Learning Objectives 1) Recognize the importance of calcium homeostasis and the major tissues involved in achieving it. - Physiological functions of Ca!- reservoir= skeleton!- adult: 1-1.25 kg Ca, 99% complexes w/phosphate--> hydroxyapatite in bone and teeth!- structural role!- critical regulatory roles: signaling muscle contraction, blood clotting, signal for secretion of hormones, neurotrans, pancreatic digestive enzymes, reg. activities of diff. enzymes/proteins in the cell!- Ca Homeostasis!- narrow range: 8.8- 10.3 mg/dL!- regulate blood Ca by controlling:!- intestine: efficiency of Ca absorption!- kidney: Ca resportion vs. excretion!- bone: Ca absorption vs. mobilization!- regulators of serum Ca: vit D, PTH, calcitonin - hypocalcemia --> tetany, hypercalcemia --> arrhyythmias!- Bone serves as a reservoir for Ca (and phosphorous)!- bone is dynamic, constantly remodeling due to osteoblasts (bone-forming cells) and osteoclasts (bone-chewing cells)!- Ca2+ serum levels fall --> osteoclast activity increases to provide Ca thru secretion of digestive enzymes and acid = Ca movement OUT OF bone!- osteoblasts secrete collagen and other matrix stuff to form the matrix for mineralization of bone by Ca and phosphate = Ca movement INTO bone!- Vit D deficiencies and Ca!- Vit D imp. in Ca homeostasis, def. in Vit D linked to rickets (rare in US)!- Rickets= childhood disease, skeletal deformities!- Osteomalacia= in adults, weak bones, bone pain 2) Know the critical steps in the synthesis and activation of vitamin D and its active metabolite - 1, 25-dihydroxyvitamin D (or 1,25-dihydroxycholecalciferol) - Vitamin D!- we can syn., but don't always make enough for what we need!- Limiting step in syn of Vit D occurs in the skin, catalyzed by UV light in a non-enzymatic process - like hormone because syn. in 1 place and exerts effect in another!- Synthesis of Vit D (after syn. has to get activated)!- Note: biolog activity of Vit D2 and D3 are =, only diff. is one more double bond in D2!- cholesterol --> 7-dehydrcholesterol --> skin, UV --> cholecalciferol (vit D3) (from meat, fish, dairy, eggs)!- Activation of Vit D - Step 1!- Vit D (hydrophob) + metabolites carried in blood bound to DBP (vit D binding prot)!- vit D has no bio activity until hydroxylated 2x!- 1st hydroxy happens in liver at 25 position --> 25-(OH)-D3!- this is the principal circulating metab., has long half life= 10/20 days, measured clinically to asses Vit D status!- Step 2!- 2nd hydroxy rxn happens in kidney at 1 position --> 1,25-dihydroxyvitamin D!- most highly reg. step!- patients in kidney failure or w/mut can't do this --> symptoms of low serum Ca!- half life of 1,25-(OH)2 vit D = 4/6 hours 3) Explain the pathway that leads to increased Ca when blood Ca is low and the role of PTH and 1,25-dihydroxyvitamin D in this process - Formation of 1,25-(OH)2 Vit D in the kidney is controlled by parathryoid hormone!- PTH= polypep hormone produced by parathyroid glands!- Low levels of serum Ca --> secretion of PTH via Ca2+ receptors on pm!- PTH binds to receptors on pm of kidney --> activates signaling pathway leading to activation of the 1-hydroxylase (post-translation mod)!- Actions of 1,25-(OH)2 Vit D - Intestine!- Med. by binding to nuclear hormone receptor (like Vit A), Vit D acts as a txn factor to increase Ca2+ absorption!- Receptor functions as a ligand activated txn factor to stimulate syn. of specific prots!- In enterocytes of intestine active Vit D stimulates txn of genes for:!- Ca2+ channel on brush border!- Calbindin= Ca2+ binding proteins, transports Ca2+ from brush border to basolateral membrane for release into blood!--> increase in Ca2+ absorption!- Actions of 1,25-(OH)2 Vit D and PTH - Kidney and Bone - work together to stimulate the reabsorption of Ca2+ in distal renal tubule!- In bone: work together to stimulate formation and maturation of osteoclasts --> promote mobilization of Ca2+ from bone!--> increased serum Ca2+ levels!- when Ca2+ levels rise above normal --> PTH release inhib. --> calcitonin released from C cells of thyroid --> promote Ca2+ deposition in bone! 4) Understand the imp. of osteoporosis as a major healthcare problem and how Ca nutrion can impact its development. - How much should we be taking? - vitD may have beneficial actions in other physiological processes: immune function, beta cell function for insulin secretion, cardiovascular function!- Vit D - New Guidelines!- new dietary reference intake for Vit D made in 2010, assume no sun exposure!- 600 IU (measures bio activity)/day for under 70, 800 IU/d > 70 years!- toxicity can occur at very high doses --> calcification of soft tissues!- tolerable upper intake level= 2000 IU/day (cup of milk = 120 IU)!- Osteoporosis: skeletal disease characterized by low bone density, increased freq. of fragility fractures!- most common in post-menopause women, and peeps 70-75 years old!- lots of fractures, lots of people die, huge costs!- how to prevent= make lots of bone when you're young !- max. bone density reached in 3rd decade of life, then declines up to 10% per decade!- occurence inversely related to bone density in young adult!- women: estrogen has a positive effect on bone formation and mineralization!- decrease in estrogen at menopause --> period of bone resorption that can't be blocked by Ca2+ intake!- estrogen replacement therapy helps prevent this, but contraindicated by increased cancer and cardiovascular disease risk!- bisphosphonates decrease rate of resorption and used to treat/prevent osteoporosis (may block osteoclast activity)!- RDAs for calcium (mg/d)!- adolescents: 1300!- adults (19-50): 1000!- adults (51+): 1200!= lots of calcium! Food is the best way to get it.!- there is a very small percentage of the US above adequate intake levels for Ca and Vit D aka most people don't get enough (esp. teenage
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