Calcium homeostasis and bone metabolism Flashcards
What should extracellular calcium concentration be maintained at?
2.5 mM, about half of this is free Ca2+
What 3 hormones are involved in calcium homeostasis?
- Parathyroid hormone (PTH)
- calcitonin
- Vitamin D
What happens as a result of changes in extracellular Ca2+ concentrations?
Changes the excitability of excitable cells e.g. neurons, muscle cells
Ca2+ controls membrane permeability to Na+:
- Low extracellular calcium= increase in Na+ permeability (increase in Na+ entering the cell= more positive charge) leads to depolarisation of the membrane
- High extracellular calcium- decrease in Na+ permeability causing hyperpolarisation of the plasma membrane
What is hypocalcaemia and its consequences?
Too little Ca2+ outside the cell
- This causes an increase in muscle/nerve excitability due to depolarisation of the membrane
- This can cause muscle spasms in the respiratory muscles e.g. diaphragm preventing respiration and can be fatal.
What is hypercalcaemia and its consequences?
Too much extracellular Ca2+
- This causes a decrease in muscle/nerve excitability due to hyperpolarisation of the membrane
- This can cause cardiac arrhythmias- the changing of the membrane potential of the heart effects its function and can be fatal.
What are the two types of bone?
Tribecular bone (20%) - has a spongy appearance, inner supporting structure
Cortical bone (80%)- more dense in appearance, outer structure
What is the structure of cortical bones
- Formed from circular rings caused osteons that surround a central canal where the blood vessels are found.
These rings are made of osteocyte cells
Osteoblasts connect with the osteocytes to form the osteocytic-osteoblastic bone membrane
osteoclasts are found on the outside of bone and are multi-nucleur
What is mineralised bone made up of?
Made up of a crystalline matrix of hydroxyapatite crystals.
These crystals contain Ca2+, OH- and PO4^3- (phosphate) ions
Is bone static?
No bones are constantly being turned over- remodelling
Which cells perform bone deposition (making) and which perform bone resorption?
Osteoblasts- deposition
Osteoclasts- resorption
How do osteoclasts and osteoblasts work in bone remodelling?
- Osteoclasts produce hydrochloric acid to dissolve the mineral bone and the enzyme cathepsin K to breakdown the collagen matrix.
- The osteoclasts then die or migrate to another area so osteoblasts move in and fill the cavity by secreting osteoids. Calcium and phosphate ions precipitate around it to form mineralised bone
How do osteoblasts and osteoclasts regulate each other?
- As osteoclasts breakdown the bone, they release growth factors- IGF and TGF-B into the bone fluid.
These factors cause the differentiation of precursor cells in the bone marrow into osteoblasts. The osteoblasts then attach to the bone to stimulate deposition of the bone - Osteoclast numbers are controlled by factors secreted from osteoblasts:
- RANKL- when this ligand binds to its receptors it causes increase in osteoclast differentiation and decreases osteoclast apoptosis. the increase in number promotes bone resorption
- Also secretes osteoprotegerin (OPG)- A ‘decoy’ that binds to the RANK ligand to prevent it binding to the RANK receptor and its downstream signalling. This decreases osteoclast differentiation and promote bond deposition
What is the main hormone involved in ca2+ homeostasis?
Parathyroid hormone- secreted from the parathyroid glands behind the trachea
What is the role of parathyroid hormone in calcium homeostasis?
- The secretion of parathyroid hormone is increased when there is a decrease in ca2+ concentration. The calcium concentration in the extracellular fluid is detected by a GPCR protein called ‘ calcium sensing receptor’ on the parathyroid cells:
- if ca decreases, pth secretion is increased causing an increase in plasma calcium. This change will be detected and sends a negative feedback loop
What are the 2 phases of calcium release from the bone stimulated by parathyroid hormone?
Fast exchange- Causes a rapid efflux of calcium ions from the fluid within the canaliculi of the bone and into the plasma. The GPCR receptors for PTH are on the osteoblasts and osteocytes and are couples to g alpha s. When these are stimulated, cAMP production is increased which causes the movement of calcium ions from the bone fluid and into the cells. The cells are connected by gap junctions so allow the movement of calcium through and then pumped out by osteoblasts into the plasma.
Slow exchange- occurs during more prolonged hypocalcaemia.
PTH activates osteoblasts and increases RANK ligand expression. This causes an increase in number of osteoclasts by increasing the differentiation of stem cells in the bone marrow. Osteoclasts cause an increase in bone resorption and therefore increases plasma calcium ion concentration. Breaking down bone is not sustainable long time, so balance is restored when calcium absorption from the GIT is increased.
