Intro to Bone

Question 1

What is the signal that allows a mesenchymal stem cell to become a mature osteoblast?

Answer 1

RUNX2 = Master regulator of bone formation

Mesenchymal Stem Cell –> Pre Osteoblast –> Osteoblast –> Mature Osteoblast

Question 2

What happens if RUNX2 is knocked out?

Answer 2

No bone formation, lethal

Heterozygous form – severe craniofacial deformations

Question 3

What is in bone canaliculi?

Answer 3

Processes from osteocytes that connect cells – communicate via gap junctions encoded by connexin 43

No connexin 43 = problems with bone formation

Question 4

What is the dual signalling that is required for the differentiation cascade of osteoclasts?

Answer 4

m-CSF & RANK-L – activate specific osteoclast pathway to initiate the development of osteoclasts

Question 5

What does TRAP do?

Answer 5

TRAP = tartate resistant and acid phosphatase

Fuses to become macrophages – makes sealing zone around bone they will resorb

Question 6

What is the sealing zone’s function?

Answer 6

Ruffled border on osteoclast to increase the amount of surface area to secrete H+ and Kathepsin K, adheres to bone matrix and dissolves mineral in bone

Question 7

Cortical bone

Answer 7

• 80-90% of volume is calcified
• Fulfills mainly a mechanical and protective function
• Always found on outside of bones and surrounds trabecular bone
• 4/5 of skeleton

Question 8

Trabecular Bone

Answer 8

• 15-20% of volume is calcifed
• Fulfills mainly a metabolic function
• 1/5 of bone volume

Question 9

How does the histology of cortical and trabecular bone differ?

Answer 9

Cortical bone has layers that are organized around a channel, difference in orientation of type I collagen fibers in matrix

Trabecular bone is organized in plates/rods and interspersed wtih adipose/hematopoietic tissue

Question 10

Why are osteocytes considered the orchestrators of bone turnover and what protein helps mediate this?

Answer 10

Osteocytes can sense force on skeleton to determine where bone will be deposited and absorbed.

Sclerostin: expressed by osteocytes, inhibits maturation of osteoblasts – when a bone is mechanically loaded, stop making Sclerostin so osteoblasts can make bone!

Question 11

Intramembranous ossification

Answer 11

Form directly from dense connective tissue

Question 12

What kind of ossification occurs at the growth plate?

Answer 12

Endochondral ossification: linear growth in length of long bone mediated by division of chondrocyte.

Cartilage in growth plate is doing the growing and bone comesin to replace the cartilage, then bone plate fuses and linear growth stops!

Question 13

What digests away calcified cartilage in endochondral ossification?

Answer 13

Chondroclasts

Question 14

What is the remodeling cycle like for Trabecular or cancellous bone?

Answer 14

• 12 bone remodeling units activated each minute, with annual turnover rate of 25%
• High turnover rate because of higher surface-to-volume ratio
• Complete remodeling cycle takes 4-6 months
• Osteoid laid down in discrete layers, 3 micrometer thick
• Lamellae deposited in curved sheets that follow the contour of the trabeculae

Question 15

Remodeling cycle for cortical or compact bone

Answer 15

• 3 bone remodeling units activated each minute with annual turnover rate of 2-3%
• Lower turnover rate
• Less vascularity
• Remodeling cycle takes 4-6 months
• Osteoblasts plus blood vessels follow osteoclasts through hollowed-out tunnel
• Concentric lamellae laid down

Question 16

What can be used to meausre mineralization rate?

Answer 16

Tetracycline labeling: Tet binds tightly to front of mineralization in newly formed osteoid – put bone under fluroescent light and see bright yellow bands where tet was deposited. In path lab can measure the distance between them and will give you microns per day of growth

Question 17

What are the stages in fracture healing?

Answer 17

1. Hematoma formation
2. Fibrocartilaginous callus formation
3. Bony callus formation
4. Bone remodeling

Question 18

Assembly of pro-alpha collagen and processing into Tropocollagen

Answer 18

Type I collagen is the most abundant protein in bone.

3 strands wound together in left handed triple helix, globular domains at ends cleaved off and assembled mature protein is secreted into extracellular space.

Gives tensile strength to resist being pulled apart

Question 19

How are collagen cross-links formed?

Answer 19

Form from lysines in neighboring chains in enzymatic fashion. Mature to aromatic form called pyridinoline which are non-reducable and really strong. Mature collagen has high tensile strength with adequate density of x-links.

Question 20

Is it easier to form breaks against lamellae grain or with lamellae grain?

Answer 20

With lamellae grain – the amount of energy to produce the two is different

Question 21

Disease that arises from osteoblast’s defective synthesis of the organic component of bone matrix.

Answer 21

Osteogenesis Imperfecta

Question 22

What is a common cause of Osteogenesis Imperfecta?

Answer 22

Mutations in type 1 collagen alpha1 or 2 chain – leads to bent and frayed collagen molecules that do not assemble properly –> weak bone

Question 23

Defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium (vit D).

Answer 23

Osteomalacia

Question 24

Defect in osteocytes where there is a mutation in sclerostin. If sclerostin doesnt work, bone thinks it is always loaded and leads to overgrown bones and nerve entrapment, facial palsy and deafness.

Answer 24

Sclerosteosis

Question 25

Osteoclasts are unable to resorb bone during remodeling – abnormally high bone density.

Answer 25

Osteopetrosis

Question 26

Uncoupled remodeling gone wild.

Pain, osseous bowing and enlargement, neurologic symptoms.

Lab: increased markers of bone turnover – serum alkaline phosphatase, urinary hydroxyproline.

Presdisposition to osteosarcoma.

Answer 26

Paget’s Disease

Question 27

What is the treatment for Paget’s disease?

Answer 27

Bisphosphonates to stop osteoclasts in their tracks and let everything heal