Bone Flashcards
What is Bone?
• Mineralized, rigid connective tissue
• Functions: o Supports soft tissues o Muscle attachment to move body o Protects vital organs o Surrounds bone marrow (blood cell formation) – don’t want to expose it to UV radiations of the sun that could cause mutations o Reservoir of calcium, phosphate, etc.
• Cells:
o Osteoblasts
o Osteocytes
o Osteoclasts
Bone Matrix
• Matrix contains a significant amount of inorganic material – matrix is very MINERALIZED
• Inorganic matter in matrix:
o Calcium, phosphorus, magnesium, potassium, etc.
o Calcium and phosphorus form hydroxyapatite crystals
• Organic matter in matrix
o Type I collagen
o Ground substance
• Metabolites can’t diffuse through the matrix, so CANALICULI allow
communications among cells (they are like tunnels)
How to make histological
slides
• Decalcified bone sections
o Acid solution removes
calcium salts and softens
bone – can’t just slice it
with a microtome like
other tissues
o Bone can then be
embedded and
sectioned
o Osteocytes are distorted
• Ground bone sections
o Saw bone in slices and grind pieces down until very thin
o Cells are destroyed, but it will keep integrity of the matrix
Osteoblasts
- Matrix (osteoid) synthesis
- Basophilic cytoplasm
*ORIGIN - MESENCHYME
- Osteoprogenitor > preosteoblast > osteoblast
- Line surfaces of bone tissue (resemble simple epithelium)
• Cuboidal to columnar in shape when active in matrix synthesis; more
squamous when less active
- Become bone lining cells or osteocytes
- Functions:
o Synthesis of unmineralized bone matrix (osteoid)
o Osteoid resorption
o Osteoclast stimulating factors
o Involved in matrix mineralization
Osteocytes
o Derived from osteoblasts
(osteoprogenitors > turn
into Osteoblasts > turn
into Osteocytes)
o Matrix maintenance – do NOT secrete matrix
o Found in lacunae (surrounded by matrix)
*ORIGIN = MESENCHYME
• When osteoblasts surround themselves with matrix, they become
osteocytes
o Each osteocyte is in a space in the matrix called a lacuna
o Osteocytes have long cytoplasmic processes, these are in tunnels
called canaliculi
• Gas, waste, nutrient exchange can’t occur
through mineralized matrix
o The osteocyte processes contact each other via gap junctions
o Exchange using the gap junctions can provide nourishment for a
chain of about ten cells
• Functions:
o Maintain matrix
o Mechanosensory: detect mechanical loading and therefore need
for bone increase or decrease
Osteoclasts
see ppt for pictures
Matrix resorption
o Large, multinucleated (5-50) cells
o Also found on the surface of bone but look much different that
osteoblasts
- Have microvilli
- Sit in a cavity called Howship’s Lacuna as bone is removed
*ORIGIN = HEMATOPOIETIC
Joints see other card deck as well
• Functional classification:
o Synarthrosis – limited/no movement
o Amphiarthrosis – slightly moveable
o Diarthrosis – freely movable
• Structural classification:
o Fibrous joints: connected by dense CT
- Suture: non-movable, only in skull
- Syndesmosis: limited movement, e.g. between radius and ulna
- Gomphosis: limited movement, only dentoalveolar joint
o Cartilaginous joints: connected by cartilage
- Symphysis: fibrocartilage, e.g. pubic symphysis
- Synchondrosis: hyaline cartilage, temporary joint that will eventually fuse, e.g. between sphenoid & occipital
o Synovial joints: articular surfaces with hyaline cartilage, synovial fluid in a capsule; hyaline cartilage in synovial joints does not have perichondrium and are nourished by synovial fluid
Synovial Joints
- Ends of bones are lined by ARTICULAR CARTILAGE, hyaline cartilage with no perichondrium
- Joint held together by ligaments and a joint capsule
• Capsule is lined by a SYNOVIAL MEMBRANE that secretes a lubricating
fluid
• Synovial membrane does not line articular cartilage or discs/menisci (if
present)
Types of Bones
• Bone can be classified in several ways
o SHAPE: long, short, etc.
o MACROSCOPICALLY: compact vs. spongy
o MICROSCIPICALLY: woven vs. lamellar
o EMBRYOLOGICALY ORIGIN: type of ossification
Shapes of Bones
• LONG BONES: longer than they are wide (Most of the limb bones)
• SHORT BONES: approximately cube-shaped
(Mostly spongy bone like wrist and ankle bones)
• FLAT BONES: thin and flat
Two layers of compact bone, with one layer of spongy bone (diploe) between (sternum, ribs, skull bones)
• IRREGULAR BONES: none of the above (some skull bones, hip bones, vertebrae)
Long Bone Anatomy
From outside to inside:
periosteum > compact bone > endosteum > spongy bone
• Diaphysis: shaft
• Epiphyes: at ends
- Spongy bone at
epiphyses
• Metaphysis: between diaphysis and epiphyses
• Epiphyseal plate/line:growth
• Periosteum
- Outer fibrous layer (dense CT)
- Inner osteogenic layer
- On the outside of the
compact bone
• Endosteum
o One the inside of the compact bone
• Articular cartilage (instead of periosteum) –
at joint surfaces
Periosteum and Endosteum
- Surfaces of bone covered by periosteum (external) or endosteum (internal)
- Periosteum has TWO layers
• SHARPEY’S FIBERS: periosteal collagenous fibers; bind periosteum to bone
o Type I collagen
• Endosteum is thinner than periosteum – it has ONE layer
Compact and Spongy Bone
• Compact bone (AKA cortical bone)
- Dense, looks smooth
- Surrounds the spongy bone
- Will have OSTEONS
• Spongy bone (AKA cancellous bone, trabecular bone)
- Small needle-like or flat pieces of bone (trabeculae)
- Open spaces between the trabeculae that are filled with bone marrow
- NOT penetrated by blood vessels: NO OSTEONS
Woven bone
- immature bone, primary bone
- Found in recently ossified bone
- Prenatal, growth and development, healing of a fracture
- First bone to form during development or bone repair
• Abundant osteocytes – lots of cells compared to
lamellar bone
- Irregular bundles of type I collagen
- Less mineralized than lamellar bone
- Cells appear to be scattered randomly
Four Lamellar Bone
1) Outer circumferential lamellae
2) Inner circumferential lamellae
3) Osteons (Haversian systems)
4) Interstitial lamellae
Outer Circumferential Lamellae
Just deep to
periosteum (Layers that go in a circle around the outside just deep to periosteum)
Contain sharpey’s
fibers (collagen bundles that anchor periosteum to bone)
Inner Circumferential Lamellae
Encircle marrow cavity (Layer that goes around in a circle around the INSIDE)
Spongy bone trabeculae extend from this layer into the marrow cavity
Osteons
(Haversian System)
§ Cylinders of lamellae
§ 4-20 concentric layers around a
blood vessel in a HAVERSIAN
CANAL
§ Haversian canals are connected
by VOLKMANN’S CANALS,
oriented perpendicular to
Haversian canals
§ Blood stays IN THE CANALS
§ Each osteon is bounded by a CEMENT LINE (calcified
ground substance, with little collagen)
§ Collagen bundles are parallel to each other within a
lamella, but perpendicular to those in adjacent lamellae
§ Cytoplasmic projections of osteocytes are connected via
gap junctions
§ Cell body sits in lacuna, and the canaliculus is the extension
of the lacuna that the projections of the cell go through so
they can exchange nutrients (can view empty spaces of the
lacuna/canaliculi histologically)
Osteons
(Haversian System)
- Cylinders of lamellae
- 4-20 concentric layers around a blood vessel in a HAVERSIAN CANAL
- Haversian canals are connected by VOLKMANN’S CANALS, oriented perpendicular to Haversian canals
- Blood stays IN THE CANALS
- Each osteon is bounded by a CEMENT LINE (calcified
ground substance, with little collagen) - Collagen bundles are parallel to each other within a
lamella, but perpendicular to those in adjacent lamellae - Cytoplasmic projections of osteocytes are connected via
gap junctions - Cell body sits in lacuna, and the canaliculus is the extension of the lacuna that the projections of the cell go through so they can exchange nutrients (can view empty spaces of the lacuna/canaliculi histologically)
Bone remodeling
• Tissue is removed by osteoclasts, replaced by osteoblasts
- Newer osteons replace older ones
- To replace woven with lamellar, and to replace old lamellar with new lamellar
- As bone is remodeled, osteoclasts resorb osteons and osteoblasts replace them
- Remnants of old osteons remain as INTERSTITIAL LAMELLAE, located between current osteons
• Bone remodeling is done by a basic multicellular unit (BMU), a wandering team of cells that dissolves an area of the bone surface and then fills it with new bone • Remodeling follows the A-R-F sequence o Activation o Resorption and reversal o Formation and mineralization
Ossification
- Bone formation; bone that appears first is woven bone, which is eventually replaced by lamellar bone
- Primary ossification center
- First area to start ossifying
- Usually during prenatal development
- Located in diaphysis (middle of bone) in developing long bones
• Secondary ossification center
- Appears after primary
- Usually during postnatal development
- Located in epiphyses in developing long bones
(top or bottom of bone)
Two Kinds of Ossification
o INTRAMEMBRANOUS OSSIFICATION:
- Develops from mesenchyme (i.e. no cartilaginous precursor; direct transition to mesenchyme)
- Direct mineralization of matrix secreted by osteoblasts
- Flat bones of the skull (frontal, parietal, etc.), lacrimal, nasal, palatine, vomer, maxilla, mandible (except condyle), some of clavicle
o ENDOCHONDRAL OSSIFICATION:
- Has cartilaginous precursor (template of hyaline cartilage)
- Cartilage does not become bone – the cartilage model is replaced by bone (cartilage cells die and disappear and bone tissue grows in its place)
- Usually long bone ossification as an example
Intramembranous Ossification
- Mesenchyme condenses and is
highly vascularized - Mesenchymal cells differentiate
into osteoblasts - Osteoblasts secrete bone
matrix (osteoid) to form
trabeculae
“osteoid” is a term for bone matric that does not yet have minerals in it
- Trabeculae fuse together to
form woven spongy bone (form the mineralized matrix) - The periphery of the spongy
bone will be remodeled into
lamellar compact bone; deeper
bone will be remodeled into lamellar spongy bone
Endochondral Ossification
- Hyaline cartilage model is formed
o See cartilage lecture for
cartilogenesis steps
2. Bone collar appears o Formed via intra-membranous ossification within the perichondrium o Hollow cylinder of bone around the mid-portion of the cartilage model (diaphysis in long bones)
o Note: the process of endochondral
ossification involves some
intramembranous ossification (to
make the bone collar)
- Chondrocytes in center hypertrophy, degenerate, and die
o Cartilage matrix is calcified - Empty spaces are invaded by the periosteal bud
o Vessels, mesenchymal cells, osteoprogenitor cells - Osteoprogenitors differentiate into osteoblasts, secrete osteoid on
surface of calcified cartilage - Bone collar increases in thickness and length, but osteoclasts resorb the
calcified cartilage and bone
o Results in marrow cavity which will be populated with marrow
cells - Secondary ossification centers form in a similar manner in the epiphyses
Growth in length and in width can occur – growth in length is only
possible while epiphyseal plate is present
*NOTE: Cartilage remains at EPIPHYSEAL PLATE (to
allow for growth in length
until adulthood) and at the
ARTICULAR CARTILAGE
Zones of Ossification
1) Zone of rest/reserve
- Typical hyaline cartilage
- Chondrocytes arranges randomly
2) Zone of proliferation
- Chondrocytes undergo mitosis and are arranged in
columns
3) Zone of maturity/hypertrophy
- Chondrocytes become enlarged, contain a lot of
glycogen
- Chondrocytes secrete alkaline phosphatase
4) Zone of calcification
- Cartilage matrix is calcified
- Chondrocytes are dying/dead due to calcified matrix – leave empty lacunae
5) Zone of ossification (primary spongiosa)
- Osteoprogenitors invade, differentiate into osteoblasts
- Osteoblasts secrete matrix (osteoid) on surface of calcified cartilage
- Matrix becomes calcified
- Osteocytes remove calcified cartilage and bone
(woven bone removed, lammellar bone replaced)
- Primary spongiosa is remodeled into secondary
spongiosa (lamellar bone)
Bone Matrix – Inorganic
Matter
• Very mineralized
• Inorganic matter is ~65% of dry weight
o For hardness and resistance
• Consists of calcium and phosphorus (mostly) – also bicarbonate, citrate,
magnesium, potassium, and sodium
• Calcium and phosphorus form HYDROXYAPATITE CRYSTALS:
Ca10(PO4)6(OH)2
• Also non-crystalline CALCIUM PHOSPHATE
Hydroxyapatite Crystals
- HA crystals look like rods along collagen fibrils
- Give bone hardness and compressive strength
• Hydration shell: layer of water around each HA crystal (surface ions of
crystal are hydrated)
o Facilitates ion exchange between the HA crystal and extracellular fluid
Bone Matrix – Organic
Matter
• Organic matter is ~35% of dry weight
o For flexibility and strength
• Collagen
o 90% of organic matrix
o Mostly type I collagen
o Gives bone tensile strength
o Triple helix, super coiled, typical 67 nm cross banding
o Greater number of cross-links within and between molecules than
in non-bone tissue
• Proteoglycans
o Give bone compressive strength
o Chondroitin sulfate and heparin sulfate
Bone Matrix – Non-
collagenous proteins
• Osteocalcin
o Produced by osteoblasts
o Involved in regulation of bone turnover
o Stimulated by 1,25 dihydroxyvitamin D3; inhibited by PTH
• Osteonectin o Produced by platelets and osteoblasts o Phosphorylated glycoprotein o Affinity for calcium, hydroxyapatite, and collagen, so it may play a role in organizing matrix mineralization
• Alkaline phosphatase
o May function in mineralization
o Blood serum levels increase during active bone formation – used
as a marker for bone formation
• Cell attachment molecules o Fibronectin o Thrombospondin o Bone sialoprotein o Osteopontin (bone sialoprotein I)
• Growth factors o Fibroblast growth factors (FGFs) o Insulin-like growth factors (IGFs) o Transforming growth factor β (TGF-β) o Bone morphogenic proteins (BMPs)
Osteoprogenitor Cells
• Mesenchymal stem cells
- On bone surfaces (i.e. inner/osteogenic layer of periosteum)
- Active during bone growth, fracture repair, bone remodeling
- Differentiate into osteoblasts (under influence of TGF-β and BMP)
Osteoblasts recruit
Osteoclasts
- In presence of PTH, osteoblasts release macrophage colony-stimulating factor that induces formation of osteoclast precursors
- Induce preosteoclasts to differentiate into osteoclasts
Osteoblasts recruit
Osteoclasts
• In presence of PTH, osteoblasts release macrophage colony-stimulating factor that induces formation of osteoclast precursors
• Induce preosteoclasts to differentiate into osteoclasts
o Preosteoclasts have RANK (receptor for activation of nuclear
factor kappa B) on cell surface
o Osteoblasts have RANKL (RANK ligand)
• Release osteoclast-stimulating factor which activates osteoclasts to
resorb bone
• Resorb osteoid before osteoclasts can attach to bone; secrete
osteopontin to seal osteoclasts to bone surface
What do Osteoblasts do?
• Osteoblasts do the following:
o Secrete M-CSF to induce formation of preosteoclasts
o Have RANK ligand (which binds with RANK on preosteoclasts)
o Secrete OSF and osteopontin (not shown in above diagram)
o Inhibit osteoclast activity by producing OPG – OPG prevents RANK-
RANKL interaction
§ Osteoprotegerin (OPG) produced by osteoblasts
§ Binds to RANKL and blocks RANK
• Inhibits differentiation of osteoclast precursors into
mature osteoclasts
• Regulates osteoclast activity
§ Decreases bone resorption
SUMMARY: in addition to other factors, M-CSF and RANKL INCREASE rate of bone resorption, and OPG DECREASES rate of bone resorption
Cortical Bone Remodeling
remodels by osteoclastic tunneling (cutting cone) o Osteoclastic resorption à layering of osteoblasts à formation of lamellae o Osteoclasts make up head of cutting cone, followed by capillaries and then osteoblasts which lay down the osteoid to fill the cutting cone
Spongy bone Remodelling
remodels by
osteoclastic resorption and
osteoblastic deposition of layers of lamellae
o No osteons are formed (no concentric circles of lamellae around a
vessel)
Bone Remodelling
• Bone remodeling has an equal amount of bone resorption and deposition
o No change in overall bone mass
o Replace old bone with new bone
• Bone modeling results in changes to bone mass or changes to bone form
o Change in size and shape due to resorption and deposition in
unequal amounts and on different surfaces
o Due to development and changes in loading patterns
o Ex: the mandible doesn’t stay the same shape as it grows (a baby’s
mandible is a different shape than an adult’s
• Resorption (-) and deposition (+) on the external and internal surfaces of a bone can produce differential changes in both size and shape, or relocation
Growth vs. Remodeling
Growth in length =
1) cartilage grows, is replaced
Remodeling = bone reabsorbed, bone added by appositional growth, bone resorbed
Steps of Bone Repair
- Blood vessels at the fracture site will break; hematoma (mass of clotted
blood) forms a fracture
o Tissue swells
o Inflammation
o Bone cells are dying (cut off from blood supply) - Hematoma is removed by macrophages; replaced by a soft callus; periosteum re-grows if necessary
o Fibroblasts and osteoblasts migrate in through growing capillaries
o Soft callus, rich in collagen and fibroblasts
o Amount of type I collagen increases over time - Soft callus is invaded by blood vessels and osteoblasts; soft tissue is
replaced by spongy bone, forming a hard callus
o First bone formed is woven bone – irregular trabeculae unite the
broken ends of the bone
o Endochondral ossification (at location of callus) and intra-
membranous ossification (at the periphery) - Bone of hard callus is remodeled
o Compact or spongy bone as appropriate
o Full vasculature is re-established
o Excess material is removed
Note: granulation tissue is
connective tissue and blood vessels that form during the healing process
Problems with Bone Repair
• DECREASED MINERALIZATION
o Calcium or vitamin D deficiency (rickets, osteomalacia)
o Bone resorption exceeds bone formation due to increased osteoclast activity or decreased osteoblast activity (osteoporosis)
• INCREASED MINERALIZATION
o Bone formation exceeds bone resorption;decreased osteoclast activity or increased osteoblast activity (osteopetrosis)
• PROBLEMS WITH ORGANIC MATRIX
o Impaired collagen formation (scurvy, osteogenesis imperfecta)
• ALSO: imbalance of growth factors, benign or malignant tumors,
infections, injury, etc.
Rickets
(Decreased Mineralization)
• Softening and weakening of bones in children, usually due to vitamin D
deficiency of Calcium or phosphate or both is insufficient in concentration to
properly mineralize bone
- Deficiency of calcium or phosphorus in diet
- Vitamin D deficiency»_space; intestinal mucosa can’t absorb
calcium - Poorly calcified bone matrix, distortion at epiphyseal plates
- Bones can become deformed because they can’t bear body weight
Osteomalacia
(Decreased Mineralization)
• Similar to rickets, but in adults
o Lack of available calcium or phosphorus (or both) for mineralization of newly formed osteoid
(Cannot mineralize bone like normal everyday)
• Decrease in the amount of calcium per unit of bone matrix
Scurvy
• Vitamin C deficiency
• Prevents hydroxylation of proline and lysine»_space; collagen contains only
non-hydroxylated proline and lysine à collagen fibrils lack hydrogen bonding and lose mechanical stability
• Leads to failure of collagen synthesis and osteoid formation
Osteoporosis
(Decreased Mineralization)
- Uncoupling of resorption and deposition
- Bone is histologically normal, but there is too little of it
- Most common metabolic bone disorder, especially common postmenopausal women (either enhances osteoclast or inhibits osteoblast activity)
o Estrogen prolongs osteoblast lifespan and suppresses M-CSH &
RANKL (so it inhibits osteoclast activity)
o Diminished estrogen»_space; osteoclast activity is greater than osteoblast activity»_space; decreased bone density
• Many classes of medications can cause osteoporosis as a side effect (e.g. corticosteroids)
• Bisphosphonates are used to treat osteoporosis
o Inhibit bone resorption by osteoclasts
o Incorporated into bone matrix and taken up by osteoclasts
- Metabolized by
osteoclasts to form an
inactive form of ATP
- cells undergo
apoptosis
- Block and enzyme in
the HMG-CoA
reductase pathway >
cell structures are
damaged, including
cytoskeleton >>
ruffled border can’t be
maintained
Osteogenesis imperfecta
- AKA “brittle bone disease”
- Genetic disorder
- Usually autosomal dominant
- Caused by mutations in the genes that code for type I procollagen
Osteopetrosis
(Increased mineralization)
• AKA “marble-bone disease”
• Genetic disorder; many
forms
o Mutations in genes that regulate osteoclast differentiation or osteoclast function (e.g. mutated RANKL or defective proton pumps on osteoclasts)
o Depending on the underlying genetic defect, the number of osteoclasts may be normal, increased, or decreased
• Failure of osteoclastic activity
o Increased bone density and thickening
o Bone tissue may be brittle – fractures easily
o Anemia and infections (decreased marrow space); blindness,
deafness, etc. (nerve damage)
• Osteopetrosis was the first genetic disease treated with hematopoietic
stem cell transplantation, which is effective because osteoclasts are
derived from hematopoietic precursors
– the normal osteoclasts
produced from donor stem cells reverse many of the skeletal
abnormalities
Paget’s Disease (Osteitis Deformans)
Increase in osteoclastic activity followed by a compensory increase in osteoblastic activity
- Disorganization of bone tissue»_space; increased fracture risk
- Marrow cavity is filled with fibrovascular tissue
- increased bone density in some locations, decreased bone density in others
SYMPTOMS:
- Asymptomatic or bone pain, nerve compression, deafness, bone deformities,
Combination of genetic and environmental (viral?) risk factors
In rare cases, can transform into sarcoma
Arthritis
• Inflammation of the joints
• Many types of arthritis
o Osteoarthritis
o Rheumatoid
arthritis
o Also psoriatic
arthritis, lupus, septic arthritis, gout, and othersOsteoarthritis
• Degenerative joint disease
• Degeneration of cartilage
o Disease in which chondrocytes respond to chemical and/or mechanical stresses, resulting in matrix breakdown
o Leads to structural and functional failure of synovial joints
• Joint deformity can occur, but fusion does not take place
• Collagen fibers are cleaved, leading to fissures in surface or articular cartilage – eventually, chondrocytes die and cartilage is dislodged into the
joint – bone is exposed and becomes the new joint surface
o Fractures are common and synovial fluid can enter the bone,
causing cysts
• Surface of articular cartilage breaks down, leaving exposed bone
Rheumatoid Arthritis
• Chronic inflammatory autoimmune disorder
• May affect many tissues and organs (but principally the joints)
o Destruction of articular cartilage
o Ankylosis of the joints (ankylosis =
abnormal fusion/adhesion of the bones of a joint)
• Synovium becomes edematous, thickened, and hyperplastic
o Covered by villi (normally thin and
smooth)
• A pannus develops (mass of edematous
synovium, inflammatory cells, granulation
tissue, and fibroblasts)
o Grows over the articular cartilage and erodes it
o After the cartilage has been destroyed, the pannus bridges the
opposing bones to form a fibrous ankylosis
o Fibrous ankylosis can ossify into a bony ankylosis
