Lecture 1: calcium is complicated Flashcards
what are the physiological roles of calcium?
- Structural
- 2nd messenger
- neural transmission
- muscle contraction
- blood coagulation
- enzyme activity (Quaternary structure of proteins)
- Hormone release
Most common disruption to calcium metabolism
oestrogen deficient state (most commonly post menopausal state)
Most common site osteoporotic fracture?
Neck of the femor
Define kyphosis
excessive outward curvature of the spine, causing hunching of the back.
Generally due to multiple oseoporotic fractures (called crush fractures).
Where is calcium absorbed?
All along the digestive tract. Predominately in the proximal part of the intestine in the duodenum where it is actively absorbed.
How is calcium excreted.
- Incorporated into bone
- Filtered by glomerulus and excreted in the urine
- Reenters gastrointestinal tract in secretions all along the GIT such as bile, saliva, gastric juices
when is peak bone mass achieved?
About 25 years
When do humans begin to lose bone?
About 35 years
Extracellular concentration of calcium?
10^-3 M
Intracellular concentration of calcium?
10^-7 M
Effect of hypocalcaemia on neuronal transmission?
excitable neuronal transmission
Effect of hypercalcaemia on neuronal transmission?
sluggish neuronal transmission
Name the three fractions that calcium exists in the circulation?
50% in the free form
40% bound (mostly to albumin)
10% complexed (phosphate, citrate, oxalate, lactate)
What forms of calcium are filtered at the glomerulus?
Ultrafilterable - free and complexed forms
Name the three calciotropic hormones.
- Parathyroid hormone
- Vitamin D
- Calcitonin
Name hormones that modulate effects of calciotropic hormones at their target tissues.
Androgens, glucocorticoids and oestrogens
Where is calcitonin produced
It is a polypeptide hormone produced in the parafollicular C cells of the thyroid
What stimulates the production and release of calcitonin?
Raised extracellular calcium. For example after a meal high in dairy.
Target tissue of calcitonin?
- Renal tubules: blocks reuptake of calcium form glomerula filtrate.
- Osteoclasts: blocks re absorption of calcium from bone
Where is parathyroid hormone produced?
Polypeptide hormone produced in the chief cells of the parathyroid gland.
What stimulates production and release of parathyroid hormone?
Decreased ECF concentration of calcium.
Effect of PTH?
Acts at all sites of calcium reabsorption/influx. Stimulates bone re absorption, acts at convoluted tubule to stimulate reabsorption of calcium and acts on a enzyme responsible for vitamin D activation which in turn is responsible for the active absorption of calcium in the duodenum.
Describe the action of parathyroid hormone on the kidney.
- Increases tubular reabsorption of calcium
- Increase phosphate excretion
- Increase bicarbonate excretion and thus lowers ECF pH leading to a higher percentage of ionised calcium (H+ displace calcium from albumin)
- Activation of vitamin D to stimulate Ca++ absorption in gut
Describe renal handling of ultrafiltrable calcium.
95% reabsorbed at PCT and LOH. 5% reaches DCT where PTH acts.
Describe mechanism of calcium transport through a cell.
- Vitamin D binds to its receptor and interacts with promoters of several genes that stimulates cellular receptor TRPV5 (process is enhanged by stimulation from PTH)
- TRPV5 is a calcium channel on the luminal surface of cells.
- Calcium enters via TRPV5 and is bound to Calbindin d285.
- Calbindin d285 interacts with PMCA to pump calcium into circulation.
Action of PTH on bone?
Stimulate osteoblasts and osteoclasts to release calcium and phosphate from bone. This process requires active vitamin D.
Describe the key steps in bone remodeling.
- Resting bone is covered by lining cells
- Event occurs that disrupts lining cells, i.e., a microfracture/crack.
- Exposed resting bone releases chemotactic factors which attract preosteoclasts which fuse together to form osteoclasts.
- Osteoclasts reabsorb bone.
- Mononuclear cells enter and “clean up” the site known at the reversal phase.
- Preosteoblasts enter the site and differentiate into osteoblasts.
- Lay down collagen matrix
- Bone undergoes mineralization and some osteoblasts get trapped within the bone and become osteocytes.
Describe process of vitamin D metabolism.
7 dehydrocholesterol is a steroid which is abundent in the skin is converted to vitamin D in the presence of sunlight.
Enters the circulation and passes through the liver where the enzyme vitamin D-25-hydroxylase converts it to 25 hydroxyvitamin D.
25 hydroxyvitamin D-1-hydroxylase (CYP27B1) is an enzyme in the kidney that converts it to 1,25 dihydroxyvitamin D.
Action of 1,25 dihydroxyvitamin D in GIT?
Increase ECF calcium and phosphate by increasing intestinal absorption of dietary calcium and phosphate.
What cell is RANK ligand on?
osteoblast
What cell is RANK ligand receptor on?
osteoclast progenitor
What controls the production and secretion of RANK ligand and OPG (osteoprotegerin)
Prostaglandins
IL-11
Active vitamin D
Parathyroid hormone
What stimulates differentiation and fusion of osteoclasts into multinucleated cells able to absorb bone?
RANK
Function of OPG?
Decoy, block RANK ligand receptor sites
Action 1,25 dihydroxyvitamin D on the bone?
Stimulate osteoblast differentiation and thus bone turnover.
Local production of 1,25D regulated by osteoblast CYP27B1 paracrine/autocrine action
Action of 1,25 dihyroxyvitamin D on kidney?
Increase calcium re absorption at the DCT
Medical condition resulting from a frank vitamin D deficiency?
Rickets - Osteomalacia. Rubbery bones. Normal amount of collagen, but undermineralised.
Mild deficiency can lead to development of osteoporosis.
RDI of calcium for young adult?
1000 mg
Effect of PTH on bone?
Stimulates calcium and phosphate release
Effect of PTH on kidney?
Decrease phosphate reabsorption
Increase calcium reabsorption
Increase 1,25 vitamin D activation
Effect of 1,25 Vitamin D on bone?
with PTH increase calcium and phosphate release
Effect of 1,25 Vitamin D on kidney?
with PTH increase calcium reabsorption
Effect of 1,25 Vitamin D on GIT?
Increase calcium absorption.
