12. Physiology of bone repair Flashcards
Bone physiology basics
Healthy Bone Physiology is a balance
between:
Bone resorption
Bone formation
imbalance on bone resorption side leads to osteopetrosis (osteopenia, rickets)
imbalance on bone formation side -> osteoperosis
Classifications of bone structure
• Long bone • Flat bone Macroscopic: • Cortical bone • Cancellous (spongy) ○ Spicules, trabeculae (bits and pieces) Microscopic • Lamellar ○ Osteons • Woven ○ Immature ○ Disorganised
Composition of bone
living cells and acellular matrix 3 principle cell types: osteoclasts osteoblasts osteocytes Mostly extracellular matrix
Osteoblasts
on surface bone, produce protein component acellular matrix – regulate bone growth and degradation
Osteocytes
quiescent mature cells embedded in bone matrix.
Maintain bone.
Osteoclasts
responsible for bone degradation and remodelling
Organic vs inorganic components of bone
Organic – cells and proteins
Inorganic – minerals, eg Ca2+ & PO4- (hydroxyapatite)
bone dominated by extracellular matrix - few cells
Haversian system in lamellar bone
As opposed to woven bone
Communication system between cells immobilised in bone matrix
Osteons with Lamellae surrounding Haversian canals in centre to allow fluid movement
Osteocytes embedded in canaliculi in osteon
Ground substance between cells
Haversian system runs parallel to bone and along long axis of bone
Where do osteocytes come from?
From mesenchyme
From precursor cells in bone marrow stroma
Osteoblasts are post-mitotic
Most osteoblasts will undergo apoptosis
Number of osteoblasts decrease with age
A low % of osteoblasts will become osteocytes locked in lacuna
Osteoclasts
Function: Resorption Multinucleate 40-100 micrometer in diameter. 15-20 closely packed oval-shaped nuclei. Can proliferate
Same precursor as monocytes (haematopoietic stem)
- Phagocytose (bone matrix & crystals)
- Secrete Acids
- Secrete proteolytic enzymes from lysosomes
Ruffled border = where bone resorption occurs
Bone constituents
Extracellular matrix is 70% minerals
Plus abundant proteins and sparse cells
High compressive strength and tensile strength
Acellular elements of bone
collagen fibres – protein, flexible but strong
hydroxyapatite – mineral, provides rigidity
calcium/phosphate crystals > 50 %
What are glycosaminoglycans
long polysaccharides Highly negative Attract Water Repel each other Resists compression
Abundant in Cartilage
These are another set of organic molecules in bone ground matrix
Growth factors in bone ECM
Growth factors are suspended in matrix
They are revealed by osteoclast action
Which leads to proliferation & mineralisation
bone remodelling = bone turnover = the activation-resorption-formation sequence
Bone cells remodel bone
- Osteoclasts resorb bone to make Howship’s lacuna, then migrates away
- Osteoblasts deposit bone onto pre-existing bone
osteoblasts lay down bone but also encourage osteoclasts
bone remodelling is very active
Bone formation
bone forms either as compact or cancellous and by either intramembranous or endochondral bone formation
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.
Intramembraneous 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 integrity of skeleton
Effect of mechanical stress on bone
strengthens bone
- inhibits bone resorption
promotes deposition - Surface osteoblasts & osteocyte network detect stresses
-skeleton reflects forces acting on it
Without weight bearing
bone rapidly weakens
e.g. bed rest, or lack of gravity e.g. astronauts
Bisphosphonates
For osteoporosis
E.g. Alendronate
inhibit osteoclast-mediated bone-resorption
related to inorganic pyrophosphate
- the endogenous regulator of bone turnover
- Accumulate on bone & ingested by osteoclasts
- Interfere with osteoclasts metabolism
Teripatide
For osteoperosis
Encourages osteoblast formation of bone
portion of human parathyroid hormone (PTH)
Intermittent application activates osteoblasts more than osteoclasts
Denosumab
For osteoperosis
Prevent osteoclast maturation
Monoclonal antibody targetting RANKL
Molecular mechanism of osteopetrosis (autosomal recessive)
Molecular Mechanism Osteoclasts cannot remodel bone due to: - Defective Vacuolar proton pump or - Defective Chloride channel
Results of osteperosis
Excess bone growth
Bone growths at foramina press on nerves
Brittle (dense) bones
Blindness
Deafness
Severe anaemia
Phases of fracture healing stages
- Reactive phase: haematoma and inflammation
- Soft callus formation
- Hard callus formation
- Remodelling
Duration: upper body 2-3 weeks, lower body > 4 weeks
Hormones of calcium regulation
PTH – parathryoid hormone, parathormone
- 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
Vitmin D: production and activation
Cholecalciferol (Vitamin D3) -> 25-OH cholecalciferol -> 1, 25-di-OH cholecalciferol (calcitriol) -> increased Calbindin in gut enterocytes -> increased Intestinal absorption of Ca2+ and increased
Ca2+ reabsorption in kidneys
-> increased plasma Ca2+
How does PTH stimulate resorption via osteoblasts?
PTH binds PTH-R on osteoblast, causing RANKL to bind RANK on osteoclast precursor
osteoclast precursos differentiates and fuses and forms activated osteoclast
activated osteoclast carries out bone resorption
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
Low Intake
Insufficient ingestion of Calcium
Rickets (low vit D)
Parathyroid dysfunction
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+
Results of chronic hypocalcaemia
Skeletal deformities
Increased tendency toward bone fractures
Impaired growth
Short stature (adults less than 5 feet tall)
Dental deformities
Rickets can be caused by chronic hypocalcaemia
Acute hypocalcaemia
Leads to excitability
C – Convulsions
A – Arrhythmias
T – Tetany
Chvostek’s Sign (Latent Tetany) Trousseau’s Sign Carpopedal spasm (Latent Tetany) DiGeorge Syndrome
How does low plasma calcium cause excitability?
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
Signs and symptoms of decreased excitability
Can be asymptomatic
Reduced excitability
Esp. Constipation
Depression + other psychiatric
Abnormal heart rhythms
Short QT interval, ST segment gone
Widened T wave
Severe hypercalcemia
Coma
Cardiac arrest
