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PHAR6205 Pharmacology
Question:
RANK ligand (RANKL) and macrophage colony-stimulating factor (M-CSF)?
Topic:
Bone Mineral Homeostasis:
206 bones make up the human skeleton 25% organic and 75% inorganic components. Composed of organic and inorganic compounds Organic:
1. Osteoblasts, osteoclasts, osteocytes and osteoid (organic matrix made of type I collagen)
2. Inorganic: calcium phosphate salt (99% calcium in body is stored as hydroxyapatite)
1. Functions of bone
2. Structural support
3. Protection of internal organs
4. Hematopoiesis
5. Mineral storage
6. Mineral Balance
Calcium is absorbed in the small intestine 300mg/day is absorbed from diet. Can reach up to 600mg/day in presence of calcitriol absorption balanced by calcium lost through renal excretion (about 200mg/day) and salivary and biliary secretion (about 100mg/day).
Parathyroid Hormone (PTH):
Most important endocrine regulator of calcium homeostasis and regulated in response to plasma calcium levels PTH acts directly on kidneys and bone and indirectly on gastrointestinal tract.
1. Reabsorption and clearance through kidney tubules
2. Increase RANL and decrease OPG expression
3. Increase hydroxylation to calcitriol to promote calcium reabsorption
4. Promotes osteoblast precursor differentiation to mature osteoblasts
Stimulation of Galpha(s):
1. Increase adenylyl cyclase activity; increase cAMP
2. cAMP anti-apoptotic for osteoblasts and promotes IGF-1 release
3. Fibroblast Growth Factor 23 (FGF-23) and Phosphatonin
4. Alters and regulates renal clearance of inorganic phosphate
5. Decreased renal secretion of calcitriol (1,25(OH)2D)
6. Phosphatonins
7. Secreted frizzled-related protein (s-FRP-4)
8. Fibroblast growth factor 7 (FGF-7)
9. Matrix extracellular phosphoglyoprotein (MEPE)
10. Expressed in osteocytes
Mutations of FGF-23:
Conditions associated with decreased levels of FGF-23 have proven to cause hyperphosphatemia hypercalcemic intoxication ectopic calcification and defective bone mineralization.
Calcitonin, Glucocorticoids, Thyroid hormone and Gonadal steroids. Calcitonin is synthesized and secreted by parafollicular C cells in the thyroid in response to hypercalcemia. Glucocorticoids decrease bone formation and resorption by inhibiting osteoblast activity and promoting osteoblast and osteocyte apoptosis.
Excess in thyroid hormone results in increased bone loss. Gonadal steroids, estrogen and androgens, inhibit osteoclast activity to reduce bone loss and bone turnover.
PHAR6205 Pharmacology
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