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Section I • Histology and Cell Biology
ChapterSummary
•Connective tissue (Cl) provides support for parenchymal cells (epithelial and other functional cell types) that carry out the specific tissue and organ functions.
•Connective tissue is comprised of support cells, guest cells, and their associated extracellular matrix (ECM) or ground substance. Support cells include fibroblasts, myofibroblasts, chondroblasts, osteoblasts and their derivatives, adipocytes. The permanent guest cells are macrophages and mast cells.
•The extracellular matrix consists offibrillar proteins (collagen, elastin, fibrillin, fibronectin), proteoglycans that are associated with water and form a gel matrix, and glycoproteins that form structural proteins and include laminin, entactin, and tenascin.
•Fibrillar proteins are mainly collagen, but various connective tissues may also have a variable content of elastin and fibrillin, and fibronectin, which help to anchor cells to basal lamina. Collagen is produced by fibroblasts and myofibroblasts.
•Type I collagen is found in skin, tendon, ligaments, bone, and cornea.
•Most of the body's collagen is type I. Type II collagen is found in cartilage,
intervertebral discs, and in vitreous body of the eye.
•Type Ill collagen is found in blood vessels, and it forms reticular fibers in various organs and tissues. It links the basal lamina ofcells to the underlying extracellular matrix in many tissues. Type Ill collagen comprises the main supporting fibers in the extracellular matrix surrounding the parenchymal cells of lymphoid (lymph node and spleen) organs, bone marrow, and liver.
•Type IV collagen is found in the basal lamina.
•Elastic fibers are composed of elastin and fibrillin and are especially prominent in the dermis ofthe skin, the walls of blood vessels, especially arteries, and the lun
•Fibronectin can bind to collagen and other matrix components, as well as to cell surface receptors, including epithelial cells, and therefore are important in the interactions of cells with matrix.
•Proteoglycans consist mostly of long unbranched glycosaminoglycans
(GAGs) linked to a protein core.
•Glycoproteins have a relatively greater content of protein compared to proteoglyc.ans. Laminin, entactin, and tenascin are non-filamentous structural glycoproteins in the ECM.
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Cartilage and Bone |
3 |
CARTILAGE
Cartilage, like all connective tissue, consists of cells and extracellular matrix (ECM). The ECM is rich in type II collagen fibrils and glycosaminoglycans (GAGs). Some specialized types of cartilage may have additional components in the matrix. Cartilage is avascular, and it can serve as the template for bone formation.
Cartilage formation takes place by differentiation ofmultipotential mesenchymal cells into chondroid precursor cells, which give rise to chondroblasts, which give rise to chondrocytes. The cartilage mass is surrounded by perichondrium, a membrane of connective tissue containing the stem cells which can give rise to both fibroblasts and chondroid progenitor cells. The chondroid progenitor cells change from small elongated cells to chondroblasts, which are more oval shaped, with more cytoplasm. They secrete type II collagen and some GAGs to produce extracellular chondroid matrix. The immature matrix initially surrounding chon droblasts is relatively acidophilic (pink staining), as it has proportionately more collagen compared to GAGs. As the chondroblast matures into a more rounded chondrocyte trapped in a lacuna within the matrix, the matrix also matures with proportionately more GAGs compared to collagen and more basophilic (blue staining). As the mass ofcartilage is formed, it is not penetrated by blood vessels.
Cartilage can enlarge in 2 ways. In appositionalgrowth, new cells can be added from the outer perichondrium. In internal or interstitial growth, the chondro cytes embedded deep within the cartilage can continue to produce additional ECM.
Chondrocytes are not polarized and can secrete new matrix circumferentially, in contrast to osteoblasts, which secrete only in one direction, adding onto a sur face. The interstitial growth depends more on continuing extracellular secretion and less on cell proliferation. Typically there are or 4 chondrocytes within a lacuna.
Types ofCartilage
There are 3 types of cartilage, all containing type II collagen and GAGs. Some times they have additional extracellular components produced by the chondro cytes.
Hyaline cartilage is the type ofcartilage that forms a template for bone forma tion during embryogenesis, as well as comprising the articular cartilage on the surface ofbones at synovial joints, and the cartilage ofthe nose, portions ofthe larynx, and the cartilage of the trachea and bronchi. Hyaline cartilage is rich in hyaluronic acid, chondroitin sulfate, and keratan sulfate. It has high water con tent, and resists compression, making it a good shock absorber.
Clinical Correlate
Rheumatoid arthiritis may damage articular cartilage, causing joint pain and ankylosis. Gout results from the deposit of uric acid crystals in joints and is common in individuals using thiazide diuretics for hypertension.
MEDICAL 35
Section I • Histology and Cell Biology
Copyright McGraw-Hill Companies. Used with permission.
Figure 1-3-1. Tracheal hyaline cartilage perichondrium (arrow)
Elastic cartilage contains elastic fibers in addition to the other components of cartilage (type II collagen), giving it greater flexibility. It is found in the external ear, the auditory canal, and the epiglottis ofthe larynx.
Copyright McGraw-Hi// Companies. Used withpermission.
Figure 1-3-2. Elastic cartilage (external ear), elastic fibers (arrows)
Fibrocartilage has type I collagen in addition to type II, giving it greater resis tance to being stretched (tensile strength), and is the type of cartilage found in intervertebral disks ofthevertebral column and the menisci oftheknee, and may form the attachment of ligaments and tendons to bone. Fibrocartilage perichondrium and contains less water in its ECM, compared to the other types ofcartilage.
36 MEDICAL
Chapter 3 • Cartilage and Bone
BONE
Bone is a unique connective tissue in that it not only has cells and ECM called osteoid including type I collagen and GAGs, but also the matrix is calcified and rigid. This requires adaptations ofthe resident cells not seen in most tissues. Unlike cartilage, bone is vascularized.
Bone Cells
Osteoblasts secrete bone ECM (osteoid). Osteoblasts are derived from osteo progenitor cells, which are formed from multipotent mesenchymal stem cells, the same cells that form allconnective tissue. These osteoprogenitor cells may be carried into preexisting cartilage in the connective tissue from surrounding blood vessels that grow into cartilage during embryogenesis or from connective tissue residing in the bone marrow spaces during subsequent bone growth and remodeling.
Copyright McGraw-Hill Companies. Usedwith permission.
Figure 1-3-3. Haversian canal lined by osteoprogenitor cells and osteoblasts (arrowheads) and containing blood vessels (arrow)
Osteoblasts are specialized to synthesize and secrete the components ofosteoid, type I collagen, and GAGs. The unique structure ofthe osteoid, in particular the ordering of the collagen, promotes the formation of a crystalline structure, hy droxyapatite, which is comprised ofcalcium and phosphate ions that are precipi tated from the extracellular fluid. Osteoblasts usually adhere to a surface, such as cartilage or preexisting osteoid, and secrete new osteoid in a polarized manner onto the attached surface, leading to ofbone.
As osteoblasts are added, other osteoblasts become surrounded by osteoid and transform into osteocytes. These osteoblasts become totally surrounded byosteoid, and areresponsible formaintenanceofthe bonematrix. Osteocytesextendthrough canaliculi that are tiny channels in the osteoid that form gap junctions with pro cesses ofother osteocytes. In this way, osteocytes can exchange signals, nutrients, and wasteproducts. There is also a small amount ofextracellular fluid surrounding each osteocyte and its intracanalicularprocesses. The combination ofgapjunctions and extracellular fluid allow survival ofosteocytes embedded in bone.
Clinical Correlate
There are 2 forms of bone:
•Compact bone (solid mass)
•Spongy or cancellous bone (network of spicules or trabeculae separating spaces occupied by bone marrow)
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Chapter 3 • Cartilage and Bone
Mechanisms of Bone Formation
All bone, regardless of formation, undergoes remodeling throughout life. All
3 processes, bone formation, bone growth, and bone remodeling, have simi larities.
lntramembranous boneformation
In intramembranous bone formation, primitive mesenchyme can give rise di rectly to bone. Intramembranous bone formation takes place in the formation of flat bones of the skull during embryogenesis, and in the growth in thick ness of dense cortical bone on the surface of bones. During embryogenesis, flat bones begin as small collections of condensed mesenchymal cells that are induced to become osteoblasts. As the collections grow they fuse into intercon nected cords (trabecula) with intervening mesenchyme. This forms primary
and has randomly arranged collagen fibers in its matrix.
As the bone further develops, some trabeculae fuse to form dense cortical bone, without intervening large spaces filled with mesenchyme. The cortex gets remodeled into lamellar bone, and forms the outer surface of bones and does not have cavities for bone marrow and hematopoiesis. Other trabeculae widen and form an anastomosing network of trabeculae with intervening spaces that can house bone marrow, as the intervening mesenchyme becomes populated with hematopoietic cells.
•This is known as trabecular or cancellous bone, and comprises the interior ofmost bones, whose outer surface is covered by cortical bone.
•Thus, flat bones ofthe skull have 2 outer layers of cortical bone with intervening trabecular bone.
Figure 1-3-6. lntramembranous bone formation
Newly formed spicules (arrows) containing osteocytes in lacunae (arrowheads) are surrounded by mesenchyme of primary spongy bone
MEDICAL 39
Section I • Histology and Cell Biology
Clinical Correlate
Rickets results from calcium deficiency during bone growth and may be due to insufficient dietary Ca+ or vitamin D.
Endochondral boneformation
In endochondralbone formation, bone is formed on the template ofpreexisting hyaline cartilage. Endochondral bone formation occurs in long bones ofthe ex tremities and in vertebrae and bones ofthe pelvis, and starts as ahyaline cartilagi nous template that is formed from chondroblast and chondrocyte differentiation from chondroid progenitor cells derived from mesenchyme.
the surface of preexisting cartilage is endo
• In long bones, this initially takes place in the center of the shaft (diaphy sis) of the cartilage template and is the primary center ofossification.
This leads to the progressive replacement of the inner cartilage with trabecular bone, which progressively is laid down toward the ends of the bones, leading to increase in bone length.
•At the same time, other osteoprogenitor cells at the surface periosteum begin to lay down osteoid as a layer on the outer surface ofthe cartilage template, and this form of intramembranous bone formation will ulti mately form the outer cortex of the long bones.
•Later in development, secondary (or late) centers ofossification form separately through a process of cartilage hypertrophy, ingrowth ofves sels from outside the cartilage template, and replacement of cartilage by new trabecular bone and marrow. This takes place at the ends (epiphy ses) of long bones.
•In long bones, most but not all ofthe cartilage is replaced by bone and marrow.
•At the ends of the bones that will form synovial joints, the cartilage per sists; and at the interface of the epiphysis with the diaphysis, some ofthe cartilage persists as the epiphyseal growth plate, important in the elon gation of bones.
•Depending on the complexity of shape ofbones, there is some variation
in the formation of primary and secondary centers ofossification. Both the initial surface dense corticalbone and the trabecular bone in the ossi fication centers is woven bone, later to be remodeled into lamellar bone.
In long bones, a band of cartilage is present at each end of the diaphysis and persists even after appearance of the secondary center of ossification and until the bone reaches its ultimate length. The progressive growth of this band of cartilage toward the ends of the bone by a combination of chondrocyte prolif eration and interstitial growth of chondroid matrix is the mechanism bywhich the bone lengthens.
•Advancing cartilage is replaced by new bone, which advances behind the growing epiphyseal plate.
•At puberty, the bone growth eventually catches up and completely replaces this cartilage, halting the growth and closing the epiphyseal plate, an event recognizable on x-ray by loss of the previous relatively lucent band of cartilage near the epiphyseal-diaphyseal interface.
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Chapter 3 • Cartilage and Bone
CopyrightMcGraw-Hill Companies. Used with permission.
Figure 1-3-7. Endochondral Bone Formation
The hyaline cartilage is to the left and bone marrow is to the right. On the far left is the reserve zone of resting
cartilage. In the middle is the zone of proliferation (arrows). On the right near the marrow is the zone of hypertrophy (arrowheads).
Sequence of Bone Growth
The epiphyseal growth plate shows the following sequence for bone growth from early fetal development up to puberty.
•The reserve zone consists of chondrocytes at the epiphyseal end of the growth plate.
•The proliferatingzone is deep to the reserve zone and consists of prolif erating chondrocytes that form clones aligned in columns parallel to the long axis of the bone.
•The zone ofhypertrophy consists of chondrocytes deep to the prolifer ating zone that undergo hypertrophy by becoming larger and producing type X collagen and growth factors. Hypertrophic chondrocytes then undergo apoptosis.
•Stem cells of the neighboring perichondrium are induced to differentiate into osteoprogenitor cells, thereby changing the limiting membrane from perichondrium to periosteum. Osteoclast precursors, derived from mono cytes, are recruited to this site,with osteoclasts leading the process by attack ing cartilage matrix. Blood vessels grow into the cartilage, carrying with them on their surface primitive connective tissue and osteoprogenitor cells.
Once inside the cartilage, the osteoprogenitor cells adhere to the surface ofspaces cleared into the cartilage, then differentiate into osteoblasts and deposit osteoid on the new cartilage matrix surface. The invasion occurs first in the spaces cre ated by dying chondrocytes, leaving intervening columns of calcified chondroid matrix. Osteoblasts form on the surface of these chondroid matrix columns and deposit osteoid on their surfaces. The osteoid becomes mineralized and gradually leads to the formation ofnew spicules ofwoven bone. The spicules are gradually converted into trabeculae of cancellous bone with intervening bone marrow.
Note
Cortical or lamellar bone consists of:
•Periosteum
•Outer circumferential lamellae
•Osteons
•Inner circumferential lamellae
•Spongy bone
•Endosteum
MEDICAL 41
Section I • Histology and Cell Biology
Both thetrabeculae ofnewlyformed woven bone and the newlyformed densebone oftheoutercortexgth undergoremodeling, the end result ofwhichis to produce high ly ordered larnellae ofcollagen in the matrix, which gives the mineralized osteoid greater stren and resistance to breaking. This forms lamellar or cortical bone.
The processbywhich wovenbone isconvertedtolamellarbone is analogous to the constant remodeling ofalready existing lamellar bone that takes place throughout life. In dense cortical bone new blood vessels, preceded by osteoclasts, bore into the preexisting cortical bone, usually following lines of stress. The resulting tun nels form Haversian canals that are generally oriented along the long axis ofthe bone, but otherwise directed by stress lines in other bones. The Haversian canals start out with a relatively large diameter, and new osteoblasts form on the inner surface ofthe osteoid thatwascarved outbythe osteoclasts. Successive concentric lamellae ofosteoidwith alternating orientation ofcollagen are laid down, progres sively reducing the diameter of the Haversian canals and trapping osteocytes in concentric rings within the lamellae.
There is always a persisting small cylindrical space in the center ofthe concentric lamellae where a small amount ofconnective tissue with nourishing vessels per sists. Even at their smallest, Haversian canals are muchlarger than the canaliculi that connect them.
An osteon is a Haversian canal with its surrounding lamellae constituents and forms the basic unit of mature lamellar bone. The resulting highly ordered la mellar bone is much stronger than immature woven bone. Lamellar bone will continue to be remodeled throughout life, so it is common to see interstitial lamellae that are incomplete portions ofolder osteons located between the more recent complete osteons.
Copyright McGraw-Hill Companies. Used with permission.
Figure 1-3-8. Osteons or Haversian systems
Each Haversian canal is surrounded by circumferential lamellae (arrows). Remnants of remodeled Haversian systems (arrowheads) form interstitial lamellae.
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Chapter 3 • cartilage and Bone
Trabeculae of cancellous bone are similarly remodeled. The process takes place mostly at the surface of the trabeculae, carried out by osteoclasts and osteoblasts from the adjacent marrow.
Mature long bones are covered on all surfaces by dense cortical bone with an outer periosteum, with the exception of articular surfaces, which are covered by hyaline articular cartilage. The inner bone at the epiphyses and the nearby end portions of the diaphyses (the flared metaphyses) are filled with cancellous bone and bone marrow. The central most portion ofthe diaphysis oflarger long bones is filled with bone marrow, either hematopoietically active or fatty, without inter vening bony trabeculae.
The main nutrient arteries ofa long bone remain as relatively large arteries enter ing the diaphysis and the epiphyses, Once in the medullary cavity, they give rise to many small branches, some of which can reenter the cortex from the inner surface through Volkmann's canals. In addition there are many small branches along the periosteum, which in turn may perforate into the cortical bone from the outside, also giving rise to additional Volkmann's canals, all ofwhich are per pendicular to Haversian canals, Volkmann's canals are perpendicular to Haver sian canals, and are distinguished by the lack of a surrounding osteon.
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