What is the signal that allows a mesenchymal stem cell to become a mature osteoblast?
RUNX2 = Master regulator of bone formation
Mesenchymal Stem Cell --> Pre Osteoblast --> Osteoblast --> Mature Osteoblast
What happens if RUNX2 is knocked out?
No bone formation, lethal
Heterozygous form -- severe craniofacial deformations
What is in bone canaliculi?
Processes from osteocytes that connect cells -- communicate via gap junctions encoded by connexin 43
No connexin 43 = problems with bone formation
What is the dual signalling that is required for the differentiation cascade of osteoclasts?
m-CSF & RANK-L -- activate specific osteoclast pathway to initiate the development of osteoclasts
What does TRAP do?
TRAP = tartate resistant and acid phosphatase
Fuses to become macrophages -- makes sealing zone around bone they will resorb
What is the sealing zone's function?
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
- 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
- 15-20% of volume is calcifed
- Fulfills mainly a metabolic function
- 1/5 of bone volume
How does the histology of cortical and trabecular bone differ?
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
Why are osteocytes considered the orchestrators of bone turnover and what protein helps mediate this?
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!
Form directly from dense connective tissue
What kind of ossification occurs at the growth plate?
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!
What digests away calcified cartilage in endochondral ossification?
What is the remodeling cycle like for Trabecular or cancellous bone?
- 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
Remodeling cycle for cortical or compact bone
- 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
What can be used to meausre mineralization rate?
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
What are the stages in fracture healing?
1. Hematoma formation
2. Fibrocartilaginous callus formation
3. Bony callus formation
4. Bone remodeling
Assembly of pro-alpha collagen and processing into Tropocollagen
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
How are collagen cross-links formed?
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.
Is it easier to form breaks against lamellae grain or with lamellae grain?
With lamellae grain -- the amount of energy to produce the two is different
Disease that arises from osteoblast's defective synthesis of the organic component of bone matrix.
What is a common cause of Osteogenesis Imperfecta?
Mutations in type 1 collagen alpha1 or 2 chain -- leads to bent and frayed collagen molecules that do not assemble properly --> weak bone
Defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium (vit D).
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.
Osteoclasts are unable to resorb bone during remodeling -- abnormally high bone density.
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.
What is the treatment for Paget's disease?
Bisphosphonates to stop osteoclasts in their tracks and let everything heal