Bone physiology and Calcium Metabolism Flashcards
What is bone composed of?
Bone comprises the largest proportion of the body’s connective tissue mass.
Consists of:
Cellular component
and
Extracellular matrix
How is bone different to other connective tissue matrices?
It is physiologically mineralised and constantly regenerates throughout life
What are the functions of bone?
Structural: providing mobility for muscle attachments as well as mechanical support
Protection: cranial and thoracic
Primary mineral reservoir
Haematopoiesis
What kind of material is bone?
It is a composite material Consisting of mineral, collagen and non-collagenous protein and lipids
What is the inorganic (mineral) phase of bone for?
Strength and rigidity
What is inorganic phase of bone made up of?
Nanocrystalline analogue of hydroxyapatite
Mineral substitutes Mg, Na, K, CO3, Fl, heavy metals
What is the organic phase made up of?
Predominantly type 1 collagen
Non-collagenous proteins
What is the purpose of the organic phase?
Resilience and flexibility
What are the types of bones?
Cortical (80% of skeleton)
Cancellous (trabecular/spongy)
What is contained in the cortical bone?
Osteons or haversian systems
Outer border defined by cement lines
What is the size and shape of bone suited for?
Size and shape of bone best fits function
What guide changes in bone?
Modelling (shaping)
Remodelling (resurfacing)
What is the formation of new bone at one site and removal of old bone from another site within the same bone called?
Modelling
What is removal and replacement of bone at the same site called?
Remodelling
When does modelling take place?
Bones grow in size and shift in space via this process
During childhood formation of new bone occurs in outer periosteal surface
At puberty bones get thicker and formation of bone on both the outer and inner surfaces
When does remodelling occur?
Remodelling occurs throughout life
Bone reaches peak mass by the early 20s
Most of the adult skeleton is replaced every 10 years
What is the purpose of bone remodelling?
Allows repair of microscopic areas of damage within bone to maintain skeletal strength
Allows release of calcium to maintain serum calcium levels
What is cellular communication coupling between resident cells?
Intercellular communication that occurs directly or indirectly which can initiate various responses within different cells.
What is a basic multicellular unit (BMU)?
Local collection of osteocytes, osteoblasts and osteoclasts work together to control bone formation and resorption creating a functional unit.
What are osteoblasts?
Mesenchymal “osteoprogenitor” cells and bone-lining cells
What is the morphology of osteoblasts like?
Plump and polygonal
What is the function of osteoblasts?
To synthesize bone matrix. They lay down ECM and that is then mineralized to form bone.
What is a new bone matrix that hasn’t been mineralised yet called?
Osteoid
How do osteoblasts regulate osteoclast formation?
Osteoblasts produce M-CSF and RANKL which bind to c-fms and RANK receptors respectively.
How do osteoblasts communicate with osteocytes?
Via gap junctions
What are the types of bone deposition?
Woven: primary bone, random collagen weave, mechanically weak
Lamellar bone: Secondary bone created by remodelling of woven bone into sheets that are mechanically strong.
Where do osteocytes come from?
Entombed osteoblasts residing in bone matrix residing in lacunae become osteocytes.
What do osteocytes look like?
Spider like dendritic processes which radiate through the bone in tiny canals called canaliculi
What are osteocytes?
Most abundant bone cells
What do osteocytes do?
They function as a network
They regulate bone formation
Control calcium and phosphate levels
Mechanotransduction
Inhibit bone formation via sclerostin
What does sclerostin do?
Inhibits bone formation
How do osteocytes communicate and exchange nutrients with each other?
Via gap junctions and hemichannels (called connexin 43 found in dendrites of osteocytes)
What is the origin of osteoclasts?
Haematopoietic (fused mononuclear progenitors (monocytes - macrophages)
What cytokines drive osteoclast formation?
Macrophage colony stimulating factor (M-CSF)
Receptor Activator of NFkappaB ligand (RANKL) binds to RANK receptor and drives cell differentiation and fusion.
How is formation of osteoclasts regulated?
By RANK/RANKL/OPG signalling axis
What is OPG?
Osteoprotegerin - a soluble decoy receptor for RANKL expressed by osteoblasts to decrease number of osteoclasts
How do osteoclasts differentiate?
Stem cell (osteoclast progenitor stem cell) contains RANK receptor
Osteoblast contains M-CSF which binds to c-FMS on osteoclast progenitor receptor.
M-CSF binds to C-Fms on osteoclast progenitor which converts it into osteoclast precursor and then into osteoclast
RANKL activates NFkappaB ligand by binding to RANK receptor which drives cell differentiation and fusion
Osteoprotegrin is produced by osteoblasts to decrease binding of RANKL to RANK thus decreasing osteoclast formation
What is the bone resorption cycle?
Attachment (attachment of RGD peptides and integrins to bone surface) sealing zone or active zone is formed
Polarization (Cytoskeleton reorganisation or sealing zone, a ruffled border is formed because of cytoskeleton changes increasing surface area of osteoclast degradation)
Resorption (Inorganic/organic phase degraded to form different metabolites)
Removal (Transcytosis of products)
How are the inorganic and organic borders degraded by osteoclasts?
Inorganic matrix degradation: Dimineralisation of hydroxyapatite via H+ and Cl-
Organic matrix degradation: Cathepsins (K) - Type I collagenase and TRAP - Tartrate Resistant Acid Phosphatase
How does bone remodelling occur?
In a cyclical manner: Activation - Resorption - Formation (ARF) cycle.
Activation triggered by osteocyte cell death followed by osteoclast resorption of bone and then formation of new bone.
How is activation stage of bone remodelling initiated?
Mediated by osteocyte cell death near micro fractures due to recruitement of osteoclasts by RANKL release.
How do osteoblasts communicate with surrounding cells?
Osteoblasts communicate either through formation of hormones or directly through the gap junctions (with osteocytes)
How does bone resorption occur?
Osteoclasts attach and degrade bone making them undergo apoptosis and switch between resorption and formation called the reversal phase
How does bone formation occur?
Osteoblasts are recruited and lay down new bone (osteoid) This process is terminated by osteocytes via sclerostin
What percentage of calcium is in the bones
99%
Where is the rest of the calcium located?
<1% in cells and soft tissues
0.1% in the blood (10^-3M) and ECF
What is the concentration of calcium in cells?
10^-6M
Where in cells is calcium stored?
Mitochondria
ER
How is calcium carried in the blood?
45% is bound to plasma proteins (albumin) or to small anions (PO4 and citrate) and partly ionized
Only ionized Ca2+ can move in and out of cells
What is the concentration of normal total calcium in the blood?
2.12 - 2.62mM
What is the concentration of normal ionized calcium in the blood?
1.16 - 1.31 mM
How much calcium is taken in by the kidneys each day and how much of it is reabsorbed?
- 0g/day taken in
9. 8g/day reabsorbed
How much calcium is absorbed by the intestines each day and how much of it is excreted?
1g/day absorbed
0.8g/day excreted
What systems regulate calcium homeostasis?
Calciostat system (CaSR)
Parathyroid hormone (PTH) - increases plasma [Ca2+]
Vitamin D3 (1,25 D) - increase in plasma [Ca2+]
Calcitonin decreases plasma [Ca2+]
How is plasma [Ca2+] regulated?
3 hormones:
Calcitriol (active form of D3) from kidney = Increase
PTH from parathyroid = Increase
Calcitonin from thyroid = Decrease
How does D3 increase Calcium levels in the blood?
It promotes GIT Ca2+ absorption and reduces Ca2+ excretion
It also exerts negative control of PTH synthesis and further calcitriol synthesis
What does PTH do to D3 metabolism/
It activates 25-OH-D3 (inactive D3) to form active 1,25(OH)2 D3
How is PTH production controlled?
Regulated by ECF calcium. Low calcium is sensed by CaSR and PTH production is increased in response.
What is the principle effect of PTH?
Increases ECF calcium concentration by:
Mobilising calcium from bone
Increasing tubular reabsorption
Indirectly on the gut by increasing calcitriol synthesis
How is PTH effect antagonised?
Calcitonin release
What is the effect of PTH on bone?
Increases bone degradation in 2 ways:
Rapidly via increasing osteocyte membrane permeability for Ca2+ -> liquid Ca2+ enters the cells -> Ca2+ pump transports Ca2+ to the ECF -> increased serum [Ca2+]
Delayed action is via increasing osteoclast activity and producing more osteoclasts which increase serum [Ca2+]
Overall result in increase in release of Ca2+ from bone
Where is calcitonin synthesized?
Synthesized and secreted by parafollicular “C” cells of the thyroid gland
When is calcitonin secreted?
It antagonises PTH in Ca homeostasis and is produced when [Ca2+] is too high in the plasma
What is the target cell for calcitonin?
Bone osteoclasts
What receptor does calcitonin bind to?
Calcitonin receptor (CTR) (cAMP mechanism)
What does calcitonin do?
Inhibits osteoclast formation
Decreases kidney Ca2+ reabsorption (more calcium lost from kidneys than normal)
Inhibits Ca2+ absorption by intestines
PTH does the opposite
