![2
Development of Bones &
Teeth
Calcium & Phosphate are
required for the formation of
hydroxyapetite
gives physical strength
to skeletal tissue.
Muscle Contraction Ca interacts with troponin C
Ca activate ATPase
trigger muscle contraction
↑es the interaction between
Actin & Myosin
Blood Coagulation Several reactions in
coagulation cascade are Ca-
dependent on
factorIV
Membrane Integrity &
Permeability
Calcium influences the
membrane structure
& thus transport of water
& several ions across it
Activation of Enzymes Direct activation ATPase, Lipase, SDH,
Amylase
Calmodulin mediated
action
Calcium-Calmodulin complex
activates
Adenylate Cyclase, Ca-
dependent Protein Kinase
Calcium as intracellular
messenger
Ca as 2nd
messenger
Ca as 3rd
messenger
Epinephrine(in Liver for
glycogenolysis)
ADH[act through cAMP &
then Calcium]](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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Calcium metabolism made asy
- 1. Biochemical functions of Calcium Development of bones & Teeth Membrane Integrity & Permeability Calmodulin mediated action of Calcium Calcium as intracellular messenger Contact Inhibition Action on Heart 1 •Muscle contraction •Blood Coagulation •Activation of enzymes •Release of Hormones •Secretory Process •Nerve Transmission
- 2. 2 Development of Bones & Teeth Calcium & Phosphate are required for the formation of hydroxyapetite gives physical strength to skeletal tissue. Muscle Contraction Ca interacts with troponin C Ca activate ATPase trigger muscle contraction ↑es the interaction between Actin & Myosin Blood Coagulation Several reactions in coagulation cascade are Ca- dependent on factorIV Membrane Integrity & Permeability Calcium influences the membrane structure & thus transport of water & several ions across it Activation of Enzymes Direct activation ATPase, Lipase, SDH, Amylase Calmodulin mediated action Calcium-Calmodulin complex activates Adenylate Cyclase, Ca- dependent Protein Kinase Calcium as intracellular messenger Ca as 2nd messenger Ca as 3rd messenger Epinephrine(in Liver for glycogenolysis) ADH[act through cAMP & then Calcium]
- 3. 3 Release of Hormones Ca mediated Release of some hormone Insulin, PTH, Calcitonin Secretory process Calcium regulates microfilament & microtubules mediated process Endocytosis, Exocytosis, Cell Motility Action on Heart Calcium acts on myocardium prolongs systole Contact Calcium is believed to be involved in cell to cell contact & adhesion of cell in a tissue Cell to cell communication
- 5. 5th most abundant of all elements. Most abundant mineral & prevalent cation in our body. Approximately, an average human body contains 1- 1.3 Kg (2.5 mMol) of Calcium. 98% in skeleton 1% in soft tissue <0.2% in ECF 5
- 6. The skeletal contains Ca, predominently as extracellular crystals of unknown structure with a composition approaching that of hydroxyapetite [Ca10(PO4)6(OH)2] 6
- 7. 7
- 8. Normal plasma Ca-level= 9.2-11.0 mg/dL [4.6-5.5 mEq/L] [2.3-2.8 mMol/L] Out of those 50% in ionized form [free form] 40% in protein bound form 10% in complexed form [with anions] Free (ionized) form in plasma is the biologically active form. 8
- 9. Protein bound form:- 80% is associated with albumin 20% is associated with globulin As Ca binds to –vely charged sites on protein. Thus, binding is pH dependent. 9 Alkalosis ↓ ↑ in –ve charge on protein ↓ ↑ in Ca-binding to protein ↓ ↓ in free Ca-level in plasma Acidosis ↓ ↓ in –ve charge on protein ↓ ↓ in Ca-binding to protein ↓ ↑in free Ca-level in plasma
- 10. Why in case of multiple myeloma there is increase in total plasma calcium level? 10
- 11. Complexed calcium (in plasma) Usually complexed with Inorganic ions Organic ions Example: [HCO3 - , PO4 3- , Citrate, Lactate…..etc] 11
- 12. PLASMA CALCIUM Diffusible 50% Ca2+ ionized 10% combined with anions (citrate, phosphate) Non-diffusible 40% combined with plasma proteins 12
- 13. Protein bound calcium ↔ Free Calcium ↔Complexed Calcium Calcium can be redistributed among three plasma pools acutely/ chronically due to :- Change in concentration of proteins & anions Change in pH Change in quantity of free Calcium/ Total Calcium 13 Three plasma pools for Calcium
- 14. Physiologically Calcium in human body is classified into Intracellular & Extracellular Calcium. Skeleton is a major reservoir for providing calcium for both intracellular & extracellular compartments. Intracellular concentration of Calcium in cytosol of unstimulated cell is < 10-6 to 10-7 mol/L. [1/1000 times less than in that of ECF] 14
- 15. Intracellular Ca has key role in many important physiological functions. Muscle contraction Hormone secretion Glycogen metabolism Cell division 15 Extracellular Calcium provides Ca++ for the:- Maintenance of intracellular Calcium Bone mineralization Blood coagulation Plasma membrane potential
- 16. Dietary source of calcium 16 Rich Source Good Source Poor source Egg-yolk Green leafy vegetables Cereals [Rice, Wheat] Beans Fish as trout, salmon and sardines Fresh fruits Lentiles soybean flour &cottonseed flour Nuts Almonds, brazil nuts, dried figs, hazel nuts Cabbage Dairy products as milk, cheese, ice cream
- 17. Daily requirement of Calcium Adults:-1000mg/day Children:- 1200mg/day Pregnancy Lactation 1500mg/day After age of 50yrs:- 1500mg/day [to prevent osteoporosis] 17
- 18. Absorption of Calcium Principal forms of dietary calcium are:- Ca3(PO4)2 CaCO3 Ca-tartarate Calcium is absorbed by an active transport (involve energy & Ca++ -pump)process in duodenum & upper jejunum against chemical & concentration gradient. Or by direct exchange of Na+ & Ca+ . 18
- 19. 19
- 20. Transport mechanism Active and passive transport mechanisms Active: is a saturable, transcellular process which involves calbindin (calcium-binding protein) – regulated by the active form of vitamin D Passive: is a nonsaturable, paracellular low efficiency process, which is not affected by calcium status or parathyroid hormone Both processes occur throughout the small intestine
- 21. Factors affecting Ca- absorption Absorption decreased by: - Vitamin D deficiency - Calcium-phosphorus imbalance - Oxalic acid - Phosphorous - Dietary fiber - Excessive fat - High alkalinity - Also stresses & lack of exercise 21 Absorption is ↑ed by: - Body need - Vitamin D - Protein - Lactose - Acid medium
- 22. Fatty Acid Forms Insoluble Ca- Soaps-- excreted in faeces ↓es Ca-absorption Sugars & Organic Acids ↑es Ca-solubility ↑es Ca-absorption Phytic Acids Forms insoluble Salts ↓es Ca-absorption Fibres Interferes with Ca- absorption ↓es Ca-absorption Phosphate & Mg ↓es Ca-absorption 22
- 23. Iron Maintains Ca/P ratio for optimal Ca- absorption ↑es Ca-absorption High protein diet Amino acids ↑es Ca- salt solubility High protein diet (15% Ca- absorption) Low protein diet (5% Ca- absorption pH of intestinal milieu Ca3(PO4)2 & CaCO3 are acid soluble. acidic condition favors Ca- absorption & alkaline condition lowers Ca-absorption 23
- 24. Hormonal regulation of Ca-absorption PTH Stimulates 1,α-hydroxylase (Kidney) ↑es synthesis of 1,25-(OH)2-D3 ↑es Ca-absorption Calcitonin Inhibits 1,α-hydroxylase ↓es Ca-absorption Glucocorticoids ↓es Ca-absorption 24
- 25. Excretion of Calcium 90 % (900 mg/day) of the daily intake is excreted in the feces 10 % (100 mg/day) of the ingested calcium is excreted in the urine Excretion increased by: - Low parathyroid hormone (PTH) - High extracellular fluid volume - High blood pressure - Low plasma phosphate - Metabolic alkalosis 25 Excretion decreased by: High parathyroid hormone -Low extracellular fluid volume -Low blood pressure -High plasma phosphate -Metabolic acidosis -Vitamin D3
- 26. Calcium Balance Intake = output Negative calcium balance: Output > intake -ve Ca2+ balance leads to osteoporosis Positive calcium balance: Intake > output Occurs during growth Calcium is essential, we can’t synthesize it 26
- 27. Calcium balance:-On average, in a typical adult, 1 g of elemental calcium is ingested per day. Of this, 200 mg/d will be absorbed and 800 mg/d excreted. Approximately 1 kg of Ca is stored in bone and 500 mg/d is released by resorption or deposited during bone formation. Of the 10 g of Ca filtered through the kidney per day, only 200 mg or less appears in the urine, the remainder being reabsorbed. 27
- 28. 28
- 29. Calcium Homeostasis Calcium homeostasis is maintained by involvement of 3 organs:- Small intestine Kidney & the skeleton Mammary gland during lactation Placenta & foetus during gestation Sweat glands are also responsible for a small but significant excretion of calcium. 29 Also play imp. role
- 30. Calcium Homeostasis Calcium homeostasis is regulated by various hormones that act principally upon the major organs involved in calcium homeostasis. Most important hormones PTH 1,25-dihydroxy cholecalciferol Calcitonin Other hormones that affect calcium- metabolism but whose secretion determined primarily by factors other than change in plasma calcium & phosphate level are:- Thyroid hormone GH GC Gonadal steroids 30
- 31. Bones which are in dynamic state serves as Ca- reservoir. Osteoblasts are responsible for Bone formation. Osteoclasts are responsible for demineralization. 31
- 32. Calcium cycling in bone tissue Bone formation Osteoblasts Synthesize a collagen matrix that holds Calcium Phospate in crystallized form Once surrounded by bone, become osteocyte Bone resorption Osteoclasts Change local pH, causing Ca++ and phosphate to dissolve from crystals into extracellular fluids 32
- 33. Role of kidney in calcium homeostasis Kidney filters about 250mMole of Ca/day. 95% of this is taken up by PCT without hormonal regulation. A fine adjustment to the amount reabsorbed, occurs in DCT, under influence of PTH. It also synthesizes Calcitriol, which increases Calcium reabsorption in intestine. 33
- 34. Role of Vitamin D (Calcitriol) in Calcium homeostasis Calcitriol binds to the chromatin of target tissue & expresses the genes for Ca binding protein & Ca++ ATPase in intestinal cells. This ↑es the Ca-reabsorption by actively transporting Ca++ across the plasma memb. against electrochemical gradients. Calcitriol promotes the synthesis of Ca- binding protein like osteocalcin & Alkaline phosphatase. These ↑es the bone mineralization by ↑ing Ca++ & PO4 --- in bones. 34
- 35. Role of Vitamin D (Calcitriol) in Calcium homeostasis Calcitriol promotes the synthesis of Ca- binding protein like osteocalcin & Alkaline phosphatase. These ↑es the bone mineralization by ↑ing Ca++ & PO4 --- in bones. 35
- 36. 1,25 Vitamin D3 Increases Ca++ uptake from the gut Increase transcription and translation of Ca++ transport proteins in gut epithelium Minor role: also stimulates osteoclasts Increase Ca++ resorption from the bone 36 Cholesterol precursor 7-dehydrocholesterol UV Vitamin D3 25 Vitamin D3 1,25 Vitamin D3 Low plasma Ca++ increase kidney enzymes
- 37. Role of PTH in Calcium homeostasis Plasma level of ionized calcium is the principal regulator of PTH secretion by a simple negative feed back mechanism. PTH secretion is also subjected to feedback by Vit. D metabolite 1,25- dihydroxy cholecalciferol. PTH rapidly stimilates bone resorption, & osteoclastic activity, causing an increase in plasma calcium & phosphate level. Vit. D play an important role. PTH slowly (in days) stimulates osteoblastic activity. 37
- 38. Role of PTH in Calcium homeostasis PTH via cAMP:- ↑es the Calcium reabsorption in DCT ↓es the phosphate reabsorption in DCT Also stimulates Vitamin D, which inturn increases intestinal absorption of calcium. 38
- 39. Parathormone (PTH) Increases Ca++ in blood Increases Ca++ resorption from the bone Stimulates osteoclasts Increases number of osteoclasts Increases Ca++ reabsorption from nephron 39
- 40. Role of Calcitonin in calcium homeostasis Secreted from the C cells in the thyroid Lowers Ca++ in blood Promotes deposition of Ca++ into bone (inhibits osteoclasts) 40 CT
- 41. bone 1000 g Ca++ stored in bone Calcium homeostasis 41 Blood Ca++ small intestine kidney Ca++ lost in urine Calcium in the diet calcium lost in feces Ca++ absorbed into blood calcium resorption calcium deposition
- 42. intake excretion 1000 g Ca++ stored in bone Calcium homeostasis Blood Ca++ small intestine kidney Ca++ lost in urine Calcium in the diet calcium lost in feces Ca++ absorbed into blood calcium resorption calcium deposition storage bone 42
- 43. Hormonal Regulators Calcitonin (CT) Lowers Ca++ in the blood Inhibits osteoclasts Parathormone (PTH) Increases Ca++ in the blood Stimulates osteoclasts 1,25 Vitamin D3 Increases Ca++ in the blood Increase Ca++ uptake from the gut Stimulates osteoclasts. 43
- 44. Calcium homeostasis Blood Ca++ small intestine kidney Ca++ Ca++ Ca++ bone 1,25 Vit. D3 (+) 1,25 Vit D3 deposition Calcitonin (-) Ca++ PTH Parathormone (+) resorption 44
- 45. Calcium homeostasis Blood Ca++ small intestine kidney Ca++ lost in urine Calcium in the diet calcium lost in feces bone Ca++ absorbed into blood calcium resorption calcium deposition 45
- 46. Phosphate metabolism Total body phosphate content= 700gm (25mole) (both in organic & inorganic form) Found in every cell of body. Mostly in combination with calcium in bone & teeth. 10% is found in association with protein, Lipid & Carbohydrate in muscle & blood. Remaining is distributed in various chemical compound. 46
- 47. Plasma contain both inorganic & organic phosphate. Organic phosphate > inorganic phosphate But only inorganic phosphate is measured. Inorganic phosphate occurs in two forms:- H2PO4 - HPO4 -- Their ratio is pH dependent. In acidosis, ratio is =1:1 At pH 7.4, ratio is 1:4 In alkalosis, ratio is 1:9 47
- 48. Serum phosphate= 3-4 mg/dl 10% -protein bound 35% -complexed with Na, Ca, Mg 55% -free Organic phosphate is located primarily within the cellular elements of blood. Phosphate level of whole blood =40mg/dl 48
- 49. Biochemical functions of phosphate ATP is involved in many energy intensive physiological functions. Muscle contraction Neurological functions Electrolyte transport Phosphate is an essential component of cyclic nucleotides. (cAMP, NADP) Phosphate is present in many coenzymes (TPP, NADP, PLP). Thus phosphate is required for activity of many enzymes. 49
- 50. Biochemical functions of phosphate Phosphate is essential for formation of:- Phosphoproteins Phospholipids Nucleic Acids Phosphate is essential for absorption & metabolism of carbohydrate. Phosphate buffer, easily handled by kidneys. Essentials for pH maintenance in blood & cells. Phosphate is essential for development of bone & teeth. 50
- 51. Absorption of Phosphate 90% of daily dietary phosphate gets absorbed. Absorption occurs in jejunum. Ca: P ratio in diet affects the absorption & excretion of other is increased. If one is ↑ed in diet, excretion of other is increased. Absorption of Ca & phosphate is optimum when Ca:P ratio is between 1:2 to 2:1. Acidity favors phosphate absorption. Phytate ↓es phosphate absorption. 51
- 52. Excretion of phosphate Renal threshold for phosphate = 2mg/dl 500mg of phosphate is excreted/day in urine. Reabsorption of phosphate from renal tubules is inhibited by PTH. 52
- 53. Regulation of phosphate level Regulation of Ca & Phosphate is under the similar control mechanism by kidney with respect to PTH & Vitamin D. Role of kidney Phosphate reabsorption (Na+-dependent ) occurs in PCT. & ↑ed when dietary intake is reduced by a PTH-dependent mechanism. Also ↑ed 1,25-dihydroxy-D3 activity leads to ↑ed phosphate reabsorption & vice versa. 53
Editor's Notes
- Citrate柠檬酸盐
- Figure 1 Calcium balance. On average, in a typical adult, 1 g of elemental calcium (Ca+2) is ingested per day. Of this, 200 mg/d will be absorbed and 800 mg/d excreted. Approximately 1 kg of Ca is stored in bone and 500 mg/d is released by resorption or deposited during bone formation. Of the 10 g of Ca filtered through the kidney per day, only 200 mg or less appears in the urine, the remainder being reabsorbed.
- Two processes: bone formation and bone resorption, going on continuously Calcium phospate crystals called ‘hydroxyapatite’ surface of crystals can exchange Ca++ and phosphate ions with extracellular fluid Write on board: -osteoblasts: builds bone (takes up Ca++ into bone) -osteoclasts: breaks down bone (removes Ca++ from bone) Now that we understand how calcium cycling happens at the bone, we can go back to the overall picture
- 1,25 Vitamin D3 -made in the liver, the skin, the liver, and the kidney Liver: cholesterol precursor transformed to 7-dehydrocholesterol Skin: UV transforms 7-dehydrocholesterol to Vit D3 Liver: Enzyme transforms Vit D3 to 25-OH-Vit D3 Kidney: Enzyme transforms 25-Vit D3 to 1,25 Vit D3 -lack of melanin pigment in Northen Europeans was thought to account for the lower light level: let more UV across the skin to ensure high enough levels of Vit. D3 -increases Ca++ uptake from the gut -made from cholesterol…….acts like a steroid…..what kind of receptors? How would they act? (they increase transcription and translation of Ca++ transport proteins in the epithelial cells of the gut) -minor roll: also acts to stimulate osteoclasts, (which would do what?) increasing Ca++ resorption from the bone -control of secretion: -low Ca++ levels causes increase of PTH, which increases enzymes in the kidney (more enzyme, more 1,25 Vit. D3)
- PARATHORMONE (PTH) -secreted from cells of the parathyroid glands (chief cells) -increases Ca++ in the blood -remove the gland, plama Ca++ levels plummet, tetanic convulsions and death result -increases Ca++ resorption from the bone (how could it do that?) -stimulates the osteoclasts -increases the number of osteoclasts -increases Ca++ resorption from the pre-urine filtrate in the nephron (draw this!) -Control of secretion: -low extracellular Ca++ causes PTH release -Similar Ca++ receptor as found with CT (how does this work?) -except, when bound by Ca++, activates Gi protein, inhibiting cAMP levels, which decreases PTH secretion -PTH action needed for fine control of plasma Ca++ levels
- CALCITONIN (CT) -Secreted from the C-cells in the thyroid gland -Lowers Ca++ in blood -Promotes deposition of Ca++ into bone -actually inhibits bone resorption in osteoclasts (ask them what osteoclasts do) -control of secretion: -increased plasma Ca++ stimulates C-cells to synthesize and release CT -Ca++ receptor on the cell membrane (draw on board!!) -when Ca++ binds the extracellular domain, activates Gs protein—Adenylate Cyc--increasing Camp -CT action needed -after meals, to prevent post-prandial hypercalcemia -gastrin (secreted in response to food in the stomach) also stimulates CT secretion -CT also important during pregnancy and lactation, to protect mother from Ca++ demands of fetus
- Why is calcium homeostasis important? 1. One of the major intracellular messengers (draw cell with high Ca++ outside, low Ca++ inside) a. Precise levels necessary for muscle contraction b. Responsible for exocytosis of secretory granules in neuronal synapses c. Serves as second messenger in many cells 2. Ca++ is necessary for blood clotting When would Ca++ levels change? after a large meal during a growth spurt during pregnancy or lactation Blood: Ca++ level usually 10 mg/100 ml (so 500 mg total in plamsa = 0.5 g) Regulation of calcium levels occurs in three different organs: bone, kidney, and small intestine small intestine: ingestion of Ca++ in food, taken up across the gut kidney: Ca++ is filtered through the nephron, and can be excreted in the urine bone: major storage site for Ca++
- Think of it this way: Calcium is ingested through the gut (get more Ca++ into system) Calcium is secreted out of the body through the urine and the feces Calcium is stored in the bones To understand how calcium regulation occurs at the bone, we need to understand how bones work…
- Define osteoblasts (builders) and osteoclasts (resorbers) again Calcitonin Parathormone Vit D3 Other hormonal regulators of Ca++ homeostasis: Estrogens -stimulate osteoblast activity , limits osteoclast activity, and enhance PTH secretion -although there is a lot of disagreement on what estrogens do exactly in bone -estrogens changes the set point of PTH cells in the parathyroid so a greater reduction of Ca++ is needed to increase PTH secretion (so E2 decreases Ca++ loss from bones) Clinical aspects: -(there are not many clinical problems with Ca++, because it rapidly leads to death) -Osteoporosis: decalcification and loss of bone matrix from the skeleton -maximum bone mass is achieved in women at age 35 -in the 30 years after menopause, women lose 30-50% of their bone mass -more common in women than men, may be because women have smaller bone calcium reserves -treatment: -estrogen replacement -increased Ca++ in the diet (slow down Ca++ turnover from bone) -exercise (especially weight bearing activities) stimulates bone deposition raquet arm of tennis players is 35% more dense than other arm
- Three hormones that affect regulation of calcium in the blood (write on board) Calcitonin Parathormone 1,25 Vitamin D3