Bone Development and Remodelling Flashcards
What are the functions of bone?
- Skeletal support.
- Muscle attachment.
- Houses haematopoiesis (in bone marrow).
- Reservoir for calcium and phosphate.
- Involved in homeostasis.
What are the developmental origins of bone?
Cranial neural crest - gives rise to osteoblasts that make the craniofacial skeleton.
Mesoderm - gives rise to the axial skeleton.
What are osteoblasts?
Cells that make bone.
What are osteoclasts?
Cells that resorb bone.
What are chondrocytes?
Cells that produce cartilage matrix.
What is the master gene for osteoblasts?
Runx2
What happens if there is a mutation in the Runx2 gene?
Bone deformities.
Where are osteoclasts derived from?
Haematopoietic stem cells.
What factors are required to make osteoclasts?
Haematopoietic stem cells respond to Colony Stimulating Factors (CSF):
E.g. M-CSF and RANKL
When does ossification begin?
6 weeks IU
What are the 2 types of ossification?
- Intramembranous
- Endochondral
Define ossification
Bone formation
What is the difference between Intramembranous and Endochondral ossification?
- 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).
Describe how Intramembranous ossification occurs
- Bone formed from fibrous membranes (condensation).
- Direct formation of osteoblast precursors results in formation of periosteum.
- Differentiation to osteoblasts occurs at ossification centre.
- Osteoblasts secrete extracellulate matrix and deposits calcium - this mineralises and hardens the matrix.
- Non-mineralised part of bone (osteoid) continues to form around blood vessels, forming spongey bone (vascularisation).
- Connective tissue in matrix differentiates into red bone marrow.
- Spongey bone is remodelled into thin layer of compact bone on surface.
Describe how Endochondral ossification occurs
- Chondrocytes form cartilage model (perichondrium).
- Cartilage mineralises to form bony collar (periosteum - connective tissue).
- Capillaries and osteoclasts invade the cavities to create marrow (primary ossification centre).
- Bone continues to grow and elongate as cartilage cells at epiphyses divide.
- Centres of epiphyses calcify (forms secondary ossification centre).
What is the epiphyseal growth plate?
Cartilage plate at end of long bones.
What is the purpose of the epiphyseal growth plate?
Responsible for growth of long bones.
What can be caused by defects in the epiphyseal growth plate?
Achondroplasia (dwarfism).
What is the purpose of bone remodelling?
- Calcium homeostasis (along with gut/kidneys).
- Important for maintenance of skeletal mass.
What factors does bone remodelling respond to?
- Disease (e.g. hypocalcaemic so patient needs calcium).
- Mechanical loading and adaptation.
Patient
Describe the process of bone remodelling?
- Hormone growth factors activate osteoblasts from lining cells (ACTIVATION)
- Osteoclasts resorb bone (RESORPTION)
- Negative feedback - stops osteoclasts and allows formation of osteoblasts for bone deposition (FORMATION)
What mediates osteoclast differentiation?
Osteoblasts
How do osteoblasts mediate osteoclast differentiation?
- Vitamin D / IL-11 / parathyroid hormone acts on osteoblast, it stimulates production of M-CSF and RANKL.
- Osteoprotegerin (OPG) protein is produced which inhibits RANKL.
(no RANKL to produce osteoclasts). - OPG is a soluble inhibitor for osteoclast differentiation.
What controls osteoclastogenesis?
Balance between RANKL and OPG
What is osteoclastogenesis?
Formation of osteoclasts
What causes osteopetrosis?
Knockout of RANKL and c-FOS. Therefore, there isn’t enough osteoclasts.
What causes osteoporosis?
Knockout of OPG causes production of too many osteoclasts.
Bones become weak.
What causes a decreased (or no) production of osteoblasts?
Knockout of Runx2 / Cbfa1
Describe the bi-directional coupling mechanism in osteoclast formation
- If person is low in calcium, parathyroid hormone (PTH) is secreted.
- PTH acts on osteoblasts - produce RANKL and M-CSF. RANKL is also produced by osteocytes.
- These act on Haematopoetic stem cells to differentiate into mononuclear cells.
- Fos is upregulated to allow for fusion of these mononuclear cells to form osteoclasts.
- TGF-beta and BMPs are present locally where bone has been resorbed.
- This signals to osteoblasts that they need to deposit bone here.
What law describes functional adaptation?
Wolff’s Law
What does Wolff’s Law state?
- 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.
What cells are best suited to respond to forces?
Why?
Osteocytes
- They are the mechanosensors of bone.
- They require mechanical loading for survival.
What is mechanotransduction?
Process where forces are converted to biochemical signals by cellular signalling. This causes remodelling of bone.
What factors does mechanotransduction depend on?
Duration, magnitude and rate of loading.
Upon loading, fluid flows away from the compressed area of bone. Which cells are most sensitive to this fluid flow?
Osteocytes
How do osteocytes regulate bone remodelling?
Through signalling cascades.
What is Sclerostin?
Protein produced by osteocytes that inhibits bone formation.
What causes Sclerosteosis?
Mutation in the Sclerostin (Sost) gene in osteocytes.
What is Sclerosteosis?
With increased mechanical loading, Sclerostin secretion decreases, causing increased bone formation.
What causes osteosclerosis?
Not enough Sclerostin and too many osteoblasts.
Describe the process of alveolar bone remodelling in tooth eruption
Osteoclasts allow resorption of the tooth cavity to allow for tooth eruption.
Increases osteoclast presence enhances root growth, causing faster eruption.
Describe the process of alveolar bone remodelling in periodontal disease
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.
