7.6B. Physiology of bones

Question 1

I. Types of bones
1. What are the 2 types of bones?

Answer 1

1) Dense cortical/compact (long bones)
2) Trabecular (spongy bones)

Question 2

I. Types of bones
2. What are the characteristics of Dense cortical/compact (long bones)?

Answer 2

• Comprises 80% if all bones
• Functional unit of bones = osteon (Volkmann + Haversian canals, osteocytes, osteoblasts etc.)

Question 3

I. Types of bones
3. What are the characteristics of Trabecular (spongy bones)?

Answer 3

• Comprises 20% of all bones; located in the vertebral body, neck of femur, inner part of long bone
• High surface area (more than long bones) -> ↑turnover of bone formation and resorption -> remodeling of bone (↑speed in trabecular bones because of high surface)

Question 4

II. Formation of bones
1. What can the formation of bones be linked to?

Answer 4

The formation of bones can be linked to osteoblasts (≈fibroblast cells)

Question 5

II. Formation of bones
2. What are the types of proteins that osteoblasts secretes?

Answer 5

1. Structure proteins
2. Regulatory proteins
3. Catabolic enzymes

Question 6

II. Formation of bones
3. What are the structure proteins that osteoblasts secrete?

Answer 6

1. Type I collagen: 90% of secreted protein
2. Osteocalcin: belongs to Gla-protein family, Vitamin K dependent protein
   -> -> -> Bind Ca2+ and hydroxyapatite
3. Osteonectin: also binds Ca2+ and hydroxyapatite
4. Alkaline phosphatase

Question 7

II. Formation of bones
4. What are the catabolic enzymes that osteoblasts secrete?

Answer 7

• Catabolic enzymes: during the formation of the bones, they are not active
• the environment has to change to activate them
  +) Collagenase
  +) Gelatinase

Question 8

III. Phases of formation
1. Summary of bone formation

Answer 8

Osteoblasts will form a layer that will separate the bone matrix from the environment = interstitium

Question 9

III. Phases of formation
2. What are the 2 phases of bone formation?

Answer 9

1. Osteoid formation
2. Mineralization

Question 10

III. Phases of formation
3. What happen during Phase 1: Osteoid formation

Answer 10

• Osteoid = protein matrix of bone
• Will provide site for nucleation of the mineral component of the bone =
  hydroxyapatite
• Can get this protein matrix by collagen secretion:
  +) Collagen secreted from osteoblasts as monomers
  +) Self-associate into helical structures -> collagen fibers
• Process takes between 10 to 14 days

Question 11

III. Phases of formation
4. What happen during phase 2: mineralization

Answer 11

• Takes weeks (3-4 weeks)
• Formation of hydroxyapatite (Ca5(PO4)3OH) by the addition of the released Pi-
  groups from alkaline phosphatase
• Hydroxyapatite will precipitate/build into the protein matrix = nucleation (
  protein surface with negative charge can bind anything with positive charge, i.e. Ca2+, hydroxyapatite, metals used as poison)
  => Will give rigidity of the bones
  => Takes about 6 weeks
  => During this process, the osteoblast cells will be enclosed into the mass (matrix) of the bone and become osteocytes
  +) Regulatory proteins and catabolic enzymes will also be trapped -> BONE MATRIX

Question 12

IV. Resorption of bones
1. What is Resorption?

Answer 12

• Resorption is when the bone mass is degraded and disappears. Osteoclasts are responsible for the resorption.
• Osteoclasts derived from hematopoietic cell line, require M-CSF, RANK ligand and IL-6 for differentiation and activation

Question 13

IV. Resorption of bones
2. What happen during resorption of bone?

Answer 13

• Osteoclasts are huge cells that attach to the surface of the bone
• Once attached, the cell will become polarized -> separates the interstitial and bone
  mass compartment by the formation of the resorption cavity
• Proton pumps will secrete H+ into the apical surface together with lysosomal enzyme (TRAP = acid phosphatase) enzyme (TRAP = acid phosphatase)
• H+ and acid phosphatase will cause the release of Ca2+ + Pi from the bone ( -> blood)

Question 14

IV. Resorption of bones
3. What are other effects of H+ and acid phosphatase ?

Answer 14

• They will also cause the release of catabolic enzymes + regulatory (which were produced by the osteoblasts)
• The enzymes and the proteins were built into the bone matrix, waiting till the resorption occurs -> will be released and get activated
• The enzymes will get into the resorption cavity and the regulatory proteins will also get in and regulate the osteoclast cells + resorption of the bone

Question 15

V. Reformation of bone
1. What are the 2 types of Reformation of bone?

Answer 15

1. Modeling
2. Remodeling

Question 16

V. Reformation of bone
2A. Why does modeling happens?

Answer 16

Occurs upon the presence of the change in load/stress – structure of the bone has to change in order to sense the new load = structure is different

Question 17

V. Reformation of bone
2B. What is the mechanism of bone modeling?

Answer 17

• Induced via a mechanical stimulation: fluid movement occurs in the bone canaliculi
• Upon change of load on bone
• Change in fluid flow is sensed by (resting) osteocytes, which re-activate into osteoblasts
• Osteoblasts -> osteoclasts -> resorption -> formation -> new structure of the bone

Question 18

V. Reformation of bone
3A. What are the characteristics of bone remodeling?

Answer 18

• No change of load
• No stimulation
• Still have a continuous resorption and formation
  => Function of remodeling: structure will be the same, but there will be ‘’renewal of the bone’’

Question 19

V. Reformation of bone
3B. What is the mechanism of bone remodeling?

Answer 19

• Initiated by osteoclasts, without being activated (no stimulus needed)
• Osteoclasts will attach to the surface of the bone -> activation -> start resorption
• As a result of the resorption, we will have a 20μm deep tunnel (14 days)
• After 14 days, the osteoclasts will die
  => Consequence: damage on the bone surface = 20μm deep tunnel
  => Osteoblasts will detect this damage -> start production of proteins, osteoid, mineralization -> BONE FORMATION

Question 20

V. Reformation of bone
3C. What is the important timing for bone remodeling? What will happen?

Answer 20

Every 5-10 years, all of our bones are completely remodeled:
- Faster in trabecular bones, since the surface area is higher = higher probability that an osteoclast will attach on the surface
-> renewal occurs in a shorter time period

Question 21

V. Reformation of bone
4. Give a summary of bone resorption and formation?

Answer 21

• There is a continuous resorption and formation, but they are in balance (rate is
  same)
• Resorption = Ca2+ + Pi are released -> balance can be changed
  => Resorption + formation are under hormonal regulation

Question 22

VI. Acute, hormonal regulation of remodeling
1. What is the purpose of Acute, hormonal regulation of remodeling?

Answer 22

To change the balance, ↑rate of resorption, in order to release more Ca2+ + Pi from the bone

Question 23

VI. Acute, hormonal regulation of remodeling
2. What are the 5 factors that lead to Acute, hormonal regulation of remodeling?

Answer 23

1. PTH, calcitriol
2. Calcitonin
3. Glucocorticoids
4. Estrogens
5. Inflammation

Question 24

VI. Acute, hormonal regulation of remodeling
6. How does estrogen affect Acute, hormonal regulation of remodeling?

Answer 24

• Opposite effects to GC -> ↓ RANKL:OPG ratio -> inhibit the development of osteoporosis
• When estrogen↓ (menopause) -> ratio↑ -> osteoporosis↑

Question 25

VI. Acute, hormonal regulation of remodeling
3B. How does PTH, calcitriol induce secretion of RANK ligand?

Answer 25

• RANK ligand: will bind RANK (receptor activator of nuclear factor kappa-B) which is on the surface of osteoclasts -> activation + differentiation -> osteoclast resorption↑ -> [Ca2+] + [Pi]plasma↑
  => PTH stimulate osteoblasts to produce RANKL, and this
  RANKL is how they indirectly stimulate osteoclasts to
  resorb more bone and ↑[Ca2+] + [Pi]plasma

Question 26

VI. Acute, hormonal regulation of remodeling
3C. How does PTH, calcitriol induce secretion of OPG (osteoprotegerin)?

Answer 26

• OPG (osteoprotegerin): acts on osteoclasts and inhibits their
  activity
• Ratio of RANKL:OPG determines the osteoclast activity:
  +) If high ratio -> ↑osteoclast activity
  +) If low ratio -> ↓osteoclast activity

Question 27

VI. Acute, hormonal regulation of remodeling
4. How does Calcitonin affect Acute, hormonal regulation of remodeling?

Answer 27

It directly acts on osteoclasts and inhibits their activity

Question 28

VI. Acute, hormonal regulation of remodeling
5. How does Glucocorticoids affect Acute, hormonal regulation of remodeling?

Answer 28

Cortisol and synthetic GC (medications):
=> Act on osteoblasts, ↑ the RANKL:OPG ratio -> activation of osteoclasts (resorption)↑
=> Long time use of GC -> osteoporosis (total mass of bone↓) -> fracture of bones

Question 29

VI. Acute, hormonal regulation of remodeling
3A. How does PTH, calcitriol affect Acute, hormonal regulation of remodeling?

Answer 29

Act on osteoblasts only, inducing secretion of RANK ligand and OPG

Question 30

VI. Acute, hormonal regulation of remodeling
7. How does Inflammation affect Acute, hormonal regulation of remodeling?

Answer 30

Immune cells + tumor cells can also express RANKL
-> osteoclast activity↑ (local effect)
-> local resorption of bone ([Ca2+]plasma↑ = hypercalcemia)
-> easily detected on X-ray images -> §Indication of the presence of tumors etc.