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Flashcards in Introduction to Bone Deck (50)
1

_____ Is the Master Regulator of Bone Formation

RUNX2 (Cbfa1)

  • Also mediated by osterix (SP7)

2

What is the job of osteoblasts?

synthesize the organic components of the bone matrix

3

Osteoblasts differentiate from __________ ______ ______.

Mesenchymal Stem Cells

4

What are the two final destinations for osteoblasts in vivo?

  1. undergo apoptosis

or

  1. undergo terminal differentiation to osteocytes

5

What would you use Aliziran red for?

What would you use Alcian blue for?

  • Alizarin red stains calcified tissue
  • Alcian blue stains cartilage

6

How do osteocyte processes in the canalicular network communicate with one another?

via gap junctions

  • encoded by connexin 43

7

Where do osteoclasts arise from?

myeloid progenitor

  • monocyte/macrophage lineage

8

What do osteoclasts require in order to differentiate?

Communication with osteoblasts:

  • Require:
    1. M-CSF
      • recpetor: CSF1R 
    2. RANK-L

9

RANKL is produced by _________.

osteoblasts

10

Describe the role of osteoprotegrin (OPG):

  • also produced by osteoblasts
  • protein that is a soluble decoy receptor for RANKL 
  • RANKL that binds to OPG is not able to bind RANK 
  • high OPG levels inhibit terminal osteoclast differentiation

11

What stimulates osteoclast activity?

What inhibits osteoclast activity?

  • Stimulation:
    • PTH
    • 1, 25 di-OH-D
  • Inhibition:
    • calcitonin

12

  • How do osteoclasts degrade bone?
  • What is secreted?
  • What is the morphology?

  • mature osteoclasts bind tightly to the bone surface via the sealing zone to enclose a compartment in which bone matrix can be degraded
  • osteoclasts secrete: 
    • HCl to dissolve the mineral
    • cathepsin K to degrade the bone matrix proteins
  • cell membrane of the osteoclast within the sealing zone assumes a characteristic ruffled border appearance

13

Osteocytes signal to the ____ _______.

bone surface

14

Bone Components:

  1. Cortical
  2. Trabecular

Cortical and trabecular bone are constituted of the same cells and the same matrix elements, but there are structural and functional differences

  1. Cortical
    • ​​80-90% of volume is calcified
    • Fulfills mainly a mechanical and protective function
    • Always found on outside of bones and surrounds trabecular bone
    • ~80% of bone
  2. Trabecular
    • ​​15-25% of volume is calcified
    • Fulfills mainly a metabolic function
    • ~20% of bone

15

Bone Components:

  1. Intramembranous 
  2. ​Endochondral

  1. Intramembranous
    • ​​Intramembranous bone is formed by formation of osteoblasts
    • bone is formed de novo
    •  
  2. Endochondral
    • ​​replace previously formed cartilage models
    • grow in length by proliferation of chondrocytes within the growth plate 
    • Linear growth ceases when the growth plates fuse

16

Give examples of intramembranous bone:

Examples: 

  1. many bones of the skull 
  2. ribs
  3. Also formed in the bone collar region of a healing fracture and at the periosteal surface of long bones as they model to achieve greater diameters

17

What is the growth plate?

a specialized structure present within growing endochondral bones

18

Give examples of endochondral bone:

long bones of the limbs

19

Describe growth of endochondral bone:

(i.e. what occurs in the growth plate)

  • Growth plate is a highly organized tissue in which chondrocytes are arrayed in columns
    • with different positions within the column occupied by cells at a distinct point of maturation
  • Chondrocytes in the proliferative zone divide
    • replenishing the growth plate
  • Chondrocytes then hypertrophy, undergo apoptosis, and are mineralized
  • Blood vessels invade the zone of calcified cartilage,
    • which is resorbed by chondroclasts
    • space is filled by osteoblasts and bone matrix

20

What does linear growth of long bones depend on?

Depends on the relative speed with which:

  • cells in the hypertrophic zone undergo apoptosis 
  • cells in the proliferative zone divide

21

In humans, the growth plate closes in ____ _________ in response to ________ _________?

In humans, the growth plates close in late adolescence in response to estrogen signaling

22

At any given time, about ___ of the skeleton is being remodeled

10%

  • albeit not all at the same rate

23

Why is trabecular bone much more actively remodeled than cortical bone?

Trabecular bone has a more prominent role in maintaining mineral homeostasis

24

2 essential principles to understanding the bone remodeling cycle:

  1. bone resorption and bone formation are coupled processes
  2. bone resorption is relatively rapid, requiring ~2 weeks, while bone formation is slow, requiring 4-6 months for full mineralization to take place

25

Describe the remodeling process of trabecular bone:

  • Remodeling of trabecular bone provides a mechanism by which extracellular fluid can buffer its calcium and phosphate content 
  • PTH and 1, 25 di-OH vitamin D are potent activators of osteoclast activity
  • bone resorption involves dissolution of the bone mineral 
    • providing free Ca and PO4 that can enter the extracellular fluids and blood

26

What is essential for moment-to-moment mineral homeostasis?

  • excess Ca and PO4 can be deposited into the bone.
  • Amount of Ca exchanged by trabecular bone each day is approximately twice the amount that is absorbed from food or lost in urine each day
  • Active exchange of minerals between the bone and the circulation is essential for moment-to-moment mineral homeostasis

27

Define the concept of bone modeling:

What is it mediated by?

What is an example of bone modeling?

  • Bones do not only grow in length, but grow in radial size and change shape as well
  • mediated at least in part by physiological responses to mechanical loading
  • Example:
    • seen in elite racquet sport athletes, comparing dominant and non-dominant arms

28

At the level of the whole bone, _____ is the primary stimulus to modeling

strain

  • fractional change in length

29

What appears to be the critical stimulus for bone modeling at the cellular level?

shear stress

  • requiring both:
    1. anchoring of osteocytes by focal adhesion complexes
    2. fluid flow sensed by each cell’s primary cilium

30

Describe the process of fracture healing:

  1. Hematoma formation at the fracture site
    • consequence of the inflammatory process.
  2. Soft callus forms via mesenchymal stem cells
  3. Blood vessels invade the soft callus
  4. Hard callus forms 
    • Bone replaces cartilage
    • very similar to that seen in the growth plate  
  5. Simultaneously, osteoblasts on the subperiosteal surface form an intramembranous bone collar
  6. Hard callus undergoes remodeling to form lamellar bone and modeling ⇒ reduce the bulge at the fracture site

31

How long does it take for a fracture to heal?

Time required is ~8-12 weeks, though the final remodeling and mineralization may take considerably longer

32

Define strain:

What causes negative strain?

What causes positive strain?

Strain:

  • fractional change in the length of a structure as a result of a force being applied to it
  1. Pure compression causes negative strain
  2. Pure stretching causes positive strain

33

What does mechanical loading result in?

mechanical loading results in a mixture of compression and tension, as occurs in the case of either bending or shear

34

Where does the compressive and tensile strength come from in bone?

  1. Compressive strength comes from the mineral phase
    • 2/3 of the bone ECM by mass
  2. Tensile strength comes from the protein and water
    • 1/3 of the bone ECM by mass

35

What is the primary protein component of bone’s extracellular matrix?

type 1 collagen

36

After collagen assembles there are spaces left in between the fibrils.  What is a possible explanation of why the spaces are left?

The pattern of assembly leaves empty spaces that are thought to function as nucleation sites for the mineral phase

37

Describe the process of cross-linking between collagen fibrils:

  • Adjacent molecules of collagen are covalently linked by cross-links, initially formed enzymatically in a vitamin C-dependent process to yield aliphatic bonds
  • Cross-links subsequently mature non-enzymatically to aromatic pyridinolines and deoxypyridinolines

38

Why are mature aromatic cross-links harder to break compared to the aliphatic cross-links?

mature aromatic cross-links have higher bond energy than the aliphatic cross-links, and are therefore harder to break

39

What allows individual collagen molecules to be stretched?

  • The helical structure of the individual collagen molecules allows them to be stretched along the axis like springs
  • Provides yet another mechanism by which collagen imparts tensile strength to bone matrix

40

What are the most abundant ions present in bone mineral?

What other ions are also present?

  • Ca and PO4 are the most abundant ions in bone mineral
  • Significant amounts of Mg, Na, OH, CO3, SO4, and Cl are also present

41

Bone is a mineral that is described as "apatite".  What is "apatite"?  

How is it formed?

  • Apatite is a mineral that results from substitution of hydroxyapatite with other ions
  • This substitution of the mineral decreases the regular structure of the mineral lattice 
    • reduces the energy needed to solubilize ion
  • This occurs at some cost to the stiffness (resistance to bending) of the mineral
  • Important in promoting bone’s function in mineral homeostasis

42

Is the mineral phase of bone a passive or active process?

What are the inhibitors and modulators of bone mineralization?

  • Mineral phase of bone is intercalated into the collagen fibril structure, and appears to be deposited passively
  • Both sulfate and pyrophosphate are potent inhibitors of mineralization
  • Proteins in the SIBLING (small integrin-binding ligand, N-linked glycoprotein) family are modulators of mineralization
    • account for most of the non-collagenous protein secreted by osteoblasts

43

What provides toughness to bone?

lamellar structure of bone

44

Osteogenesis imperfecta:

  • Cause:
  • Cells affected:

  • Cause:
    • mutations in the genes encoding type 1 collagen or critical enzymes in the assembly and processing of type 1 collagen
    • results in deficient production or improper assembly of the extracellular matrix
      • susceptibility to fracture
  • Cells affected:
    • purely osteoblast disease

45

Osteomalacia:

  • Cause:

"Rickets"

  • inadequate mineralization of the bone matrix
  • can be a consequence of several different conditions: 
    • including various malabsorptive disorders
    • vitamin D deficiency or resistance
    • phosphate wasting disorders
    • low Ca diet

46

What can osteomalacia result in?

  • Osteomalacia results in weak, undermineralized bones 
  • When osteomalacia occurs in a growing individual:
    • bone modeling is abnormal
    • long bones assume a bowed shape
      • This is called rickets.
  • A disorder in which the bone cells function normally, but lack of the appropriate mineral substrates leads to abnormal bone function

47

Sclerosteosis and Van Buchem’s disease

 

  • disorders in which the skeletal mass is abnormally high, due to mutations of the protein sclerostin
  • disturbs the mechanosensory system, resulting in bones perceiving that they are being loaded even when they are not
  • These can be thought of as osteocyte diseases

Clincial Manifestations:

  • Nerve entrapment leads to facial palsy, deafness
  • Some mutations also cause syndactyly

48

Osteopetrosis

  • group of diseases in which osteoclast function or maturation is impaired
  • As a result, remodeling is deficient
  • Severe cases are lethal, as the marrow space is not formed and hematopoiesis is severely impaired as a result
  • Inability to remodel bone results in:
    • dense and massive bones that are weak 
    • unable to assume the lamellar structure that remodeling produces
  • Pure osteoclast disease

49

Paget’s disease of bone

  • Disorder characterized by focally excessive and disorganized bone remodeling
  • Can result in pain, nerve entrapment, weakening of the affected areas  
    • presence of woven (as opposed to lamellar) bone
    • bone deformity arising as the result of aberrant modeling
  • Remodeling regulation disease

50

  1. pure osteoblast disease ⇒
  2. pure osteoclast disease ⇒
  3. remodeling regulation disease ⇒
  4. osteocyte disease ⇒
  5. lack of the appropriate mineral substrates leading to abnormal bone function ⇒

  1. pure osteoblast disease ⇒ osteogenesis imperfecta
  2. pure osteoclast disease ⇒ osteopetrosis
  3. remodeling regulation disease ⇒ Paget’s disease of bone
  4. osteocyte disease ⇒ Sclerosteosis or Van Buchem’s disease
  5. lack of the appropriate mineral substrates leading to abnormal bone function ⇒ osteomalacia