Calcium and Phosphate Homeostasis Flashcards
Organic Mineral of Bone
Hydroxyapatite
RANK-L/RANK System
RANK-L is expressed by osteoblast cells and they directly bind to RANK on preosteoclasts activating their differentiation and fusion into multi-nucleated cells
*Also prolong osteoclast life by inhibiting apoptosis
OPG
Secreted by osteoblasts to bind to RANK-L and inhibit the differentiation of pre-osteoclasts
m-CSF
Promotes the differentiation of monocytes that work together w/ RANK-L to promote osteoclastogenesis
Bone Resorption
Osteoclasts bind to bone via B-integrins and form the ruffled border
=>Secretion of H+ via H-ATPases and proteases leading to the degradation of hydroxapatite and Type I collagen
CTX
Product of Type I collagen degradation
*Can be measured in the urine to determine activity of osteoclasts
Bone Formation
Osteoblasts secrete type I collagen, osteocalcin, and AP
*Increased AP levels are assoc. w/ childhood growth and bone repair
Period of quiescence
Entered by oseteocytes after bone formation; some communicate w/ osteoblasts via canalliculi and others control the influx/efflux of mineral ions (lining cells)
Calcium Intestinal Absorption
Transcellular: Ca2+ moves across TRPV5 & 6, gets bound to calbindin-d9k and transported to the basolateral surface to a Ca2-ATPase
*More common
Paracellular: Occurs when dietary Ca2+ is increased
Phosphate Intestinal Absorption
Absorbed transcellularly via Na+/Pi co-transport
PTH effects on Kidney Tubules
- Increases Ca2+ transporters in the DCT (only accounts for ~9% of reabsorption)
- Removes Na+/Pi transporters in the PROXIMAL tubules
- Activates renal 1-a hydroxylase
C-terminal fragments of PTH
Formed by proteolytic enzymes that degrade the biologically active N-terminal in secretory granules in response to hypercalcemia
Parathyroid response to hypocalcemia
- Gs activates AC leading to increased PTH secretion
- PTH mRNA stability increases
- Proliferation of chief cells
- Decreased degradation of n-terminals
Effects of Hypercalcemia on Parathyroid
- Gi inhibits AC and Gq inhibits PLC leading to an increase in intracellular Ca2+ and a DECREASE in secretion of PTH
- *Uniquely different
-Vitamin D acts at genomic level to inhibit PTH secretion
PTH/PTHrP Receptor
Increases intracellular AC and IP3 promoting RANK-L expression in the bone and PO43- excretion/Ca2+ reabsorption/1a-hydroxlyase activation in the kidneys
Hyperparathyroidism
- Bone lesions
- Duodenal ulcers
- Kidney stones
- Decreased membrane excitability leading to muscle weakness, constipation, lethargy
Hypoparathyroidism
Causes tetany in the hand and easily excitable cell membranes
PTHrP
Secreted locally (paracine) and is capable of eliciting the same effects as PTH
*Regulates the proliferation of embyonic tissues; controls Ca2+ thru the placenta
Humoral Hypercalcemia of Malignancy
Numerous tumors secrete factors into the blood promoting excessive bone resorption
*Mediated by PTHrP
Vitamin D synthesis
- 7-dehydrocholesterol in the skin is activated by UV light to Vitamin D3
- D3 undergoes conversion to 25(OH)D in the blood and further to 1,25 (OH)2D in the PT of the kidneys (highly regulated step)
* 25 (OH)D is high in concentration and is clinically measured in the serum
* !,25(OH)2D is the most active form of Vitamin D
Vitamin D effects on the intestine
- Increases the # of Ca2+ channels and calbindin-d9k
2. Increases the absorption of PO43-
Vitamin D effects on the parathyroid
- Inhibits PTH secretion
2. Induces expression of more CaSR
Vitamin D effects on bone
Promotes bone mineralization and osteoclastogenesis (increased RANK-L/decreased OPG)
Vitamin D Mechanism of Action
Binds to VDR, forms a complex w/ RXR, binds to regulatory component on genes
Vitamin D Defeciencies
Growing Bone= Rickett’s
Adult Bone= Osteomalacia
Organic Protein of Bone
Type I Collagen
Estradiol
Inhibits expression of RANK-L
cAMP
PTH stimulates increase in AC activity to produce results
Most apparent consequence of Vitamin D deficiency
Decreased bone mineralization
Para follicular cells
Found in the thyroid; secrete calcitonin
Calcitonin
Acts via a cAMP dependent pathway to decrease Ca2+ levels in the blood
*Gastrin=> Increased calcitonin secretion
