BCS Flashcards
What are the functions of calcium? (7)
Bone growth and remodelling Secretion - flux of intracellular calcium tells glands to release hormones Muscle contraction Blood clotting - calcium citrate used to help blood clot Co-enzyme Stabilization of membrane potentials - in heart and brain Second messenger/stimulus response coupling
Where is calcium stored?
Mostly in the bone (99%) The rest is extracellular
What regulates ionised ca2+
PTH and vitamin D
What are the functions of phosphate? (4)
Element in: High energy compounds e.g. ATP, Second messengers e.g. cAMP Constituent of: DNA/RNA, phospholipid membranes. bone Intracellular anion Phosphorylation (activation) of enzymes
Where is phosphate stored?
Skeleton 90% 9.97% intracellular (of which 50% is free, 50% is bound)
How is free phosphate regulated?
Controlled by kidneys, PTH, FGF23
What regulates the amount of calcium and phosphate in the blood?
The kidney Calcium - Distal CT Phosphate - Proximal CT
Order of bone remodelling process (4). How long does the process take?
30 days Osteoclasts carving REABOSORPTION well Osteoblasts form osteod, to REVERSE the changes Osteoblasts initiate FORMATION of new bone Resting state
What is an osteoclast?
Modified macrophage (from hematopoietic stem cellor mesenchymal stem cell)
Review development of osteoclasts and osteoblasts
PICTURE
Outline the hormonal control of bone remodelling
PTH activates osteoblasts, which controls bone reabsorption but releasing collagen and proteases IGF 1 is main actor
How does the osteoblast stimulate differentiation of osteoclasts? What receptor is activated? What can inhibit differentiation?
Production of RANK ligand The osteoclast recursor has a RANK receptor that is activates via activation of nuclear kappa beta OPG binding inhibits differentiation
Outline the role of osteoprotogenerin - what stimulates it?
also known as osteoclastogenesis inhibitory factor (OCIF) or tumour necrosis factor receptor superfamily member 11B (TNFRSF11B) False receptor to prevent activation of RANK receptor on osteoclast (to ultimately prevent bone reabsroption) Estrogen increases OPG expression (so dip in estrogen during menopause causes bone reabsoprtion)
Describe the activities of bone as an endocrine organ
FGF23 acts in conjunction with PTH decrease phosphate reabsorption by down-regulating NaPi2a and NaPi2c expression in the brush border of the proximal tubule resulting in hyper-phosphaturia and hypophosphatemia regulation high phospate and high 1,25 di hydroxy vit D The primary mechanisms by which adiponectin enhance insulin sensitivity appears to be through increased fatty acid oxidation and inhibition of hepatic glucose production
Outline the role of glucocorticoids, estrogen, calcitonin, thyroxine, vitamin A, androgens and GH on bone turnover
Provide overview of parathyroid gland
4 glands on upper and lower poles of each lobe of the thyroid gland Supernumerary glands not uncommon (source of PTH excess?) 30-50 mg weight Chief cells and oxyphill cells Supplied by blood from the inferior thyroid arteries (thyroid surgery)
What type of hormone is PTH? How can you measure it?
peptide (very short half life) Have to use sandwich assay to measure
What happens to calcium levels in acidosis?
HIGH
Outline the activity of the calcium sensing receptor? Where is it? What type of receptor? Ultimate results of activity
If your calcium levels are two high, what should be happening to your PTH?
There shouldn’t be any in your system
How does vitamin D regulate PTH production?
Calcitriol (1,25 OH2D3) inhibts replication and secretion of PTH To INCREASE calcium
What are the direct actions of PTH on bone activity and in kidney (4)
Stimulate osteoblasts to produce M-CSF and RANK ligand increased bone resorption Increase Ca2+ reabsorption in the distal convoluted tubule Increase phosphate excretion Increases 1-α hydroxylase in the proximal tubule
REVIEW activity of PTH on kidney in more detail
What is the active form of Vitamin D? How is it made?
D3 Cholesterol and UV light on skin / DIET
What is the regulatory step in the production of vitamin D?
Hydroxylation on C1 in kidney So issue in kidney disease with calcium levels
What are the actions of vitamin D in calcium homeostasis? (5)
Increases Ca2+ absorption in the gut Requires CaBP’s - synthesis stimulated by Vitamin D Synergises with PTH on bone Inhibits PTH synthesis Inhibits 1a-hydroxylase (feedback on itself)
How is calcium absorbed through the gut? (2)
Paracellular transport – diffusion through tight junctions dependent on concentration gradient; does not require energy Transcellular – at apical region calcium enters cell through a selective calcium transporter (TRPV), binds to calbindin, transported across cell and extruded at the basolateral membrane by a sodium-calcium exchanger and a Ca2+/ ATPase transporter.
What are the other roles of vitamin D (beyond gut, bone, kidney) (2)
PICTURE REGULATOR - possibly in cancer surveillance? Diabetes - making sure VitD levels okay to improve insulin resistance Vitamin D receptors found in more than 30 different cell types e.g keratinocytes in the skin, lymphocytes, macrophages, adipocytes, pancreatic β cells, cells of breast, testis, ovary, prostate, colon etc. Several tissues can also locally synthesis 1,25 (OH)2D from circulating 25(OH)D because they have 1α-hydroxylase (CYP27B1). Tissues/cells include macrophages and monocytes, keratinocytes, breat tissue, parathyroid, colon, placenta etc.
Where is the FGF23 receptor expressed (3) What type of receptor is it?
Expressed pre- dominantly expressed in distal convoluted tubules epithelium of the choroid plexus in the brain parathyroid glands Klotho, a single-pass transmembrane protein
What are the actions of FGF23 in calcium and phosphate homeostasis?
In kidney, down regulates phosphate channels in proximal CT which means phosphate gets excreted In kidney, it inhibits 1alpha-hydroxylase so decreases actions of vitamin D
Major causes of hypercalcaemia (6)
1o Hyperparathyroidism Malignancy (PTHrP) Some other causes: Vitamin D related Excess intake Sarcoidosis, tuberculosis and other granulomatous diseases (10% cases extra renal conversion of 25-OH D 1,25-OH D) High bone turnover e.g. hyperthyroidism, immobilization Renal failure
What are the symptoms of hypercalcemia? Neurologic, renal, MSK, CVS, GI
Major causes of hypocalcaemia (6)
Vitamin D deficiency (2o hyperprathyroidism) Hypoparathyroidism (thyroid surgery) Chelation Pseudohypoparathyroidism - receptor defect Neonatal Activating mutation of Ca2+ receptor - FIHH
Major causes of Vit D deficiency (5)
Liver/kidney disease (synthesis) Resistance to hormone (receptor) Mal-absorption Dietary insufficiency Poor exposure to sunlight Sun block Obesity Latitude Skin pigmentation (melanocytes)
What are the typical symptoms / signs of Vit D deficiency (5)
Aches and pains in bones Proximal myopathy Mild hypocalcaemia - 2o hyperparathyroidism Hypophosphataemia and hyperchloraemic acidosis Bone deformities - osteomalacia
Symptoms of hypocalcaemia
Outline the endocrine response to LOW calcium
What are the two types of bone? What are it’s two forms?
cortical bone (outside) and cancellous bone (inside) two forms: woven bone (the collagen fibres are randomly arranged, and this can be seen under polarized light. This is an immature form of bone that is produced when bone is formed rapidly eg in the neonate or in the early stages of fracture repair) and lamellar bone.