Endocrinology-Ch.4-Bk Notes BIOL 4110
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This 4 page Class Notes was uploaded by Michelle Notetaker on Monday October 3, 2016. The Class Notes belongs to BIOL 4110 at University of North Texas taught by Dr. Harris D Schwark in Fall 2016. Since its upload, it has received 2 views. For similar materials see Endocrinology in Biology at University of North Texas.
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Date Created: 10/03/16
Endocrinology Ch.4 (Textbook notes) Overview: ● Calcium(Ca) & Phosphorous (inorganic phosphate(Pi)): structure of hard tissues (bones & teeth) and metabolic regulation/signaling pathways. ● 2 primary sources of Ca & Pi: Diet and Skeleton. ● Calcitonin, Calcitriol (1,25dihydroxyvitamin D) & Parathyroid hormone (PTH) regulate intestinal absorption and release into the blood after bone resorption of Ca & Pi. Ca & Pi plasma concentrations: ● Ca: 50% ionized, 45% proteinbound, 5% complexed. ● Pi: 84% ionized, 10% proteinbound, 6% complexed. ● Hypocalcemia too little Ca in blood (<8.5mg/dL) ● Hypercalcemia too much Ca in blood (>10.5mg/dL) Regulation of Ca & Pi: Calciotropic hormones: ● PTH Origin Parathyroid glands (principal (chief) cell). Regulated by CaSR (a GPCR) & Calciumresponse element. High Ca inhibits PTH, calcitriol inhibits PTH. Structure secreted as an 84 AA; synthesized as a preproPTH; has < 5 min halflife. Target/Receptor PTH/PTHrp receptor: PTH1R – high levels in bone (osteoblasts) and kidney (proximal and distal tubules), PTH2R – high levels in CNS, pancreas, testis, placenta. Function protects against Hypocalcemia. ● Bone: osteoblast growth/survival. high levels promotes Ca & Pi release from bone. regulates MCSF, RANKL, and OPG production by osteoblasts. ● Kidney: stimulates 1ahydroxylase activity. stimulates Ca reabsorption by distal nephron (increases Ca ATPase). Inhibits Pi reabsorption by proximal nephron (represses NPT2a). ● 1,25 Dihydroxyvitamin D (Calcitriol) Origin UV light: synthesized by Cholesterol from Vit. D3 & D2. Regulated by magalin: binds to DBP, and by renal 1���hydroxylase (CYP1���): stimulated by low serum Ca & inhibited by high serum Ca. Structure circulates blood bound to vitamin Dbinding protein (DBP). Target/Receptor Small intestine, Bone, Kidney, Parathyroid gland / nuclear vitamin D receptor (VDR) that binds to Vit. Dresponsive elements. ● Small intestine: Increases Ca absorption ( by increasing TrpV channels, calbindinD, and PMCA). Marginally increases Pi absorption. ● Bone: Sensitizes osteoblasts to PTH. Regulates osteoid production and calcification. ● Kidney: Minimal actions on Ca reabsorption. Promotes Pi reabsorption by proximal nephron (stimulates NPT2a). ● Parathyroid gland: Directly inhibits PTH gene expression. Directly stimulate CaSR gene expression. Ca & Pi in Bones ● Bone accretion osteoblasts build up bone tissue and bring Ca & Pi into bone. ● Bone resorption osteoclasts break down bone tissue and release Ca & Pi into blood. ● Osteoblasts Release (MCSF) monocyte colonystimulating factor, that acts with RANKL. Derived from osteoprogenitor cells. Contain receptors for PTH and calcitriol. Synthesize organic bone matrix, produce alkaline phosphatase for mineralization. ● Osteocytes Differentiated osteoblasts (trapped in matrix). Major role in daytoday calcium regulation. ● Osteoclasts Multinucleate, derived from monocytes. Contain calcitonin receptors, but no PTH or calcitriol receptors. Produce acidic environment to resorb bone matrix. Ca & Pi in the Nephron ● Passive Ca++ reabsorption, through TRP V5 & V6. ● Active Pi reabsorption, through NPT2a, downregulated by PTH. Most filtered Ca is reabsorbed. Hypocalcemic challenge: Low blood Ca (detected by CaSR on parathyroid chief cells) stimulates PTH secretion. In the kidney, PTH increases Ca levels by increasing fractional resorption of Ca in renal distal tubules. PTH also inhibits NPT2 activity, which increases Pi excretion. Loss of Pi increases free ionized Ca in the blood. At the bone, PTH stimulates osteoblasts to secrete RANKL, which increases osteoclast activity. Osteoclast activity increases bone resorption and release of Ca & Pi into blood. Ca++/Pi & immune/inflammatory cells ● RANK, RANKL, osteoprotegerin are similar to TNFα receptor/NFκB signaling components. Activated T cells can express RANKL (stimulated by TNFα, interleukins… ● Inflammatory bone disease is associated with increased RANKLtoosteoprotegerin ratios Leads to bone erosion and osteoporosis. Regulation of Ca++/Pi metabolism by gonadal and adrenal steroid hormones ● Estadiol Stimulates Ca++ absorption in intestine, reabsorption in kidney. Promotes osteoblast survival and osteoclast apoptosis. ● Glucocorticoids have opposite effects. Disorders of Ca & Pi regulation Hyperparathyroidism • Kidney stones • Osteoporosis • GI disturbances, peptic ulcers, nausea, constipation • Muscle weakness, decreased muscle tone • Depression, lethargy, fatigue, mental confusion • Polyuria • Low serum phosphate, high serum calcium Hypoparathyroidism • Tetany, convulsions, paresthesias, muscle cramps • Decreased myocardial contractility • Firstdegree heart block • CNS problems, including irritability and psychosis • Intestinal malabsorption • Low serum calcium, high serum phosphate concentration Vitamin D deficiency Results in hypocalcemia, hypomagnesemia, decreased GI absorption of Ca++ and Pi. These changes cause increased PTH, increased bone resorption. ● Rickets: vitamin D deficiency before skeletal maturation. ● Osteomalacia: inadequate bone mineralization after skeletal growth is complete.