4.4 Food intake and calcium Flashcards
Name 7 roles of calcium
- major structural component of skeleton
- second messenger of hormone signalling (ie GPCR) –> release from endoplasmic reticulum
- membrane excitability (action potential)
- muscle contraction
- hormone secretion (2nd messenger –> exocytosis of granules)
- cofactor in blood clotting (assis in cross-linking of fibrin)
- cofactor in enzyme –> regulation of enzyme activities (induction of conformational changes or co-factor)
Calcium distribution
- total body calcium –> separated into 3
- one of them (how much) is separated into 2 –> then 1 is separated into 2 again
- skeleton (99%)
- intracellular (ie in ER) (1%)
- extracellular (0.1%) = 2.5 mmol/L OR 10 mg/dL (in plasma)
a) ionized Ca2+ (45%) around 5 mg/dL
b) bound Ca2+
- to plasma proteins (45%)
- anions (ie bicarbonate phosphate, lactate…)
- Ca2+ in which 2 places are tightly regulated?
- which Ca2+ is readily available, hence is the most important?
- extracellular and intracellular
- the non-complexed Ca2+ (ionized calcium in plasma/extracellular fluid –> 5 mg/dL
*controlled by vit D and PTH
- when was rickets in children described? how is it described as? what causes it?
- 3 remedies?
- theory behind it?
- lead to the discovery of what?
17th century –> softening, deformation and bending of bones –> calcium and vit D deficiency
- fish liver oil, sun exposure and UV irradiation of certain foods –> these treatments were given even before understanding mechanism of disease
- vit D promotes absorption of calcium from the gut –> vit D present in fish liver oil + inactive vit D precursors can be activated by UV
- to parathyroid hormone and calcitonin
parathyroid glands
- how many? weight?
- NOT regulated by what?
- which cells produce PTH?
- PTH released in response to what?
- role of PTH?
- 4 glands –> 40 mg each, located adjacent to thyroid
*about 15% of people have a 5th gland - NOT regulated by pituitary-hypothalamus axis
- Chief cells produce PTH
- released in response to low levels of ionized Ca2+ in ECF
- increases Calcium in ECF!
parathyroid hormone
- what type of hormone? how many aa?
- half-life?
- how is it synthesized?
- stored where? with ____a______
- what does ____a______ do? –> possible role?
- peptide hormone: highly conserved: 84 aa in length
- short half-life (2-4min)
- synthesized as pre-prohormone
- than stored in granules that contain mature PTH and proteases cathepsin B and H (+ carboxy terminus fragments)
- cathepsin cleaves a portion of PTH to yield carboxy terminus fragment –> possible role = modulation of PTH signalling, bc the fragment doesn’t activate the PTHR signalling
- how does calcium regulate PTH secretion? what receptor?
- low vs high calcium levels?
- Calcium sensing receptor (CaR) –> GPCR located on cell membrane of chief cells detect extracellular Ca2+ (as primary ligand) –> NOT intracellular Ca2+ (2° messenger)
HIGH CALCIUM: Ca2++ binds to receptor –> receptor activation leads to inhibition of PTH secretion
LOW CALCIUM: Ca2++ NOT bound to receptor –> NO inhibition –> PTH is secreted –> leads to increased [Ca2+] in ECF - exact mechanism of how CaR signal inhibits PTH synthesis and secretion is not well defined
- what are the effects of high vs low ECF Ca concentrations on chief cells?
HIGH [Ca]: decreased cAMP and increased IP3 & [intracellular Ca2+]
LOW [Ca]: increased cAMP and decreased IP3 & [intracellular Ca2+]
what is PTH’s receptor?
- isoforms?
- which pathway?
PTHR –> 2 isoforms: PTHR1 and PTHR2
- GPCR –> adenyl cyclase/cAMP/PKA + PLC/IP3/DAG/PKC
- on what 3 target organs does PTH functions to regulated calcium levels? explain (4)
- bone, kidney and gut
1. PTH increases bone resorption of bone by stimulating osteoclasts –> promotes release of calcium and phosphate into circulation
2. PTH increase renal Ca2+ reabsorption
3. PTH also makes kidney activate vit D –> increase in 1,25-dihydroxy-vitamin D3
4. vit D acts on gut to increase GI calcium absorption - all 4 actions –> increase serum Ca2+ (in circulation)
composition of bone
- mineral content (3)
- cells (4)
- organic matrix (4)
MINERAL CONTENT:
- 99% of total Ca2+
- 90% of total PO4^-3
- 50% of total Mg^2+
CELLS:
- osteoprogenitor cells (differentiate into osteoclast and osteoblasts)
- osteoblasts
- osteoclasts
- osteocytes (mature osteoblasts ish)
ORGANIX MATRIX:
- collagen (90-95%)
- proteoglycans
- glycoproteins
- lipids
composition of bone:
- important proteins (2) + explain
OSTEOCALCIN (osteoblasts)
- 1-2% of bone protein
- 1 mg of osteocalcin binds to 17 mg of hydroxyapatite (organic calcium)
- serum level is indicator of bone growth
OSTEONECTIN (fibroblasts)
- binds to collagen and hydroxiapatite
- may serve as nucleator for calcium deposition in bone
explain osteoblast differentiation
- 3 steps ish
- mesenchymal stem cells (fibroblast-like cells located in bone marrow) –> 2. become osteoprogenitor cells (attached to bone surface, proliferating) –> 3. become osteoblasts
explain bone formation
- 3 steps
- osteoblasts secrete collagen and other proteins to form a matrix (osteoid)
- mineralization (deposition of calcium) in 2 stages:
a) primary mineralization (60-70%) in 6-12h
b) secondary mineralization in 1-2 months for full ossification - entombed osteoblasts (surrounded by matrix and completely deposited with calcium) differentiate into osteocytes. form a network of metabolically active cells
how are osteocytes connected together?
- what does osteoblast organization looks like?
- by gap junctions!
- checkerboard ish where the lines are osteocytes and the spaces are filed with mineralized bone
- checkerboard surrounded by osteoblasts + central blood vessel on one side
- bone growth/remodeling requires precise balance btw (2)
- turnover of calcium in bone is ___% per year in infants and ___% per year in adults
- 3 factors regulate balance
- btw bone resorption (osteoclasts dissolve bone) and bone resynthesis (osteoblasts lay down new bone)
- 100% in infants (bc lots of bone growth), 18% in adults (full turnover every 5 years ish)
1. PTH
2. mechanical factors (exercise stimulates bone strengthening)
3. paracrine factors (like IGF-2 produced by osteoblasts) may act on neighbouring osteoblasts and osteoclasts
- osteoclasts are derived from what?
- how do osteoclasts dissolve bone/induce bone resorption?
- then what happens to calcium?
- derived from monocytes (bone marrow: gives rise to macrophages)
1. osteoclasts attach to bone via integrins (protein on extracellular matrix) and form a tight seal
2. proton pumps in osteoclasts (H+ dependant ATPases) move from endosomes to cell membrane where they pump out H+
3. more H+ pumped out = acidic pH –> around 4.0 in ECF –> dissolves hydroxyapatite + acid proteases break down collagen - Calcium (and degradation products) is transcytosed (movement from 1 cell to another) –> and released into interstitial fluid
- what is an index of bone resorption activity/indicator of bone health?
- are osteoclasts involved in acute regulation of calcium homeostasis?
- pyridinoline (collagen breakdown product) in urine!
- NO! osteoclasts are slow working cells, slow response
explain bone remodling and its hormonal control ish
- loop! 5 steps + repeat
- vit D and PTH tell osteoblasts on bone surface to secrete osteoclast activating factors (OAFs)
- OAFs help osteoclast differentiation and mvt in bone –> leads to osteoclasts on bone surface resorbing bone (dissolve calcium form protein + destroys osteocytes) = lots of debris
- macrophages phagocytose debris + provides stimulus for osteoblasts
- osteoblasts appear at resorption site –> deposit calcium and secrete extracellular matrix proteins
- osteoblasts fill cavity with osteoid –> osteoid is mineralized and becomes quiescent bone surface
- repeat
disease of the bone:
- osteopatrosis vs osteoporosis vs osteomalacia
OSTEOPETROSIS: (marble bone)
- increase in bone density due to defective osteoclasts –> more than normal calcium deposition = increase calcification –> bones become more brittle and are prone to fracture
OSTEOPOROSIS:
- los of bone density due to excess osteoclast function
- frequent fractures bc thinner and weaker bones (areas with trabecular bone: distal forearm, vertebral body, hip)
OSTEOMALACIA:
- loss of bone density due to excess osteoclast function –> less diffused, more patches of weaker bones
- soft bones with deformities + increased risk of fractures
- what happens to bone mass as we age?
- men or women are more affected?
- bone mass decreases!
- women are more prone to decrease bone density –> especially after menopause
- estrogen upregulates/downregulates osteoblast/osteoclast activity?
- how? (2)
- menopause (OR what?) leads to estrogen level increase/decrease –> leads to osteoclast/osteoblast activity increase/decrease? –> leads to what?
- estrogen downregulates osteoclast activity!
1. inhibition of cytokines that stimulate development of osteoclasts (IL-1, IL-6, TNF) –> decrease osteoclast
2. stimulation of cytokine TGFb that causes apoptosis of osteoclasts –> decrease osteoclast - menopause (OR removal of ovaries) leads to estrogen level decrease –> leads to osteoclast activity increase –> leads to weakening of bones
- what is hyperparathyroidism?
- occurs in __-___% of population –> more common in men or women?
- characterized by (2)
- symptoms (3)
- treatment?
- increased PTH hormone
- 0.1-0.3% of population –> more common in women (1:500) than in men (1:2000)
- primary hyperparathyroidism is characterized by (1) increased parathyroid cell proliferation and (2) PTH secretion which is independent of calcium levels –> leads to increase calcium resorption from bone
- osteoporosis (abnormal bone mineralization) + kidney stones (bc increased Ca2+ not excreted efficiently through kidney) + excessive urination (bc kidney is trying to get rid of calcium)
- surgery: removal of enlarged parathyroid gland –> remove 1 or 2 out of the 4
Hypoparathyroidism:
- may originate from 7
- major clinical symptom? explain
- treatment?
- failure of chief cells to secrete PTH
- altered responsiveness to PTH
- vit D deficiency or resistance to vit D
- surgery (removing thyroid gland)
- familial causes
- autoimmune disorders
- idiopathic causes (unknown)
- increased neuromuscular excitability (tetany) –> reduction in extracellular calcium increases permeability for Na –> increases membrane/nerve excitability –> reduces amount of excitation needed –> spasms or tremors or seizures
- calcium + vit D
MILK FEVER
- what?
- occurs when?
- symptoms?
- causes (3)
- treatment?
- hypocalcemia in fresh cows
- occurs 48-72h after parturition
- initial stages of muscle tremors and nervousness (bc increase excitability of muscles) –> followed by muscle weakness (paresis) and recumbency (cannot stay standing)
1. blood calcium levels <7.5 mg/dL
2. loss of calcium through colostrum (milk production)
3. parathyroid dysfunction - 500 mL of 23% calcium gluconate –> IV –> quickly increase blood calcium –> 1 shot, cows can get up within 15 minutes
- which cells produce calcitonin?
- role of calcitonin?
- physiologically important in humans?
- parafollicular cells or c-cells
- reduces serum Ca2+ –> only known hormone that reduces ECF calcium
- may NOT be physiologically important in human
- overproduction of calcitonin (tumors of parafollicular cells) –> no phenotypic consequences
- thyroidectomy (should decrease thryoid hormone, PTH and calcitonin) –> only low calcium due to low PTH (no symptoms related to decreased calcitonin)
vitamin D
- ___-soluble family of compounds
- deficiency leads to _______ –> causes what? (2)
- formed where by what reaction?
- deficiency common where? –> solution?
- fat-soluble family of compounds
- leads to rickets –> bone deformations/defects + loss of calcium and phosphate from the bones
- formed in skin by photochemical reaction
- used to be common in northern climates bc low sunshine –> now policy: vit D commonly added to milk and butter
how is active vit D formed? 5 steps
- sunshine/UV light can convert 7-dehydrocholesterol (present in skin) into cholecalciferol (inactive vit D3)
- can also take vit D2 and D3 from diet
- vit D2/D3 is converted to 25-hydroxyvitamin D2/D3 in LIVER
- in kidney, 25(OH)D2/D3 can be converted to 1,25-dihydroxyvitamin D2/D3 (calcitriol) = active form (acts as a hormone) –> acts on intestine to increase calcium absorption
- in kidney, 25(OH)D2/D3 can ALSO be converted to 24-25-dihydroxyvitamin D2/D3 –> uncertain role
- vit D is a _______ that regulates calcium uptake
- vit D2 is a pharmaceutical product made how? –> used in food fortification such as (2)
- HORMONE!
- made by irradiating ergosterol (present in some plants)
- used in food fortification such as margarine and milk
- what are the 2 main circulating derivatives of vit D? (made where?)
- vit D binding protein present in serum binds which metabolite to a greater extent than which other metabolite?
- all physiological effects appear to be due to which metabolite?
- 25-OH-cholecalciferol (made in liver: 3-30ng/mL) and calcitriol (made in kidney: 20-60 pg/mL)
- binds 25-OH-cholecalciferol and to a lesser extent calcitriol
- due to calcitriol (1,25-OH2-D3/D2)
- what receptor does vit D bind to? what type of receptor
- what effect does it have (5)
- vitamin D receptor –> nuclear receptor –> dimerizes with RXR + acts as transcription factor in nucleus!
1. increase osteoblast activity (mineralization)
2. increases osteoclast activity
3. increase intestinal calcium/PO4^3- absorption
4. increases renal vit D degradation (catabolism)
5. decreases parathyroid hormone synthesis
what nutrients (increase or decrease) activate/inhibit activation of vitamin D in which organ? (4)
- 25(OH)D3 –> 1,25(OH2) D3 hormone in kidney!
ACTIVATE: - decrease Calcium
- increase PTH
- decrease PO4
INHIBIT: - increase 1,25(OH2)D3
- homeostasis of blood calcium levels = ____ mg/100 mL
- what happens if blood calcium level decreases?
- vs increases?
10 mg/100 mL
DECREASES:
- increase PTH –> stimulates Ca2+ release from bones + Ca2+ uptake in kidneys + activation of vit D3 in kidneys –> active vit D3 increases Ca2+ uptake in intestines –> blood Ca2+ levels rise to set point –> homeostasis
INCREASES:
- thyroid gland releases calcitonin –> stimulates Ca2+ deposition in bones + reduces Ca2+ uptake in kidneys –> blood calcium level declines to set point –> homeostasis
*calcitonin basically inhibits PTH actions –> but not super sure it happens in humans
- what 3 cause cause vit D deficiency?
- vit D deficiency causes what? –> results in what for children vs adults?
- treatment?
- inadequate sunlight + inadequate nutrition + malabsorption (up to 50-60% of elderly, especially if institutionalized)
- causes abnormal mineralization of bone and cartilage –> rickets in children vs osteomalacia in adults
- Tx: vit D supplements
- what can cause vit D toxicity? (2)
- what (3) influences level required to be toxic?
- symptoms (5) + may lead to what? (2)
- treatment?
- overdose therapeutically or accidentally (ie take weekly pills daily…)
- difference in storage, catabolism and absorption among individuals
1. weakness
2. lethargy
3. headaches
4. nausea
5. polyureia due to hypercalcemia and hypercalciuria - may lead to ectopic calcification –> calcium deposition outside of bones (kidneys, blood vessels, heart, lungs, skin) with chronic overuse
- may lead to kidney stones
- reduced calcium or vit D intake
