Bone Development and Remodelling

Question 1

What are the functions of bone?

Answer 1

• Skeletal support.
• Muscle attachment.
• Houses haematopoiesis (in bone marrow).
• Reservoir for calcium and phosphate.
• Involved in homeostasis.

Question 2

What are the developmental origins of bone?

Answer 2

Cranial neural crest - gives rise to osteoblasts that make the craniofacial skeleton.

Mesoderm - gives rise to the axial skeleton.

Question 3

What are osteoblasts?

Answer 3

Cells that make bone.

Question 4

What are osteoclasts?

Answer 4

Cells that resorb bone.

Question 5

What are chondrocytes?

Answer 5

Cells that produce cartilage matrix.

Question 6

What is the master gene for osteoblasts?

Answer 6

Runx2

Question 7

What happens if there is a mutation in the Runx2 gene?

Answer 7

Bone deformities.

Question 8

Where are osteoclasts derived from?

Answer 8

Haematopoietic stem cells.

Question 9

What factors are required to make osteoclasts?

Answer 9

Haematopoietic stem cells respond to Colony Stimulating Factors (CSF):
E.g. M-CSF and RANKL

Question 10

When does ossification begin?

Answer 10

6 weeks IU

Question 11

What are the 2 types of ossification?

Answer 11

• Intramembranous

- Endochondral

Question 12

Define ossification

Answer 12

Bone formation

Question 13

What is the difference between Intramembranous and Endochondral ossification?

Answer 13

• Intramembranous = bone formed directly from precursors. E.g. flat bones of skull, calvaria, clavicle.
• Endochondral = bone formed via a cartilagenous intermediate. E.g. long bones, vertebrae (all bones except flat bones of skull, mandible and clavicle).

Question 14

Describe how Intramembranous ossification occurs

Answer 14

1. Bone formed from fibrous membranes (condensation).
2. Direct formation of osteoblast precursors results in formation of periosteum.
3. Differentiation to osteoblasts occurs at ossification centre.
4. Osteoblasts secrete extracellulate matrix and deposits calcium - this mineralises and hardens the matrix.
5. Non-mineralised part of bone (osteoid) continues to form around blood vessels, forming spongey bone (vascularisation).
6. Connective tissue in matrix differentiates into red bone marrow.
7. Spongey bone is remodelled into thin layer of compact bone on surface.

Question 15

Describe how Endochondral ossification occurs

Answer 15

1. Chondrocytes form cartilage model (perichondrium).
2. Cartilage mineralises to form bony collar (periosteum - connective tissue).
3. Capillaries and osteoclasts invade the cavities to create marrow (primary ossification centre).
4. Bone continues to grow and elongate as cartilage cells at epiphyses divide.
5. Centres of epiphyses calcify (forms secondary ossification centre).

Question 16

What is the epiphyseal growth plate?

Answer 16

Cartilage plate at end of long bones.

Question 17

What is the purpose of the epiphyseal growth plate?

Answer 17

Responsible for growth of long bones.

Question 18

What can be caused by defects in the epiphyseal growth plate?

Answer 18

Achondroplasia (dwarfism).

Question 19

What is the purpose of bone remodelling?

Answer 19

• Calcium homeostasis (along with gut/kidneys).

- Important for maintenance of skeletal mass.

Question 20

What factors does bone remodelling respond to?

Answer 20

• Disease (e.g. hypocalcaemic so patient needs calcium).
• Mechanical loading and adaptation.
  Patient

Question 21

Describe the process of bone remodelling?

Answer 21

1. Hormone growth factors activate osteoblasts from lining cells (ACTIVATION)
2. Osteoclasts resorb bone (RESORPTION)
3. Negative feedback - stops osteoclasts and allows formation of osteoblasts for bone deposition (FORMATION)

Question 22

What mediates osteoclast differentiation?

Answer 22

Osteoblasts

Question 23

How do osteoblasts mediate osteoclast differentiation?

Answer 23

1. Vitamin D / IL-11 / parathyroid hormone acts on osteoblast, it stimulates production of M-CSF and RANKL.
2. Osteoprotegerin (OPG) protein is produced which inhibits RANKL.
   (no RANKL to produce osteoclasts).
3. OPG is a soluble inhibitor for osteoclast differentiation.

Question 24

What controls osteoclastogenesis?

Answer 24

Balance between RANKL and OPG

Question 25

What is osteoclastogenesis?

Answer 25

Formation of osteoclasts

Question 26

What causes osteopetrosis?

Answer 26

Knockout of RANKL and c-FOS. Therefore, there isn't enough osteoclasts.

Question 27

What causes osteoporosis?

Answer 27

Knockout of OPG causes production of too many osteoclasts. | Bones become weak.

Question 28

What causes a decreased (or no) production of osteoblasts?

Answer 28

Knockout of Runx2 / Cbfa1

Question 29

Describe the bi-directional coupling mechanism in osteoclast formation

Answer 29

1. If person is low in calcium, parathyroid hormone (PTH) is secreted. 2. PTH acts on osteoblasts - produce RANKL and M-CSF. RANKL is also produced by osteocytes. 3. These act on Haematopoetic stem cells to differentiate into mononuclear cells. 4. Fos is upregulated to allow for fusion of these mononuclear cells to form osteoclasts. 5. TGF-beta and BMPs are present locally where bone has been resorbed. 6. This signals to osteoblasts that they need to deposit bone here.

Question 30

What law describes functional adaptation?

Answer 30

Wolff's Law

Question 31

What does Wolff's Law state?

Answer 31

- Bones in a healthy person will adapt to loads placed on it. - External forces determine remodelling (e.g. if loading increases over time so remodelling makes it stronger to resist the load). - Internal architecture of trabecular undergoes adaptive changes following by secondary changes to external cortical bone.

Question 32

What cells are best suited to respond to forces? | Why?

Answer 32

Osteocytes - They are the mechanosensors of bone. - They require mechanical loading for survival.

Question 33

What is mechanotransduction?

Answer 33

Process where forces are converted to biochemical signals by cellular signalling. This causes remodelling of bone.

Question 34

What factors does mechanotransduction depend on?

Answer 34

Duration, magnitude and rate of loading.

Question 35

Upon loading, fluid flows away from the compressed area of bone. Which cells are most sensitive to this fluid flow?

Answer 35

Osteocytes

Question 36

How do osteocytes regulate bone remodelling?

Answer 36

Through signalling cascades.

Question 37

What is Sclerostin?

Answer 37

Protein produced by osteocytes that inhibits bone formation.

Question 38

What causes Sclerosteosis?

Answer 38

Mutation in the Sclerostin (Sost) gene in osteocytes.

Question 39

What is Sclerosteosis?

Answer 39

With increased mechanical loading, Sclerostin secretion decreases, causing increased bone formation.

Question 40

What causes osteosclerosis?

Answer 40

Not enough Sclerostin and too many osteoblasts.

Question 41

Describe the process of alveolar bone remodelling in tooth eruption

Answer 41

Osteoclasts allow resorption of the tooth cavity to allow for tooth eruption. Increases osteoclast presence enhances root growth, causing faster eruption.

Question 42

Describe the process of alveolar bone remodelling in periodontal disease

Answer 42

Periodontal disease = inflammatory condition. Increased production of pro-inflammatory cytokines (e.g. RANKL). RANKL activates osteoclasts. Increase osteoclastic formation, leading to bone loss. Inflammatory cytokines can also act on gingival fibroblasts which make RANKL.