489, 1983.) (B) A diagram of a proteoglycan showing the core protein, which binds many side chains of GAGs, and a link protein, which binds hyaluronic acid.

B. Collagen and elastic fibers (Figure 3-2; see III A-B)

Vanni Spazzoli Pittore

Figure 3-2. Electron micrograph showing a collagen fiber and elastic fibers consisting of an amorphous core of elastin protein and microfibrils of the fibrillin protein. Note the 67-nm periodicity of collagen. (Reprinted with permission from Fawcett DW: A Textbook of Histology, 12th ed. New York, Chapman Hall, 1994, p 147. Courtesy of J. C. Fanning.)

Figure 3-2. Electron micrograph showing a collagen fiber and elastic fibers consisting of an amorphous core of elastin protein and microfibrils of the fibrillin protein. Note the 67-nm periodicity of collagen. (Reprinted with permission from Fawcett DW: A Textbook of Histology, 12th ed. New York, Chapman Hall, 1994, p 147. Courtesy of J. C. Fanning.)

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