Bone

Fibroelastic cartilage structure

***Type I collagen in the matrix (has less water and proteoglycans than hyaline) ***found in intervertebral disk, subarticular surface of mandibular condyle and the meniscus of the kneee -also found as a stage of regeneration at fracture sites

Hyaline cartilage structure

***where do you find it and what is in the matrix...ALL we need to know about each type -appears in endochondral bone formation first -trachea, nasal wall and covers articular surfaces in many joints ***MAIN COLLAGEN IS TYPE II ***Not found in the TMJ

Vitamin D conversion

**KNOW -Direct effect of Vit D on Bone: increases Ca release -Direct effect of Vit D on GI tract: enhances intestinal absorption of calcium and phospates

Calcium

-***serum level for ionized: 2.2 -2.6 mmol/L, most common to report 4.5-5.6 mg/dL (4.3 is too low) -recommended intake: 1000 mg/day (1g) -regulation: PTH, Vitamin D (stimulates osteoclasts), calcitonin (will stop Vit D, inactivates it) -Vit D is synergistic with PTH

Calcium composition

-50% ionized (the active form/free calcium) -41% bound to albumen -9% bound to ions (phosphates) **This is important so know!** -Ionized calcium is the most dangerous part?? Low levels of free ionized calcium can cause the heart to slow down or speed up, can cause muscle spasms, and can even result in coma

What makes up inorganic matter?

-50% of the dry weight of bone -calcium and phosphorous mainly --> hydroxyapatite crystals -non-crystalline calcium carbonate -magnesium, potassium, sodium and bicarbonate and citrate

What percent of phosphates are stored in bone?

-85% of the body phosphates are stored in bone -1% is extracellular -14% is intracellular

What is the percentage of calcium stored in bone?

-98.9% of body calcium is stored in bone -0.1% of calcium is in the extracellular fluid -1% of calcium is intracellular

Hydroxyapatite crystals

-Ca5(PO4)3(OH), usually written Ca(PO4)6(OH)2 to denote that crystal unit cell comprises two entities. -the crystal is surrounded by a hydration shell that facilitates exchange with body fluids

deficiency and overdose of vitamin D

-Deficiency: rickets in growing children and osteomalacia in adults (SOFT BONES) -overdose (>50,000 IU, especially in patients with high PTH) --> bone resorption -supplementation doesnt seem to improve osteoporosis -vitamin D causes bone resorption whether it is low or high

osteocalcin (uOCN) vs FGF-23

-FGF23 acts on the kidney to decrease activity of 25(OH)D-1a hydroxylase, enhance 24 hydroxylase expression, and increase excretion of inorganic phosphate -uOCN acts on pancreas B cells to increase insulin production and secretion, on adipocytes to increase adiponectin and on muscles to increase insulin sensitivity and glucose uptake

Molecular signals in bone remodeling

-PTH doesnt always stimulate bone formation, but it can under certain circumstances, normally does bone resorption (sometimes stimulating osteoblasts)

Vitamin D

-PTH then activates vitamin D -vitamin D actually stimulates bone resorption (not bone formation like we would think) -vitamin D does not help prevent osteoporosis ***KNOW: daily requirement is about 400IU/day -more than 50,000 would be toxic

What is the process of bone breakdown by osteoclasts?

-active osteoclasts show a folded, irregular border facing the bone surface called a ruffled border -the ruffled border is surrounded by a ring of organelle free cytoplasm called the clear zone. This zone attaches firmly to the bone matrix to seal off the contact area between the ruffled border and the bone surface (subcellular pocket) -the pocket will thus have high concentration of proteolytic enzymes and protons (acids) produced by the osteoclasts --> demineralization then digestion of matrix

Where is bone the toughest?

-along its axis of the osteon

Section of a haversian system or osteon

-alternation of clear and dark circles resulting from the alternation in the direction of the collagen fibers -the collagen fibers appear bright when cut longitudinally and dark when cross-sectioned. In the center of the osteon is channel (blood vessel) ***these are specific to cortical bone

Osteocytes

-are osteoblasts that became trapped inside the bone they synthesized -the osteocytes processes extend through a network of bone channels called canaliculi -extracellular fluid is believed to run within the bone canaliculi and play a role in transmitting mechanical stresses and strains, as well as nutrition to the osteocytes

The remodeling of the haversian system

-as bone remodels, new haversian systems form, while the remaining parts of the old ones becomes interstitial lamellae -remodeling is a continuous process responsible for bone adaptations, especially during growth

Bone formation/loss in females/males

-at 18 you have developed most of your bone mass -men have/gain bone more to start with and they keep it longer than women do -women have/gain less bone to start with and keep it shorter than men do

What is the function of osteoclasts?

-attach to the bone surface --> demineralize the bone, then phagocytose the matrix -they start forming a sealed depression in the bone surface, called Howships lacuna, where they either start digging a tunnel into the bone or leave and create another lacuna in a different area

Parathyroid hormone

-binds to receptors on osteoblasts --> osteoclasts stimulation (+RANKL and -OPG) --> demineralization of bone matrix --> increase in serum calcium -PTH stimulates Vitamin D synthesis so more calcium is absorbed in the GI tract -PTH also decreases serum phosphates by increasing its excretion in urine Feedback -high serum calcium --> --PTH and ++calcitonin (thyroid) --> inhibition of osteoclast induced bone resorption --> less serum calcium

Drug that prevents too much bone resorption

-bisphosphate is a drug that seems to be very effective, kill osteoclasts -often used in dental care -osteonecrosis of the jaw is a major problem seen and need to prescribe bisphosphate to prevent bone loss

Metabolic role of bone tissue

-bone contains 99% of total body calcium -there is a continuous calcium transaction between hydroxyapatite crystals in the spongy bone and the blood (rapid transfer) -primary bone tumors and bone metastasis from distant malignancies --> break down of matrix --> hypercalcemia

Wolff's law

-bone formation pattern depends on mechanical load -if you stop using certain bone parts, bone resorption will take over (if you dont use it, you loose it) -bone is programmed to resorb automatically

How is bone used as a buffer?

-bone is an important site of buffering acid load (bicarbonate) -the uptake of excess H ions by bone occurs in exchange for surface Na and K and by the dissolution of bone mineral, resulting in the release of buffer compounds (NaHCO3, CaHCO3, CaHPO4) ***at least 40% of the buffering of an acute acid load takes place in bone

Cortical bone (compact or lamellar)

-bone is arranged in concentric layers (lamellae) that form vertical columns around a central blood vessel (Haversian system or osteon) -collagen fibers in each lamella have the same direction, forming a helix that is at a right angle to the helix formed by adjacent lamellae -in between the osteons, there are layers of interstitial fluid -on the outer surface of the bone, there are outer circumferential lamella. At the marrow cavity there are inner circumferential lamellae. -when you take a longitudinal section of the canal, the channels communicate and the blood vessels are connected to one another

What are osteoclasts? Where are osteoclasts created?

-bone resorbing cells -large multinucleated (5-50 nuclei), and highly mobile -originate from fusion of monocytes from bone marrow

Bone remodeling (get rid of old bone and build new bone simultaneously)

-bone tissue is constantly being broken down and simultaneously being replaced by new bone (happens throughout life) -osteocytes seem to the be the moderators of bone remodeling based on their monitoring ability of the mechanical environment -osteocytes stimulate osteoclasts and osteoblasts -microcracks cause osteocyte apoptosis, which is one of the signals attracting osteoclasts

What is the function of calcitonin?

-calcitonin keeps osteoclasts from destroying the bone matrix --> keeps the calcium in the bone --> decrease serum calcium levels -calcitonin tones down calcium in serum by getting the bone to take up calcium (more bone formation and decreasing bone resorption)

What is the function of calcium and phosphates in bone?

-calcium is essential to muscle contraction, including cardiac and respiratory muscles -phosphates are essential for storage and utilization of energy, integral to many proteins, and essential for activation and deactivation of reactions -the main goal of homeostasis in bone is to stabilize the serum levels of calcium and phosphate ***w/o phosphate you cannot perform a single metabolic reaction

Chronic acidosis due to acids in bone

-can have severe adverse effects on bone mineralization due to this process -can result in bone dieases such as rickets, osteomalacia and osteopenia -can also result in renal failure, liver failure, alcoholism, cancer

Epiphyseal plate

-chondrocyte proliferation and ossification proceed at the same pace throughout growth, maintaining the width of the epiphyseal plate while diaphysis grows -the epiphyseal plate closes when proliferation of chondrocytes stops --> the plate completely ossifies and disappears

What is periosteum?

-connective tissue layer containing bone osteoblasts and progenitor cells covering the outer surface of the bone -two layers: outer fibrous (collagen and fibroblasts) and inner cellular (osteogenic) -bound to the bone surface by collagen fibers that penetrate the bone called Sharpeys fibers

What percentage of bone cells are osteocytes? Where are osteocytes found?

-constitute 95% of bone cells -live for decades -they reside in tiny chambers called lacunae and they communicate with each other through gap junctions at the ends of their cytoplasmic processes

Steroid hormones and bones

-cortisone can have major effects on calcium and vitamin D metabolim --> bone loss -daily 5 mg oral prednisone > 3months leads to increase risks of fractures -a person on chronic cortisone therapy is twice as likely to have a spine fracture -risk factor for ONJ (osteonecrosis of the jaw) -cortisone therapy during growth --> risk for avascular necrosis of fermoral head -the risk of fracture decrease 3 months after cessation of GC (glucocorticoid) therapy

What controls osteoclasts activation?

-cytokines including RANKL and IL-1 --> stimulation and osteoprotegrin (OPG) --> inhibition -hormones, including thyroid and calcitonin -parathyroid thyroid hormones stimulates osteoclasts indirectly through stimulating osteoblasts to produce IL-1

Intramembranous bone formation

-during development and secondary regeneration, bone can be formed within a scaffold of mesenchymal tissue condensation (begins as a membrane of connect tissue)

Haversian System (Osteon)

-each osteon is a long, may be bifurcated cylinder of 4-20 concentric rings of bone (lamellae) around a central canal -the central canal has a blood vessel, a nerve, and loose connective tissue -central canals are connected to each other and to the marrow cavity via transverse or oblique Volkmanns canals that perforate their way through the lamellae

Need a positive balance between calcitonin and PTH

-effect of calcitonin is transient cause lowering the serum calcium will stimulate PTH

Central control of bone homeostasis: Leptin

-fat cells and brain produce leptin -leptin is a adipocyte-derived hormone that controls appetite (lets you know when to stop eating) -leptin inhibits bone formation (decreases release of serotonin, bad for bone also)

Parathyroid glands

-four small (3x6 mm) glands located behind the thyroid, one on each corner -sometimes they are embedded inside the thyroid mass -lose up to half of its mass to adipose tissue in old age

What are the three types of cartilage?

-hyaline cartilage -fibroelastic cartilage -elastic cartilage **just need to know these 3 types and the difference btw them -chondrocytes and chondroblast are the same thing

Immature vs Mature bone

-immature, primary, or woven bone is composed of hypomineralized matrix that has randomly aligned collagen fiber -it is the first formed bone during both development and regeneration -subsequently, it should remodel into mature bone, either compact or cancellous -a few zones remain as primary bone such as tooth sockets

Osteocalcin

-improves diabetes control

What are the two direct affects of cortisone on bone cells?

-inducing apoptosis in osteoblasts and osteocytes, thereby decreasing bone formation -prolonging the lifespan of osteoclasts and increasing bone resorption *cortisone kills bone if used long term

Oral manifestations of hyperparathyroidism

-intraoral photograph revealing a growth extending buccally and palataly 12-18 region ***brown tumor (actual hyperparathyroidism that presents like an aggressive benign or malignant tumor) *usually serum calcium levels are high here

What is endosteum?

-line the inner cavities of the bone, including the marrow cavity and trabecular surfaces -composed of a single layer of osteoprogenitor cells -together with the periosteum, it provides a constant supply of osteoblasts

What is the function of osteoblasts?

-line themselves on the surface of existing bone and lay down more bone there (bone apposition) -synthesize the matrix (osteoid), then mineralize it -some osteoblasts become trapped in the bone they form, where they become osteocytes -inactive osteoblasts are flat, become cuboidal when activated and start showing rER in the cytoplasm

Bone resorption overview

-lysosomal enzymes packaged in the golgi and hydrogen ions produced are released into the confined compartment created by the attachment between bone matrix and the osteoclasts peripheral clear zone -the acidification faciliates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases -bone matrix is thus removed and the products of bone resorption are taken up by the osteoclasts cytoplasm, probably digested further, and transferred to the blood capillaries

Parafollicular cell structure (C cells)

-made by the thyroid -within the follicular epithelium or as clusters between follicles -long mitochondria, large golgi and less rER

Compact vs Cancellous bone

-most bones have a shell of cortical bone -at some parts within that shell, there is a core of cancellous or trabecular bone -the mandible is almost entirely cortical, except for the core of the alveolar process and part of the condylar neck -the maxilla has thin cortical plates filled at its alveolar process with cancellous bone

C cells/Parafollicular cells function in the thyroid

-numerous secretory granules containing Calcitonin -preserves bone mass by limiting osteoclasts induced bone demineralization -lowers blood calcium levels

Taking calcitonin

-often used to treat osteoporosis, Paget's disease and hypercalcemia -salmon calcitonin (nasal spray 100 IU/day) reduced the risk of vertebral osteoporotic fractures by 33%

What is the function of osteocytes?

-one osteoblasts in each lacuna -sensitive to mechanical stimuli, especially shear stress -they are long-living cells -their death triggers bone resorption, which may be followed by formation of new bone

Bone as a tissue

-organic matrix, inorganic minerals, and cells -periosteum and endosteum

Where are osteoblasts found?

-originate from osteoprogenitor cells in bone marrow and periosteum -found in blood

Bone cells structures

-osteoblasts (bone formation) -osteoclasts (bone resorption) -osteocytes (bone control centers)

PTH related protein (PTHrP)

-produced in many fetal tissues -its expression only reappears in adults when injury and or malignancy occurs -3 splice variants -necessary for normal development as a regulator of proliferation and mineralization of cartilage cells and as a regular of local calcium transport -intermittent dose stimulates bone formation and inhibits bone resorption (opposite of what you would normally think) -being used as a bone anabolic drug, typically to treat osteoporosis

What is the function of alkaline phosphatase during bone formation?

-released after chondrocytes hypertrophy -cause reabsorption of the surrounding matrix before they degenerate -meanwhile the remaining matrix becomes mineralized because of alkaline phosphatase expression by the degenerating chondrocytes -its a marker of demineralization

A small portion of an epiphyseal plate showing endochondral ossification

-remnants of calcified cartilage matrix (dark purple) appear covered by light stained bone tissue -the newly formed bone is surrounded by osteoblasts -some osteoblasts that were captured by the osseous matrix become osteocytes (arrows) *The darker purple is the matrix of the cartilage and the pink is the bone being formed -this is indicative of endochondral bone formation

Where is calcitonin made?

-secreted by the parafollicular C cells of the thyroid and other neuroendocrine cells -secretion is controlled by serum calcium through the same CaSR that regulates PTH secretion, but in an inverse manner -levels increased when serum Ca > 2.25 mmol/L

What is an epiphyseal plate?

-separates the the large and growing primary ossification center in long bone diaphyses and the secondary ossification centers in epiphyses in developing bones -connects the epiphyses to the diaphyses -chondrocytes are arranged in columns that are parallel to the direction of growth -hypertrophy of chondrocytes will thus separate the epiphysis from the diaphysis, making the bone longer -closes when bone stops growing

FGF-23 (fibroblast growth factor)

-stimulates bone resorption in general and inhibits bone formation -seems to increase with age -actually bad for bone, suspected to be a cause of postmenopausal osteoporosis by inhibiting bone formation

What is the function of the parathyroid hormone?

-stimulates osteoclastic bone resorption (via osteoblasts-releases IL-1, IL6 and RANKL) --> increase serum calcium -opposes the actions of calcitonin

What are the functions of vitamin D?

-stimulates the formation of osteoid (matrix formation, osteoid is the matrix without the calcium) -can cause bone resorption by mature osteoclasts, indirectly by osetoblasts -also promotes the fusion of monocytic precursors to osteoclasts -regulates the expression of osteocalcin by promoting transcription -has bidirectional effects on type I collagen and ALP gene transcription (NOT IMPORTANT)

Anti-resorptive agents

-such as bisphosphonates can disrupt the resorptive function of osteoclasts -RANKL antagonists can inhibit all stages of osteoclastogenesis -both reduce osteoclast activity but also reduce the osteoblast pool -drugs that kill osteoclasts -given to post-menopausal women

Cortical bone with the different canals

-the central canals are connected by smaller canals (The Haversian canals, interconnecting the latter with each other and the periosteum); Volkmans canals are any of the small channels in the bone that transmit blood vessels from the periosteum into the bone and that communicate with the Haversian canals. The perforating canals provide energy and nourishing elements for osteons.

Cutting cone containing osteoblasts and osteoclasts (Bone Remodeling Unit) ***bone resorption followed by bone formation --> continues throughout life

-this is bone remodeling that happens very slowly and pace of it is very highly controlled. -Rate of bone formation is balanced with the rate of bone breakdown -Osteoclasts lead the way by digging a tunning in old bone and breaking it down. The front is resorption front, where the first breakdown happens. Osteoclasts are releasing a lot of cytokines behind them, stimulating angiogensis (blood vessels). Osteoblasts lay down layer after layer of bone. ***osteoclast make up head of cutting cone, followed by capillaries and then osteoblasts which lay down the osteoid to fill the cutting cone

Which bones form by intramembranous bone formation?

-this is how flat bones develop, including most craniofacial bones (except portions of the mandible and skull base), hip, scapula, part of the clavicle, and sternum **this is how the mandible and maxilla develop

Cut section of endochondral ossification

-this osseous matrix, rich in collagen type I, is specifically stained with picosirius hematoxylin -the cartilaginous matrix, containing collagen type II stains blue with hematoxylin because of its high content of chondroitin sulfate -you can see this in the mandible

Micrograph of osteoclasts

-three osteoclasts digesting bone tissue. -the osteoclasts is a large cell with several nuclei and a ruffled border close to the bone matrix -where bone erosion continues, the compartment is acidified by a proton pump localized in the osteoclasts membrane --> decalcification then matrix digestion

Organic bone matrix

-type I collagen and ground substance (proteoglycans and glycoproteins) -glycoproteins are believed to play in role in stimulating and organizing mineralization of type I collagen -demineralized bone is flexible like tendons because of its collagen content. Removal of the organic matrix leaves the bone too brittle to take mechanical loading -mineralization of the type I collagen is responsible for bone hardness

What is endochondral bone formation?

1. During development and secondary regeneration, bone can form within a scaffold of cartilage 2. Bone starts to form in a collar around the center of the scaffold, then within the center, then at both ends 3. the cartilage tissue being replaced undergoes cell death (chondrocytes hypertrophy and express alkaline phosphatase 4. Bone resorption and mineralization of bone 5. blood vessels and cells invade the area 6. the calcified cartilage is broken down (by osteoclasts) and replaced by mature bone (osteoblasts)

Events that occur during intramembranous ossification

1. Osteoblasts synthesize collagen, which forms a strand of matrix that traps cell 2. as this occurs, the osteoblasts gradually differentiate to become osteocytes 3. the lower part of the drawing shows an osteoblast being trapped in newly formed bone matrix

Where is hyaline cartilage found?

1. forms scaffold for endochondral bone during development 2. forms epiphyseal cartilage in long bone --> growth 3. structural component of the tracheal and nasal wall 4. covers the articular surfaces of bones in many joints (very good in shock absorption)

What are the steps in intramembranous bone formation?

1. ossification of the mesenchyme starts at the primary ossification center, where cells differentiate into osteoblasts 2. osteoblasts lay down osteoid and later ossify it with calcium 3. several ossification centers follow, creating cavities in between that include blood vessels, nerves, undifferentiated cells and connective tissue (marrow cavities) 4. ossified islands grow wider and ultimately fuse

Bone mass in men and women

1. peak bone bone mass is higher in men than women 2. the declining phase where you loose more bone than you gain happens in women (50-55 yrs old) and men (65 yrs old) -->Women loose bone faster than men

What are the five zone of the epiphyseal plate?

1. resting zone: hyaline cartilage 2. Proliferative zone: proliferation of chondrocytes in columns parallel to the long axis of bone 3. Hypertrophic zone: hypertrophy of chondrocytes within the columns by accumulating glycogen 4. Calcified cartilage zone: chondrocytes die and matrix is calcified 5. Ossification zone: calcified cartilage is resorbed by osteoclasts, followed by invasion of blood vessels and osteoprogenitor cells forming new bone

What is the second step of embryonic development of endochondral bone?

2. At the central zone (diaphysis), the cartilage is replaced by immature bone, which is then broken down by osteoclasts, opening tunnels for vascular invasion and osteoblastic bone formation --> remodeling into lamellar bone (primary ossification center)

What is the third step of embryonic development of endochondral bone?

3. secondary ossification centers appear at the ends of cartilage scaffold (epiphyses)

What is the fourth step of embryonic development of endochondral bone?

4. The area where the epiphyses meets the diaphysis stays as cartilage as long as the bone is growing in length and is called the epiphyseal cartilage or growth plate

What is the fifth step of embryonic development of endochondral bone?

5. The end surface of the epiphysis stays cartilaginous in most joints throughout life and is called the articular cartilage

How is bone considered an organ?

According to gross architecture: 1. compact (cortical and lamellar) 2. cancellous (trabecular; spongy) According to microscopic architecture 1. immature (primary; woven) 2. mature (secondary; cortical or cancellous) According to embryologic formation mechanism 1. endochondral 2. membranous

What type of bone has the most strength?

Cortical bone The helix of each layer is perpendicular to the next layer, imparting tremendous strength

ONJ

Osteonecrosis of the jaw **need to know this term

What is the physiological role of PTH?

TARGET IS TO INCREASE SERUM CALCIUM LEVELS -drop in calcium increase PTH -bone: increased Ca(PO4) release (resorption) = calcium being released from bone to circulation -kidneys: increased reabsorption of Ca and excretion of PO4 (calcium stays and phosphates go) increase hydroxylation (activation) of vitamin D -GI tract: indirect increase in calcium reabsorption by stimulating activation of vitamin D metabolism

What are the functions of calcitonin in bone?

TONES DOWN CALCIUM SERUM LEVELS -inhibits osteoclasts mediated bone resorption -stimulates osteoblasts --> + mineralization of bone -stimulate calcium excretion in the kidney (inhibits reabsorption --> opposite to PTH)

Bone is?

a reservoir of calcium and phosphate

What is the disc of cartilage that separates adult bone from compact bone?

growth plate

Which bones undergo endochondral bone formation?

long bones and bones forming the base of the skull develop this way

Elastic cartilage structure

similar to hyaline cartilage but with elastic instead of collagen in the matrix ***Instead of collagen type II it is ELASTIC cartilage ***found in external ear and eustachian tube

What is the first step of embryonic development of endochondral bone?

1. A hollow cylinder (collar) of bone is formed around the cartilage rod via intramembranous ossification within the perichondrium

What are the hormones produced by bone?

Osteocalcin and FGF-23