L12 - The physiology of bone repair Flashcards
What does too much bone resorption lead to
- Osteoporosis
- Osteopenia
- Rickets
What does bone formation lead to
- Osteopetrosis
Classification of bone structure
Long bone
Flat bone
Macroscopic -
- Cortical bone
- Cancellous (spongy) - spicules, trabeculae
Microscopic
- Lamellar - osteons
- Woven - immature, disorganised
Composition of bone
- Osteoclasts
- Osteocytes
- Osteoblasts
- Extracellular matrix (osteoid)
Osteoblasts - function
- formation of new bone & release of signalling substances.
- Produce protein components of acellular matrix – regulate bone growth and degradation. Size = 20-25 microns, round and regular in shape, mononucleate.
- Located on developing bone surfaces.
- Inorganic
Osteocytes - function
- ‘Quiescent’ mature cells embedded in bone matrix
- For maintenance and detection of environmental and ageing stresses. Long and thin with extensive branches (that travel through canaliculi), the main cell body inside the lacuna
- Bone degradation and remodelling
- Organic
What are osteocytes derived from
- Derived from osteoblasts
Osteoclasts - function
- Giant multinucleate cells responsible for bone degradation and remodelling bone
- Located in howship’s lacunae at sites of bone resorption
- Shape is regular, cube-like, often with a ruffled border
- Inorganic
Where does the haversian canal run
- Runs parallel to bone and along long axis of bone
Where do osteocytes arise from
- Arise from osteoblasts
- From mesenchyme `(from precursor cells in bone marrow stroma
- Osteoblasts are post-mitotic - most osteoblasts will undergo apoptosis
- A low percentage of osteoblasts will become osteocytes locked in lacuna
What happens to the number of osteoblasts with age
- Number of osteoblasts decreases with age
Osteoclasts - precursor
Same precursor as monocytes (haematopoietic stem)
- Phagocytose (bone matrix and crystals)
- Secrete acids
- Secrete proteolytic enzymes from lysosomes
What happens to the ruffled border of osteoclasts
- Bone resorption occurs
Where do osteoclasts arise from
- Fusion of macrophages (which themselves are derived from monocytes)
What percentage of the extracellular matrix of bone is formed of minerals
- 70%
Constituents of bone
Collagen fibres - protein, flexible but strong
Hydroxyapatite - Mineral, provides rigidity calcium/phosphate crystals > 50%
- Similar to reinforced concrete collagen - rods crystals - cement
What are glycosaminoglycans
- Long polysaccharides
- Highly negative
- Attract water
- Repel each other
- Resists compression
Where are glycoasminoglycans abundant
- In cartilage
Growth factors in ECM
- Growth factors are suspended in matrix
- They are revealed by osteoclast action which leads to proliferation and mineralisation
What do growth factors stimulate the proliferation of
- They stimulate proliferation of osteoblasts and chondroblasts and differentiation of bone and cartilage progenitor cells
Active resorption remineralisation sequence
Osteoclast –> liberated matrix bound growth factors –> osteoprogenitor cells –> active osteoblasts –> surface osteoblasts –> IL-6, other cytokines –> osteoclast
Bone formation classification
- Bone forms either as compact or cancellous and by either intramembranous or endochondral bone formation
What is endochondral ossification
- Bone formation based on a cartilage model. Chondrocytes proliferate and secrete extracellular matrix and proteoglycans.
- Osteoblasts (derived from osteoprogenitor cells) arrive and then osteoid is laid down and mineralisation begins.
- Precise modelling of the final bone is done by osteoclasts.
What is intramembranous ossification
- Bone formation without a cartilage model. Osteoblasts (derived from osteoprogenitor cells) lay down osteoid and begin mineralisation, forming tiny bony spicules. Nearby spicules join together into trabeculae (woven bone).
Factors governing remodelling
Two major factors:
- Recurrent mechanical stress
- Calcium homeostasis - plasma calcium is essential in maintaining structural
Examples of mechanical stress that strengthens bone
- Inhibits bone resorption, promotes deposition
- Surface osteoblasts and osteocyte network detect stresses
- Without weight bearing, bone rapidly weak
- Skeleton reflects forces acting on it
eg. bed rest, lack of gravity(astronauts)
Bisphosphonates
- For osteoporosis
- Inhibit osteoclast-mediated bone-resorption
- Related to inorganic pyrophosphate
(The endogenous regulator of bone turnover, accumulate on bone and ingested by osteoclasts, interfere with osteoclasts metabolism)
Example of an bisphosphonate
- Alendronate
Drugs which encourage osteoblast formation of bone
- Teriparatide
- Portion of human parathyroid hormone
- Intermittent application activates osteoblasts more than osteoclasts
Drugs which prevent osteoclast maturation
- Denosumab
- Monoclonal antibody that targets RANKL
Osteoporosis(autosomal recessive) - Molecular mechanism
- Osteoclasts cannot remodel bone
- Defective vacuolar proton pump or
- Defective chloride channel
Osteoporosis pathogenesis
Excess bone growth - bone growths at foramina press on nerves
- Brittle(dense) bones
- Blidness
- Deafness
- Severe anaemia
What is V-ATPase
- Vacuolar Proton Pump = An H+ pump (that consumes ATP) on osteoclast plasma membranes (+ some other cells) that pumps H+ out of the cell. Its activity is essential for making Howship’s lacuna acidic, thus it is necessary for bone resorption.
Phases of fracture healing: stages 1 and 2
Reactive phase - haematoma and inflammation
Soft callus formation
What is soft callus formation
When the dividing fibroblasts link up with other parts of the fracture to make a callus made of cartilage or of woven bone
Phases of fracture healing - stages 3 and 4
Hard callus formation
Remodelling
What is hard callus formation
Hyaline cartilage and woven bone is replaced by lamellar bone, which will be turned into trabecular bone. The replacement of woven bone (that has disoganised collagen) by lamellar bone (that has parallel collagen fibres) is called Bony Substitution. The replacement of hyaline cartilage by lamellar bone is called endochondral ossification.
What is PTH
- Parathyroid hormone
- Secreted by parathyroid chief cells
- Increases plasma Ca2+
Vitamin D: 1,25-di-OH cholecalciferol (calcitriol)
Made in stages: skin –> liver –> kidney
- Increases plasma Ca2+
Calcitonin
- Made by thyroid C cells
- ‘tones down’ blood calcium, calcium goes into bone (used as a treatment for osteoporosis)
How does PTH stimulate resorption via osteoblasts
- PTH-R are found on the surface of osteoblasts
- When PTH binds to PTH-R for a long time, it causes the expression of RANKL (a signal) on the osteoblast cell surface
- When RANKL binds to RANK, it encourages differentiation of the osteoclast precursor to a differentiated osteoclast (this differentiation involves cell fusion)
Vitamin D: production and activation
Skin - Cholecalciferol (vitamin D3) —> 25-OH cholecalciferol —> 1, 25-di-OH cholecalciferol (calcitriol) —> increase in calbindin in gut enterocytes —> increase in intestinal absorption of Ca2+ and increase in Ca2+ reabsorption in kidneys –> increase in plasma Ca2+
Effects of vitamin D
Increases intestinal Ca2+ absorption - increases calbindin
Stimulates kidneys to reabsorb calcium
Stimulates osteoclasts indirectly via osteoblasts. This is a comparatively weak effect
Vitamin D facilitates bone remodelling and thus increases serum Ca2+
Causes of low plasma calcium - loss
- Pregnancy
- Lactation
- Kidney dysfunction
Causes of low plasma calcium - low intake
- Insufficient ingestion of Calcium
- Rickets (low vit D)
- Parathyroid dysfunction
What is parathyroid dysfunction most commonly caused by
- Surgery
What might chronic hypocalcaemia result in
- Skeletal deformities
- Increased tendency toward bone fractures
- Impaired growth
- Short stature
- Dental deformities
What can acute hypocalcaemia cause
- Convulsions
- Arrhythmias
- Tetany
Chvostek’s sign, trousseau’s sign and carpopedal spasm (latent tetany), DiGeorge syndrome
Features of excitability caused by low plasma calcium levels
- Effect seems paradoxical (i.e counter-intuitive)
- Hypocalcaemia makes membranes ‘more excitable’ and ‘less stable’ - sodium is more able to leak through it, explains latent tetany and its signs
- Hypercalcaemia paradoxically reduces excitability by making membranes more stable
Hypercalcaemia - signs and symptoms: decreased excitability
- Can be asymptomatic
- Reduced excitability - esp constipation, depression + other psychiatric
- Abnormal heart rhythms
- Severe hypercalcaemia - coma, cardiac arrest
