Chapter 13: Cartilage and Bone

The structure of bone can be described in terms of its structural density as well as its structural morphology. In terms of its structural density, bone can either be?

1. Be compact (also known as cortical) 2. trabecular (also known as spongy or cancellous).

What is the periceullar matrix(

1. There is a very basophilic ring around each individual cell

What is the perichondrium?

1. A layer of dense CT called the perichondrium overlies the surface of hyaline cartilage.

What is osteocalcin?

1. A protein produced by the osteoblasts that has a specific role in helping the matrix to mineralize Osteocalcin is a protein that has a specific role in helping the matrix to mineralize 2. It contains a number of γ-carboxylated glutamate residues, which are synthesized post-translationally from glutamate 3. Any time that you see a γ-carboxylated glutamate residue, know that the enzyme responsible for that post-translational modification (γ-glutamyl carboxylase) requires vitamin K (phytonadione or menaquinone) as a cofactor 4. It is specifically the γ-carboxylated glutamate residues in osteocalcin that bind to calcium, essentially functioning as "seed" calcium 5. Once seeded, the only requirement for this calcium to form calcium hydroxyapatite crystals is a source of phosphate

After damage to cartilage, what occurs?

1. After damage to cartilage, new blood vessels often invade the damaged tissue, and fibroblasts lay down type I collagen 2. This dense CT that is deposited at the site of injury can later become calcified,triggering a series of events that causes the tissue to be remodeled into bone tissue 3. Articular cartilage, in particular, has very little capacity for repair after injury

What are Alkaline phosphatase?

1. Alkaline phosphatase cleaves phosphates off of nearby proteins (in an alkaline environment), creating a high local concentration of phosphate 2. Calcium phosphate is poorly water soluble and prefers to precipitate into crystals in an aqueous solution (particularly an alkaline aqueous solution). 3. This is how the matrix ultimately becomes mineralized with calcium hydroxyapatite crystals.

What are some other treatments for osteoporosis?

1. Another treatment option is teriparatide, which is synthetic PTH a. By injecting the drug once daily, the patient is exposed to PTH for only a short period of time. b. This preferentially stimulates osteoblastic function relative to osteoclastic function. 2. A newer treatment option includes denosumab (Prolia), which is an antibody targeted against RANK-L; its effect is similar to those of osteoprotegerin 3. Hormone replacement therapy is an option for post-menopausal women. a. Synthetic sex hormones (estrogens and progestins) can improve bone density, among other effects (such as improved mood and decreased hot flushes). b. However, there are risks (such as the increased risk of blood clots, an increased risk of breast cancer, etc.) associated with HRT.

Cartilage can undergo two types of growth. What are they?

1. Appositional growth 2.Interstitial growth

As a chondrocyte secretes matrix, it walls itself off from other?

1. As a chondrocyte secretes matrix, it walls itself off from other chondrocytes 2. The area within the matrix occupied by the cell is called a lacuna.

What is a howship lacuna?

1. As the osteoclast erodes the matrix, it leaves an indentation called a Howship lacuna

Each ring of the concentric lamellae is made of mineralized matrix with the collagen fibers all oriented in a single direction. What does this do?

1. Because the collagen fibers of each ring point in a different direction, This improves the structural integrity of the bone, because if all of the collagen fibers throughout the whole Haversian system pointed in the same direction, it would leave the bone susceptible to shear forces from all other directions. 2. Osteocytes are seen at the margins of each lamella enclosed within a lacuna; typically, only the nucleus of each osteocyte is visible. 3. Radiating out in all directions from each osteocyte is what appears to be small fissures; these are called canaliculi. i. Each canaliculus is a small opening that contains a projection of the cell membrane of the osteocyte. ii. This projection makes contact with a similar projection on the neighboring osteocyte. iii. At this point of contact, gap junctions are found, indicating that the osteocytes are capable of communicating with each other.

What is an interstitial lamellae?

1. Between two Haversian systems, layers of bone tissue are often found that look as if they were once part of a Haversian system, but the original Haversian canal and much of the concentric lamellae have been overwritten by a new Haversian system

What can penetrate the perichondrium?

1. Blood vessels do penetrate the perichondrium.

Is bone alive?

1. Bone is alive; it is made of cells (mostly osteocytes) and EC matrix (sometimes called osteoid).

What is the process of bone healing similar to?

1. Bone tissue heals itself using a mechanism that is very similar to endochondral ossification.

What does calcitonin do to bone?

1. Calcitonin is a hormone made by the parafollicular cells of the thyroid gland in response to hypercalcemia; it is known to directly inhibit the function of osteoclasts without having to signal indirectly through the osteoblasts

How are Cartilage and bone identified?

1. Cartilage and bone are both identified by the content of the EC matrix

What is the remodeling price for cartilage?

1. Cartilage tissue is continually remodeling—old matrix is degraded, and new matrix is deposited

What re cells within the perichondrium?

1. Cells within the perichondrium are fibroblasts--which secrete the perichondrial matrix, which is mostly type I collagen.

Cells within the perichondrium can differentiate into?

1. Cells within the perichondrium can differentiate into chondroblasts, which give rise to chondrocytes, should new chondrocytes be needed.

Are chondrocytes alive in hyaline cartilage?

1. Chondrocytes are alive; however, the tissue itself does not contain blood vessel 2. Thus, these cells rely on diffusion to receive their oxygen, nutrients, and to remove wastes. 3. Because the matrix is mostly composed of glycosaminoglycans and proteoglycans (and is heavily hydrated), these small molecules are able to diffuse through the matrix to reach the chondrocytes. a. When force is applied to the tissue, much of the fluid is squeezed out. b. When the force is released, new fluid rushes in to fill the space, which also allows for the exchange of materials.

Other than extraceullar fluid ( which makes up the bulk of the volume), the extraceullar matrix is composed of ( in hyaline cartilage)

1. Collagen ( mostly type 2 cartilage) 2. Glycosaminoglycans 3. Proteoglycans

What are the types of lamellae?

1. Concentric Lamellae 2. Circumferential Lamellae 3. Outer circumferential Lamellae

Cortisol has the opposite effect as the sex hormones at osteoblasts; What do they do?

1. Cortisol has the opposite effect as the sex hormones at osteoblasts; it reduces the expression of osteoprotegerin 2. This is particularly relevant in patients with Cushing's disease, a condition caused by the overproduction of cortisol, or in patients treated for a long period of time with synthetic glucocorticoids (such as prednisone) for the treatment of inflammatory diseases (like rheumatoid arthritis, Crohn's disease, severe allergies and asthma, etc.) 3. In these cases, the long term exposure to high doses of glucocorticoids is known to significantly increase the risk of osteoporosis

What is cushings disease?

1. Cortisol has the opposite effect as the sex hormones at osteoblasts; it reduces the expression of osteoprotegerin. 2. This is particularly relevant in patients with Cushing's disease, a condition caused by the overproduction of cortisol, or in patients treated for a long period of time with synthetic glucocorticoids (such as prednisone) for the treatment of inflammatory diseases (like rheumatoid arthritis, Crohn's disease, severe allergies and asthma, etc.)

Where is elastic cartilage found?

1. Elastic cartilage is found in the pinna of the ear and the ear canal, the auditory tube ( eusstachian tube), and the epiglottis 2. On LM, elastic cartilage can be identified by the darkly staining basophilic fibers running between groups of chondrocytes 3. Elastic cartilage is always covered by a perichondrium 4. It is not prone to calcification like hyaline cartilage, and thus would never be replaced by bone tissue

Can elastic cartilage prone to calcification?

1. Elastic cartilage is not prone to calcification like hyaline cartilage and therefore would never be replaced by bone tissue

What is osteitis Deformans ( Pagets disease) ?

1. Fairly common, and its cause is unknown 2.Despite its unknown etiology, it begins when osteoclasts become hyperactive 3. As a result, an increased number of osteoblasts are recruited to the area to deposit new bone tissue. 4. There ends up begin a tug-of-war between the two cell types until a truce is called (for a while). i. In the process, the bone that has been formed is structurally abnormal and prone to fracture. ii. An X-ray can show irregularly arranged areas of high bone density and low bone density iii. On LM, bone tissue shows a characteristic "mosaic pattern." 5. It's estimated that approximately 3-5% of the population over the age of 50 has it

What is osteopetrosis?

1. Family of genetic diseases that cause decreased osteoclastic function. Because bone breakdown is inhibited, bone density is abnormally high; these bones are at an increased risk of fracture 2. Some of the more common genes involved in the mutations include type II carbonic anhydrase, the H+-ATPase, the chloride channel, and the RANK receptor a. The osteoclasts are either unable to secrete hydrochloric acid or are unable to be stimulated to secrete the acid and acid hydrolase. b. Other than the increased bone density, X-rays of the bones in these patients look grossly normal.

What is Fibrocartilage?

1. Fibrocartilage is characterized by the presence of fibroblasts (in addition to the chondrocytes) and a large proportion of type I collagen along with the type II collagen typically seen in cartilage 2. Much of the type II collagen is deposited by the chondrocytes while the type II collagen is deposited by the fibroblasts

What is the most abundant cartilage?

1. Hyaline cartilage

What parts of the body is made up of hyaline cartilage?

1. Hyaline cartilage makes up the majority of the trachea and larynx 2. It is also found in the nasal cavity and bronchi, costal cartilage, epiphyseal plates, and articular surfaces 3. Much of the fetal skeleton is also made of hyaline cartilage

what is a Volkmann canal?

1. If bone is sectioned longitudinally through a set of Haversian canals, a perpendicular canal is sometimes seen connecting two separate Haversian systems 2. Running through the Volkmann canal are blood vessels, which provide the blood vessels running through the more superior Haversian systems (as the large blood vessels are found deep in the bone) 3. Blood vessels are also present between the circumferential lamellae and the endosteum and periosteum, but not within the interstitial lamellae

n terms of its structural morphology, bone can be described either as?

1. In terms of its structural morphology, bone can be described either as mature or immature. 2. Mature bone is made of osteons (circular layers of bone tissue—called concentric lamellae, centered around a small opened called a Haversian canal, or osteonal canal) 3. Immature bone, also called woven bone or nonlamellar bone, does not contain any of these features

In osteoporosis, does the osteoclastic or osteoblastic activity more dominant?

1. In this disorder, osteoclastic activity outpaces osteoblastic activity, causing an overall imbalance between bone resorption and bone deposition 2. Over time, the density of the bone decreases, which increases the risk for a bone fracture 3. These changes can be seen on X-ray; you can see fractures, in addition to the fact that bones with decreased density are difficult to distinguish from the tissues surrounding them

What is endochondral ossification?

1. Initially, a cluster of embryonic mesenchymal cells will migrate towards the site where the bone will ultimately form. 2. These mesenchymal cells will differentiate into chondroblasts that will secrete the typical matrix of hyaline cartilage. 3. The cartilaginous tissue grows by appositional and interstitial growth into the general shape of the future bone. 4. Early in the second trimester of gestational development, the perichondrial cells near the center of the tissue will begin differentiating into osteoblasts instead of chondrocytes 5. The perichondrium is now technically a periosteum, and the tissue underneath this periosteum is now bone, not cartilage. 6. This ring of bone tissue around the center of the tissue is called a bony collar. 7. The chondrocytes that are in the center of the tissue now hypertrophy and begin secreting alkaline phosphatase, causing mineralization of the cartilage. a. Mineralized cartilage does not diffuse nutrients nearly as well as non- mineralized cartilage, so the chondrocytes in this region lose their nutrient supply and ultimately die by necrosis. b. Because of the inflammatory process within the central region of the tissue, new blood vessels grow into the region, bringing in new embryonic mesenchymal stem cells. c. These stem cells then differentiate into osteoblasts.d. This region is now called the primary ossification center, which continues to enlarge throughout the remainder of gestation.

As a chondrocyte secretes matrix, it walls itself off from other chondrocytes. is this cell still capable of dividing?

1. Initially, once a chondrocyte has divided, the two cells share the same lacuna 2. However, once they secrete enough matrix, they will wall themselves off from each other into separate lacuna 3. It is easy to tell on LM when a chondrocyte has recently divided, as the daughter cells will be in close proximity to each other, and the staining characteristics near those cells is distinctly more basophilic compared to other regions of the matrix 4.The matrix (called the territorial matrix) surrounding the isogenous group is more basophilic. a. There is a very basophilic ring around each individual cell—it is called the pericellular matrix (or capsular matrix). b. The matrix that is farther removed from the isogenous groups is called the interterritorial matrix. c. Inspection of the staining properties of hyaline cartilage makes it possible to determine the relative activity of the matrix, and the chondrocytes within it.

Not all of these factors stimulate the osteoblast to secrete all of the substances that it can (matrix, alkaline phosphatase, osteoprotegerin, RANK-L, IL-6, M-CSF), at least not in equal proportions. What are some examples?

1. Insulin-like growth factor-1 (IGF-1) and thyroid hormone (T3) stimulate osteoblasts to secrete the pro-bone growth factors (such as matrix, alkaline phosphatase, and osteoprotegerin); for that reason, these factors stimulate the synthesis of new bone disproportionately to the degradation of old bone.

Where is fibrocartilage found?

1. Intervertebral discs, 2. pubis symphysis 3. Meniscus of the Knee 4. Sometimes where tendons insert into the bone ( in which case the fibrocartilage is almost a transitional tissue between the dense regular connective tissue of the tendon and the bone tissue)

What is the most obvious difference between elastic cartilage and hyaline cartilage?

1. Is the presence of elastic fibers within the matrix; otherwise, the makeup of the tissue is pretty similar to hyaline cartilage II collagen fibers, glycosaminoglycans, and proteoglycans make up the bulk of the organic material

What is the easiest way to identify elastic cartialge on a light mciroscope?

1. It is to notice the dark basophilic staining fibers running between groups of chondrocytes 2. The elastic cartilage is covered in perichondrium

What are some treatments for osteoarthritis?

1. Little can be done outside of surgical replacement of the joint to manage the disease 2. Acetominophen (Tylenol) or NSAIDS (such as aspirin, ibuprofen, etc.) can be given orally, or glucocorticoids can be injected locally into the joint to relieve pain and improve mobility. 3. Low-impact exercise and weight management may also help. 4. When these more conservative methods fail, surgical replacement of the joint may be the only viable treatment option.

What is the most important enzyme responsible for the degradation of old matrix, and these enzymes are secreted by the chondrocytes theme-selves ?

1. Matrix Metalloproteinases 2. Its the most important enzyme responsible for the degradation of old matrix, and these enzymes are secreted by the chondrocytes theme-selves

Osteoblasts can be stimulated to secrete three important substances, what are they?

1. Matrix itself( Type I collagen, proteoglycans, and osteocalcin, etc. ) 2. The enzyme alkaline phosphatase 3. Osteoprotegerin

What is the enyzme, matrix metalloproteinases?

1. Matrix metalloproteinases are enzymes responsible for the degradation of the old matrix, and these enzymes are secreted by the chondrocytes themselves 2. This is not a fast process. 3. The expression of matrix metalloproteinases is low in most chondrocytes, and the half- life of collagen is long (measured in years). 4. Thus, should significant damage occur to cartilage, it may never heal appropriately.

Mature bone is composed of?

1. Mature bone is composed of Haversian systems, made of the Haversian canal (osteonal canal) and the concentric lamellae that surround it

Along with secreting RANK-L that may stimulate osteoclast activity, the osteoblasts may also secrete what?

1. May also secrete interleukin-6 (IL-6) and monocyte/macrophage colony-stimulating factor (M-CSF) 2. Instead of directly stimulating osteoclasts, these signaling molecules increase the differentiation of osteoclast precursors into functional osteoclasts.

What is osteoarthritis?

1. Osteoarthritis is an incredible common condition, affecting over 50 million Americans. 2. It is caused by the degeneration of articular cartilage. a. Overuse of the joint and decreased proteoglycan content causes the joint capsule to decrease in size. b. Ultimately, the two opposing cartilages of a joint may begin to rub against each other. 3. Over time, the cartilage may wear away, leaving only bone tissue at the joint 4. Histologically, the articular cartilage initially becomes "fibrillated". a. Later, it gets lost altogether, and the articulating bones become eburnated. b. The underlying bone (called subchondral bone) loses mineralization and may break and hemorrhage (causing cysts) within the bone 5. Osteophytes may also occur.

What are the most important cells that lay down the new matrix and then mineralize the matrix? What are the most important cells for demineralizing and removing the old matrix?

1. Osteoblasts are the most important cells that lay down new matrix and then mineralize the matrix, whereas osteoclasts are the most important cells for demineralizing and removing old matrix 2. Bone that was previously laid down may need to be removed and rebuilt due to microfractures that have occurred in the tissue or because of changes in the physical demands on the tissue (weight-bearing exercise, etc.) 3. In healthy bone, these two processes are continuously occurring—called bone remodeling

Osteoblasts can also be stimulated to secrete another molecule besides: 1. Matrix itself( Type I collagen, proteoglycans, and osteocalcin, etc. ) 2. The enzyme alkaline phosphatase 3. Osteoprotegerin What is it?

1. Osteoblasts can also be stimulated to secrete another molecule, called RANK-L (receptor activator of nuclear factor κB - ligand), which is the ligand for the RANK receptor found on osteoclasts 2.RANK-L, when secreted by the osteoblast, stimulates osteoclasts to degrade existing bone matrix 3. However, osteoprotegerin can also be secreted by the osteoblasts, which binds to RANK-L, thereby blocking the ability of RANK-L to bind to the RANK receptor; thus, osteoprotegerin reduces activation of the osteoclasts (osteoprotegerin literally means "bone protector")

What are Osteoclastomas?

1. Osteoclastomas are tumors of osteoclasts, which are also called giant cell tumors of the bone 2. They may be benign, but can become cancerous. 3. Bone pain with atraumatic bone fracture of the affected bone is typical. 4. On X-ray, "soap bubble" appearing lesions of the bone are often seen. 5. Histologically, many large aggregations of osteoclasts are seen, often with very poorly formed bone matrix. a. Because of the increased osteoclastic activity, osteoblasts are recruited to the area in an attempt to rebuild the bone. b. It is therefore not uncommon to see an increased number of poorly organized osteoblasts within an osteoclastoma, although there is usually very little matrix despite the large number of osteoblasts. 6. Other than surgical resection of the affected bone tissue or radiation to the bone, bisphosphonates and denosumab are commonly used to treat osteoclastoma.

What are osteoclasts?

1. Osteoclasts are the final type of cell found in bone tissue 2. a. They are derived from the monocyte/macrophage lineage, and not from the osteoprogenitor cell. 3. Their major role is to degrade old bone matrix as part of the remodeling process.

What is osteogenesis imperfecta (OI)?

1. Osteogenesis imperfecta (OI) is a group of genetic disorders caused by mutations in type I collagen 2. Regardless of which form of the disease that patients have, they will have bones that are easily fractured. 3. Other complications include problems with dentition, hearing loss, and aneurysms of the large arteries. Many patients also have a bluish tinge to the sclera of their eyes. a. Bone (and tooth) deformities that are associated with OI are due to the fact that the vast majority of the organic matrix of bone (and teeth) is made of type I collagen. b. The vascular complications are due to the fact that the CT of the large muscular arteries is made of mostly type I collagen, which provides these vessels with the strength to withstand high pressures. 4. Hearing loss is due to deformities of the bones of the inner ear. 5. The bluish tinge to the sclera is due to the fact that the sclera is mostly made of type I collagen fibrils arranged in an irregular pattern, providing the opacity to the tissue (compared to the cornea, which is translucent due to the regular arrangement of the type I collagen fibrils). In patients with OI, the scleral tissue is thinned, reducing the opacity of the tissue and allowing visualization of the choroidal venous plexus underneath.

What is osteoporosis? What is the most common cause for this disorder? Risk factors?

1. Osteoporosis is a disorder in which the density of bone decreases 2. The most common causes are menopause (called postmenopausal osteoporosis) and long term exposure to high levels of glucocorticoids 3.Risk factors include being female, Caucasian, having a positive family history, experiencing early menopause, and the use of glucocorticoids

What are some preventative measures against osteoporosis?

1. Preventative measures include a diet high in calcium and vitamin D as well as weight-bearing exercise 2. Weight-bearing exercise improves bone density by creating micro-fractures of the bone, stimulating osteoclasts to break down the micro-fractured bone, which is then rebuilt stronger by osteoblasts 3. This type of remodeling of the bone is called Wolff's law, which states that the architecture of bone will improve in response to the increased loading on the bone 4. For patients with established osteoporosis, along with calcium, vitamin D, and weight-bearing exercise, medication may be required to improve bone density

What is Appositional growth?

1. Refers to the production of new cartilage from the cells of the perichondrium 2. These cells are essentially fibroblasts and mostly secrete the type I collagen of the perichondrium 3. For appositional growth, these cells need to differentiate first into chondroblasts, and then into chondrocytes 4. During the differentiation process, the cells become larger, more rounded, and begin to secrete the matrix typical of cartilage

What is the periosteum?

1. Similar to perichondrium, the periosteum is quite similar to dense regular CT and contains fibroblasts in the outer region 2. The inner region of the periosteum contains periosteal cells, which are bone-lining cells capable of differentiating into osteoblasts should new bone development be needed 3. The collagen fibers of the periosteum typically travel parallel to the bone itself, except where ligaments or tendons insert at the bone a. In these regions, the collagen fibers travel closer to a 45-90 degree angle into the bone tissue itself and then intertwine with the bone matrix. b. These regions where the periosteal fibers and bone fibers intertwine are called Sharpey's fibers.

What travels though the haversian canal?

1. Small blood vessels travel through the Haversian canal to supply the tissue with nutrients

Soon after birth, cartilage at the ends of the tissue begin the process of what?

1. Soon after birth, the cartilage at the ends of the tissue begins the process of mineralization similar to what occurred at the center of the tissue earlier 2. Again, these chondrocytes will die by necrosis, vascular supply enters the necrotic tissue, and mesenchymal stem cells are brought into the region that differentiate into osteoblasts. 3. These regions at the ends of the tissue are now called secondary ossification centers. a. The region between the primary and secondary ossification centers is now called the epiphyseal plate. b. The region between the secondary ossification centers and the end of the tissue will remain for the rest of life as articular cartilage. 4. The cartilage at the epiphyseal plate will continue to grow and become replaced by bone throughout childhood and adolescence, allowing the bone to lengthen. 5. However, the rate of conversion of the tissue to bone will eventually outpace the rate of growth of the cartilage, leading the epiphyseal cartilage to become completely replaced by bone tissue. 6. At that point, the epiphyseal plate is said to have "closed," or "fused," and no further lengthening of the bone will be appreciated. 7. Prior to the epiphyseal plates fusing, several histologically distinct regions of cartilage can be seen. 8. Beneath the bone is an area called the zone of reserve cartilage. a. This area contains chondrocytes that are not actively secreting matrix, nor are they dividing. b. The cells are small, flattened, and irregularly spaced. 9. Beneath this is the zone of proliferation. a. Here, chondrocytes are rapidly dividing—so rapidly that the cells are unable to secrete any significant amount of matrix prior to dividing again. b. Because of this, the cells are organized in columns, and it would appear that many, many cells are sharing the same lacuna. 10. Underneath this is the zone of hypertrophy a. Here, the cells are not proliferating nearly as fast, and they are spending much more time secreting matrix. b. The cells begin to swell, and each appears to be within its own lacuna. 11. Below that is the zone of calcification. Here, the cells are actively secreting alkaline phosphatase, causing the cartilage to calcify 12. Below that is the zone of resorption. Here, the calcified matrix is removed and replaced with true bone tissue

What is the EX matrix of the bone made of?

1. The EC matrix of bone is heavily mineralized, making it look like rock 2. It is made of primarily type I collagen, although other proteins are also found (including type V collagen and osteocalcin). 3. Proteoglycans are also present, although not nearly to the extent that is found in cartilage. 4. The inorganic mineralized component of bone is made of calcium hydroxyapatite crystals (Ca10(PO4)6(OH)2). a. The mineralization of the collagen matrix converts the tissue from firm but flexible tissue into a firm, but more unyielding tissue. b. In addition to structural rigidity, the calcium hydroxyapatite crystals also function as a reserve of calcium and phosphate, both of which are important ions found in the EC fluid (particularly calcium).

When the osteoclast is activated, it attaches to the bone matrix and secretes hydrochloric acid and lysosomal enzymes (acid hydrolases), particularly tartate-resistant acid hydrolase (TRAP) What events occurs after this?

1. The acidity that is produced helps to stabilize the calcium hydroxyapatite crystals so that the calcium and phosphate ions are released into the EC matrix, whereas the hydrolases degrade the organic matrix.

Immediately following the fracture, bleeding occurs into the local area, which ultimately will clot. What occurs next?

1. The blood clot that forms will serve as the model for later callus formation 2. Neutrophils, followed by macrophages, will invade the tissue as would occur following any inflammatory reaction to clear out the dead tissue as well as release pro-inflammatory cytokines to recruit other cell types to the region a. Initially these cytokines recruit mesenchymal stem cells from the bone marrow and nearby blood vessels that will differentiate into fibroblasts. b. These fibroblasts, in conjunction with leukocytes and new blood vessels, will form granulation tissue (the initial CT that follows injury) which consists mostly of type III collagen and the cells. c. Within a week or so of the injury, the periosteal cells closest to the fracture will begin replicating and will differentiate into chondrocytes, which begin to lay down typical hyaline cartilage. d. The fibroblasts that initially entered the tissue also begin to secrete type II collagen, typical of hyaline cartilage.

What are chondrocytes?

1. The cells present in hyaline cartilage (and in all cartilage) are called chondrocytes, and they are responsible for the production of the extracellular matrix.

What do patients complain about in Osteitis deformans (pagets disease)?

1. The correct diagnosis is often made accidentally when a patient has an X-ray (or some other type of imaging) of the affected area or a serum alkaline phosphatase assay is ordered, and the result is abnormally high (indicating overactive osteoblastic activity). 2. The standard treatment is bisphosphonates. i. Remember, these drugs inhibit osteoclastic activity. ii. Because the initiating event in this disease is hyperactivity of the osteoclasts, these drugs work to stop the initiating event.

What is the first-line treatment for osteoporosis?

1. The first-line treatment for osteoporosis are the bisphosphonates, which includes the drugs alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), and zoledronate (Reclast) 2. These drugs deposit into bone tissue and are then taken up by osteoclasts that are actively degrading the bone 3. Once inside the osteoclasts, the drug inhibits farnesyl diphosphate synthase, which inhibits the ability of the cell to transport farnesylated proteins to the cell membrane (such as the lysosomal membrane proteins) 4. Thus, the bisphosphonates inhibit osteoclastic activity

The group of cells that arose from a single chondrocyte is called an?

1. The group of cells that arose from a single chondrocyte is called an isogenous group.

Where is the inner circumferential lamelaae found?

1. The inner circumferential lamellae is found just under the endosteum

The inner covering of bone, called the?

1. The inner covering of bone, called the endosteum, is lined in endosteal cells, which are made of osteoprogenitor cells and bone-lining cells 2. It is typically impossible to tell the difference between a true osteoprogenitor cells and a bone-lining cells, and both are capable of being stimulated to develop into osteoblasts should the need arise to build new bone 3. On the interior surface of the endosteal cells is the marrow cavity (in immature bone) or the lumen of the Haversian canal (in mature bone)

What purpose does calcium hydroxyapatite?

1. The inorganic mineralized component of bone is made of calcium hydroxyapatite crystals (Ca10(PO4)6(OH)2). 2. The mineralization of the collagen matrix converts the tissue from firm but flexible tissue into a firm, but more unyielding tissue. 3. In addition to structural rigidity, the calcium hydroxyapatite crystals also function as a reserve of calcium and phosphate, both of which are important ions found in the EC fluid (particularly calcium).

What is the distinction between the two ways that bone may develop?

1. The major distinction between the two types is whether the bone forms from embryonic mesenchymal tissue that differentiates directly into bone cells (intramembranous ossification), or whether the embryonic mesenchymal tissue initially differentiates into cartilage, which is later replaced with bone tissue (endochondral ossification) 2. Intramembranous ossification gives rise to the flat bones of the skull, the mandible, and the clavicle, whereas essentially the rest of the skeleton is initially formed using a cartilage model

The matrix of bone is composed of what?

1. The matrix of bone is composed of mostly type I collagen that has been mineralized.

The matrix of cartilage is composed of what?

1. The matrix of cartilage is composed of mostly type II collagen fibers

What is the international matrix?

1. The matrix that is farther removed from the isogenous groups is called

What is the mechanism that the osteoclasts use to produce hydrochloric acid?

1. The mechanism that the osteoclasts use to produce hydrochloric acid is similar to the mechanism used by other cells that secrete acid (such as parietal cells of the stomach) 2. Osteoclasts contain type II carbonic anhydrase, which converts carbon dioxide and water into a hydrogen ion and bicarbonate 3. The bicarbonate is secreted into the EC fluid in exchange for a chloride ion, whereas the hydrogen ion (acid) is secreted towards the bone matrix using a proton- ATPase 4. The chloride is then transported towards the matrix via a chloride channel 5. When the osteoclast is active, the region of the cell membrane that makes contact with the bone matrix develops a series of deep invaginations to increase its surface area

What is the most common primary bone cancer?

1. The most common primary bone cancer is osteosarcoma, a cancer of osteoblasts 2. These tumors often occur in children and adolescents, and it most commonly occursin the tibia or femur; however, it can affect older patients, particularly those with a history of osteitis deformans 3. The initial symptoms include bone pain and decreased mobility, but there may be no symptoms until an atypical bone fracture occurs following minor trauma a. X-ray of the affected region often shows a Codman triangle overlying a lesion that has a "moth-bitten" appearance. b. Histologically, the tumor contains matrix (owing to the fact that the tumor is derived from osteoblasts), and the cells themselves are often enlarged and anaplastic (poorly differentiated) with multiple mitotic bodies. 4. Treatment includes surgical resection of the affected bone and chemotherapy 5. Unfortunately, osteosarcoma has a relatively poor prognosis compared with other pediatric cancers, with 5-year survival rates ranging from 40-70% depending on the stage of the cancer at diagnosis

The cartilage at the articular surface is made of a series of layers from the free (articular) surface to where it contacts the bone. What are they?

1. The most superficial layer (at the free, articular surface) is called the superficial zone. The collagen fibrils are thickened here and travel parallel to the articular surface itself, which causes the chondrocytes to appear flattened. 2. The intermediate zone is just beneath the superficial zone; the collage fibers here are not well organized. 3. Deep to the intermediate zone is the deep zone. Here, chondrocytes are arranged in plates (one on top of each other) with the bulk of the matrix found between the plates of the chondrocytes 4. Beneath the deep zone is the calcified zone; here, the cartilage is calcified. 5. Below the calcified zone is true bone

where is the outer circumferential lamellae found?

1. The outer circumferential lamellae is found just underneath the periosteum.

The outer covering of bone is covered in a layer of tissue called the

1. The outer covering of bone is covered in a layer of tissue called the periosteum. ( Except the articular)

What makes fibrocartilage distinct from the other two types of cartilage?

1. The presence of fibroblasts( in addition to chondrocytes) 2. Large population of type I collagen along with type II cartilage typically seen in cartilage

The sex hormones, estrogens in females and androgens in males, play a major role in the maintenance of bone density. What do they do?

1. The sex hormones principally stimulate osteoblasts to make osteoprotegerin. 2. Thus, they reduce the activation of osteoclasts 3. This explains why women are much more likely to develop osteoporosis (low bone density) than men. a. Men keep high levels of circulating androgens throughout life. b. Women are only exposed to estrogens until menopause; after menopause, the concentration of estrogen drops precipitously, decreasing the production of osteoprotegerin.

The active form of vitamin D (1,25-dihydroxycholecalciferol, 1,25-OH-D3) and parathyroid hormone have somewhat more complicated effects on osteoblast function. What do they do?

1. These two hormones can either stimulate osteoblastic function more-so than osteoclastic function or vice versa, depending on the situation 2. PTH is made continuously by the parathyroid glands in small concentrations, but is made in much higher quantities in response to hypocalcemia. 3. PTH stimulates osteoblasts to increase the production of matrix, alkaline phosphatase, and osteoprotegerin, as well as RANK-L, IL-6, and M-CSF a. What determines the proportion of the pro-bone growth factors relative to pro- osteoclast factors is the concentration and duration of the PTH exposure. b. Low dose, short term exposure to PTH preferentially stimulates the osteoblasts to produce the pro-bone growth factors, whereas high dose, long term exposure to PTH preferentially stimulates the osteoblasts to produce the pro-osteoclast factors. 4. PTH also stimulates the activation of vitamin D a. The vitamin D that is produced has direct effects on the osteoblasts themselves, but it also reduces the secretion of PTH and increases the absorption of calcium and phosphate from the diet b. Overall, vitamin D tends to stimulate the synthesis of new bone more than stimulating the degradation of old bone, especially if the plasma concentration of PTH is relatively low.

In the fetus, the bone may develop by one of two mechanisms, what are they? What are the

1. Transmembranous ossification 2. Endochondral Ossification

What are some treatment options for Osteopetrosis?

1. Treatment options may include prescription Vitamin D, maintaining a low calcium diet, and corticosteroids to reduce bone density 2. In some patients, bone marrow transplant may be beneficial, or even curative 3. By transplanting bone marrow from a healthy donor, osteoclastic precursors are transplanted to the patient that may be able to function normally

Where is type I cartilage deposited? Where is type II cartilage deposited?

1. Type I cartilage is deposited by the fibroblasts 2. Type II cartilage is deposited by the chondrocytes

When the osteoclast is activated, what occurs?

1. When the osteoclast is activated, it attaches to the bone matrix and secretes hydrochloric acid and lysosomal enzymes (acid hydrolases), particularly tartate-resistant acid hydrolase (TRAP)

The arrangement of the chondrocytes in fibrocartilage is distinct from that of other cartilages. how so?

1. While isogenous groups are sometimes seen, these chondrocytes are often found as individual cells or in plates 2. The fibroblasts are usually found as individual cells and are far removed from the chondrocytes 3. The matrix of fibrocartilage shows a "wavy" pattern, more typical of dense regular CT, due to the large proportion of type I collagen

Keep in mind that the hyaline cartilage that is forming around the fracture is not "filling in the gap," per se...what is occuring?

1. it is replacing the original blood clot that formed 1. Because of this, the cartilage that forms is a large, rounded region that also encompasses the fracture site. 2. This structure is called a soft callus.

Any time that you see a γ-carboxylated glutamate residue, know that the enzyme responsible for that post-translational modification (γ-glutamyl carboxylase) requires what as an cofactor?

1. vitamin K (phytonadione or menaquinone) as a cofactor.

Blood vessels do penetrate the perichondrium. Except for what?

1.Articular surfaces are an exception to this. The cartilage found there does not contain a perichondrium—due to the mechanism by which bone formation occurs.

The cells in cartilage is called?

1.Chondrocytes

What is interstitial growth?

1.Chondrocytes that are already within the matrix are stimulated to divide and produce more matrix 2. These cells will form isogenous groups, with the daughter cells fairly close to one another. 3. As the isogenous group lays down more matrix, the cells further separate, and the tissue continues to expand.

Figure 13.16 shows radiographs of two bone fractures with the callus clearly visible

1.From here, the process is essentially endochondral ossification: the hyaline cartilage will calcify, which stimulates osteoclasts and osteoblasts to replace the tissue with bone 2. At this stage, the callus is still present, it is just made of bone instead of cartilage; it is now called a bony callus. 3. Over time, remodeling of the bony callus occurs, reshaping it so that it is consistent with the original shape of the bone. 4. The whole process can take 6-12 weeks, oftentimes longer for full remodeling of the hard callus.

What are the thee types of cartilage?

1.Hyaline cartilage 2.Elastic cartilage 3.Fibrocartilage.

What are Osteoprogenitor cells?

1.Osteoprogenitor cells are stem cells of other bone cells; when new bone cells are needed, they can be derived from the osteoprogenitor cell 2. When these cells are stimulated to differentiate into other bone cells, they first become osteoblasts. i. Osteoblasts are thought of as "bone builders," because their main function is to lay down the new bone matrix. ii. Once the osteoblast has walled itself off into its own matrix, it is called an osteocyte. 3. The osteocyte is still capable of producing more matrix as well as remodeling its matrix to some extent. 4. Bone-lining cells are another cell type found in bone, specifically on the bone surface; they can also lay down new matrix but are pretty quiescent until stimulated.

The structure of bone can be described in terms of its structural density as well as its structural morphology. In terms of its structural density, bone can either be compact (also known as cortical) or trabecular (also known as spongy or cancellous). What are these types of structures?

1.The outer region of a long bone is quite dense without any open spaces—this is compact bone 2. Much of the interior of the bone is a meshwork of bone tissue filled with small open spaces—this is spongy bone a. In living specimen, the open spaces constitute the bone marrow. b. The marrow is filled with either adipocytes (yellow marrow) or hematopoietic cells (red marrow).

How do the X-Rays work under Osteogenesis Imperfecta (OI)? What are the treatment options?

1.X-rays can depict a multitude of abnormalities in the bones of these patients 2. The treatment for OI can vary based on the type of disease a patient has a. While bisphosphonates are used, their overall efficacy is limited. b. Physical therapy and physical aids to improve mobility are commonly employed, although surgical correction of bone deformities may be required.

For an osteoclast (which is derived from the monocyte/macrophage lineage) to complete its differentiation. What is required?

1.the osteoclast precursors require a number of growth factors (including IL-6 and M-CSF). 2. Along with other growth factors, the osteoclastic precursors will begin expressing carbonic anhydrase, TRAP, and the H-ATPase. 3. These cells will then begin to fuse with each other, creating a multi nucleated cell that is capable of actively degrading bone tissue.