Bone Structure and Metabolism Flashcards
What is the organic and inorganic percentage makeup of bone?
60% inorganic calcium hydroxyapatite
40% organic (90% type 1 collagen; non-collagenous proteins e.g. protoglycans and matrix proteins)
What is lamellar bone?
microscopic Organisation
Organised stress-orientated and structurally strong bone made up of osteons formed by remodelling woven bone.
What is woven bone?
Microscopic organisation
Immature, mechanically weak bone made up of haphazard collagen fibres. Can be rapidly produced hence why found in foetal bone/fracture healing.
How does mechanical loading effect bone remodelling?
Under increased leading, there is osteoblast activation and partial osteoclast suppression leading to formation of strong bone
Under reduced loading there is osteoblast partial suppression and osteoclast activation leading to bone resorption and weaker bones.
What is mechanotransduction in bone?
When bones are loaded, fluid is forced away from areas under high compression, osteocytes sense movement of this fluid are initiate signal pathways.
Describe trabecular bone.
- Loose network of trabeculae which are remodelled along stress lines (Wolff’s law) allowing for transmission of loads.
- Is the main site for metabolic bone functions and has a high turnover.
- Less rigid and more elastic than cortical bone.
Describe Cortical bone.
- Makes up 80% of the skeleton.
- Made up of osteons with concentric lamellae surrounding haversian canal systems.
- High Rigidity and resists torsion
- Slow turnover rate
What is the physis of a bone?
The physis is the growth plate which is a specialised zone of cartilage, and the site of longitudinal growth in long bones
What are the components of long bones?
Epiphysis, Physis/Physeal scar, Metaphysis, Diaphysis, periosteum, blood supply.
How do active osteoclasts resorb bone? (5)
- Seal on one side of the cell to bone surface at sealing zones, and bone polarises to have different membrane domains.
- Ruffled border increases surface area to aid HCL secretion and absorption of products
- HCL dissolves Hydroxyapatite.
- TRAP (Tartrate-resistant acid phosphatase), helps dissolve inorganic hydroxyapatite
- Cathepsin K is a proteolytic enzyme that breaks down the organic components e.g. collagen.
- Secretory domain allows products of degradation to be released into the interstitial fluid.
What is the origin, function and features of Osteoclasts?
ORIGIN: multinucleated giant cells formed by fusion of multiple myeloid hematopoietic cells from monocyte/macrophage lineage.
FUNCTION: Resorb bone by dissolving inorganic hydroxyapatite and the organic matrix (by proteolytic digestion)
FEATURES: have calcitonin receptors, calcitonin inhibits activity. Activated by RANK-L causing fusion of osteoclast progenitor cells, hence becoming multinucleated.
What signalling mechanisms are osteocytes involved in? (3)
- When signalled, osteocytes increase osteoclast differentiation and activation by increased expression of RANK-L
- Osteocytes can release sclerostin which inhibits osteoblast differentiation and reduced bone formation. Sclerostin production increased by calcitonin.
- Increased PTH or mechanical loading reduces sclerostin production hence increasing bone formation.
What are canaliculi?
Long processes that host osteocyte dendrites allowing them to communicate with other osteocytes forming a network. Part of the cortical havarian system.
What is the origin, function and features of osteocytes?
Origin = former osteoblasts trapped in the matric ~90% of cells in skeleton
Function = Maintain bone and cellular matrix, regulate the concentration of calcium and phosphorus in the bone.
Features = Use mechanotransduction to detect when tissue is under compressive loads and can communicate over long distances via canaliculi.
What is the lifespan of osteoblast and what is its fate when it dies?
Lifespan of osteoblast = ~6 months
after which:
Become osteocytes
Undergo Apoptosis
Differentiate into lining cells can become trapped in the matrix of their making
What is OPG?
OPG (Osteoprotegerin) is a decoy receptor that irriversity binds to RANK-L
Preventing it from bind to the RANK receptors on the osteocyte precursors
Inhibiting differentiation and activation of osteoclasts therefore inhibiting bone resorption.
What is RANK-L?
RANK-Ligand is a signalling molecule that binds to RANK receptors
Stimulating osteoclast precursors to become active osteoclasts
Hence stimulating bone resorption.
How do osteoblasts contribute to osteoclast regulation?
- When signalled by PTH osteoblasts release RANK-L
- RANK-L binds to RANK on osteoclast precursors
- This activates osteoclasts, hence stimulating bone resorption
What effect does calcitonin have on osteoblasts?
When signalled by calcitonin, osteoblasts produce more
- bone matrix and alkaline phosphatase - specific bone proteins such as osteocalcin and osteonectin.
What effect does PTH have on osteoblasts?
- When osteoblasts are signalled by PTH they form type 1 collagen and alkaline phosphatase (ALP)
- This causes de-phosphorylation and calcification of the matrix by depositing calcium phosphate
What is the origin, location and function of osteoblasts?
Origin: Osteoprogenitor cells differentiate into osteoblasts under the influence of Runx2 and osterix released by osteocytes.
Location: peri/endosteum and ‘Inactive’ bony surfaces.
Function:
- Form bone by producing non-mineralised matrix. Hence have increased ER, golgi and mitochondria for bone matrix synthesis and secretion.
- Function in osteoclast regulation via RANK-OPG axis.
What is the pathway from a mesenchymal progenitor to an osteoblast? What is the clinical relevance of this?
mesenchymal progenitor -> osteo-chondroprogenitor
strain on bone -> Pre-osteoblast (osterix and runx2 released by osteocytes as precursors)
- High strain/low O2 = FB
- Mod strain/low O2 = CB
- Low strain/high O2 = OB
Clinically relevant because osteo-chondroprogenitor cells will differentiate into chondrocytes instead if there is lots of movement, hence fractures may never heal if lots of movement as hard bone may never form (non-union).
What are osteoprogenitor cells? Where are they found?
Mesenchymal stem cells derived from foetal mesenchyme that are involved in bone repair and growth
Can differentiate into more specialised bone cells
Found in the bone marrow, endosteum and cellular layer of periosteum.
What adaptation to bipedalism do we have? (3)
- Spinal curves and vertebral discs for shock absorption
- Weight bearing axis of hip and knee
- Tripod arrangement of feet
However human back not very well adapted especially lower back
Role of Parathyroid hormone in the Calcium metabolism:
Defender of extracellular calcium concentration:
- PTH is secreted from 4 parathyroid glands located within the thyroid gland.
- PTH stimulates the release of calcium from the bones by stimulating OBs to release RANK-L hence increased bone resorption and decreased bone formation.
- Reduces calcium loss in urine and stimulates the formation of calcitriol in the kidneys
- Indirectly increases calcium absorption in intestine via effects on vit D metabolism
- Low extracellular calcium stimulates PTH secretion whereas high calcium concentration prevents its release – Negative feedback system.
What is the role of Vitamin D in the calcium metabolism?
Vitamin D – Defender of bone mineralization:
- Facilitates intestinal absorption of calcium by mediating active calcium transport across the intestinal mucosa.
- Also facilitates phosphate absorption.
- Facilitates reabsorption of filtered calcium in the renal tubules of the kidney
- increased availability of these materials explains correlation between Vit D and bone mineralization rather than direct effects.
What is the role of calcitonin in the Calcium metabolism?
- decreases extracellular calcium concentration by inhibiting the breakdown on bone and by preventing the reabsorbing calcium ions in the renal tubules.
Explain what happens to the calcium metabolism when there is hypercalcaemia?
Parafollicular cells in the thyroid gland release calcitonin
Calcitonin directly inhibits OC resorption and prevents reabsorption of calcium in renal tubules.
Explain what happens to the calcium metabolism when there is hypocalcaemia?
Parathyroid gland release PTH
PTH stimulates OBs to release RANK-L indirectly increasing OC differentiation and bone resorption
PTH Increases Calcium reabsorption in renal tubules
PTH stimulates hydroxylation of vit d. into calcitriol in the kidneys.
Indirectly increases calcium uptake in the intestine and kidneys via Calcitriol.
What is the osteoid made up of? (4)
- Unmineralised organic matrix
- Type 1 collagen
- Glycosaminoglycans (GAGs)
- Hydroxyapatite crystals which enable the formation of hardered bone matrix.
How does GH (growth Hormone) influence bone metabolism?
GH directly stimulates osteoblast proliferation and activity, and osteoclast differentiation, resulting in an overall increase in bone formation/remodelling.
Give some examples of cytokines:
Bone morphogenic proteins, Interleukin-6, Insulin-Like Growth Factor-1.
How is the steep gradient between intra- and extra- cellular calcium concentration maintained?
By Ca2_ ATP-ase pumps
What is bone remodelling?
The cycle by which small increments of bone are removed and replaced with new bone. removal of microdamage and healing of macro-damaged bone and response to changing loads (Wolff’s Law).
What happens in the quiescence phase of the bone remodelling cycle?
- Resting state of 90% of bone
- Osteoblasts are inactive lining bone surface
- Osteocytes maintain matrix and sense change via mechanotransduction, inhibit OB activity by sclerostin.
What happens in the activation of the bone remodeling cycle?
Can be systemic from PTH, Vitamin D or endocrine signals
Can be from local mechanical stress or microdamage.
RANK-L and M-CSF (Macrophage colony stimulating factor) recruit, differentiate and activate OCs.
What happens in the resorption phase of the bone remodelling cycle?
- Activated Osteoclasts migrate
- attach to bone, polarise, dissolve inorganic and organic matrix
- Products of degradation and removed back to ECM
What happens in the reversal phase of bone mineralisation?
`Osteoclasts:
- Apoptose or deactivate
- signal to OPCs and OBs
Osteoprogenitor cells
- Migrate to resorption pit
- Differentiate and activate into osteoblasts.
What happens in the formation phase of bone remodelling?
Osteoblasts:
- Lay down osteoid made up of type 1 collagen, osteocalcin, proteoglycans.
- Fill in resorption pit
- control mineralisation of osteoid via ostropotin
- Then either become osteocytes of line bone.
What happens in the mineralisation phase of bone remodelling?
- 75% of mineralisation in first 1-2 weeks
- Deposition of hydroxyapatite
- Precipitation of soluble calcium and inorganic phosphate
- Soft osteoid into hard bone.
What are the phases of bone remodelling cycle?
quiescence -> activation -> resorption -> reversal -> formation -> mineralization.
How is bone remodelling regulated Locally?
- Inhibited by Inorganic Pyrophosphate (PPi) which blocks calcification, inhibits hydroxyapatite formation. Present in the ECF, synovial fluid and plasma.
- Osteoblast-derived proteins:
> osteocalcin stimulates and promotes mineralisation
> Osteopontin inhibits mineral binding and crystal growth.
How is bone remodelling regulated systemically?
Endocrine regulators of serum Calcium and Phosphate:
- PTH (mostly)
- Vit. D
- FGF23
How is FGF23 gene involved in bone remodelling?
FGF23 is produced by osteocytes and osteoblsts in response to increased calcitriol/active VIt D.
- INcreases PPi secretion
- Decreases PTH and Vit D. levels
- Part of the negative feedback loop.
What signalling occurs in osteoclastic bone resorption?
- Increased PTH
- Decreased calcitonin (direct) and oestrogen (via RANK-L)
What signalling occurs in osteoblastic bone formation?
Increased PTH, Vitamin D, Oestrogen, GH
What is the diaphysis?
Shaft
What is the epiphysis?
Proximal and distal ends on the bones, in early developments separated from the diaphysis by the physis.
What is the metaphysis
Region between the epiphysis/physis and the diaphysis?
What is the medullary cavity?
The hollow space in diaphysis of long bone AKA the bone arrow cavity
In adults long bone yellow marrow
IN flat bone red marrow.
