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Physiology Ch 79 p 955-971 Parathyroid Hormone, Calcitonin, Ca and PO4 metabolism, Vitamin D, Bone, Teeth Overview of Ca and PO4 regulation in extracellular fluid and plasma – Ca regulates contraction of all muscles, blood clotting, transmission of nerve impulses -hypercalcemia causes depression of CNS, hypocalcemia causes overexcitement of CNS -most Ca is stored in bones (98.9%) which release Ca when extracellular fluid Ca decreases -85% of phosphate in body is stored in the bones, 15% in cells and 1% in extracellular fluid Ca in Plasma and Interstitial Fluid – 41% of Ca in plasma is combined with proteins and nondiffusible, 9% is diffusible but bound to anionic substances like phosphate, and 50% is diffusible AND ionized and can cross capillary membrane -normal plasma Ca ion concentration of about 1.2mm/L, controlling many effects in the body Inorganic Phosphate in Extracellular Fluids – comes in 2 forms: HPO4 and H2PO4 -HPO4 is normally 1.05mm/L and H2PO4 is 0.26mm/L; when total amount rises, both rise -when pH becomes acidic, there is relative increase of H2PO4 and decrease in HPO4, and opposite occurs when extracellular fluid becomes alkaline -often expressed as phosphorus per deciliter Nonbone Physiologic Effects of Altered Ca and PO4 in body fluids – increases in concentrations does not cause major immediate effects, but decreases in extracellular fluid causes BIG changes Hypocalcemia Causes Nervous System Excitement and Tetany – when extracellular fluid falls below normal, CNS becomes more excitable because it causes increased membrane permeability to Na ions allowing easy action potentials -at concentrations of <50%, neurons are so excitable that they begin to discharge spontaneously to elicit peripheral muscle tetany and can cause seizures -tetany occurs when blood concentration reaches 9.4mg/dl Hypercalcemia Depresses CNS and Muscle Activity – above normal levels, CNS becomes depressed and reflexes are sluggish, and QT interval of heart decreases and causes lack of appetite and constipation; above 17mg/dl causes CaPO4 crystals to form Absorption and Excretion of Ca and PO4 1. Intestinal Absorption and Fecal Excretion of Ca and PO4 – usual intakes are 1000mg/day, and normally Ca ions are poorly absorbed without help of Vitamin D (35% of Ca absorbed while the remaining is excreted). Additional 250mg/day enters intestines by GI juices and sloughed cells so a total of 90% of all Ca is excreted in the feces. a. Absorption of PO4 is easy, and excretion occurs in combination with Ca 2. Renal Excretion of Ca and PO4 – 10% of ingested Ca excreted in urine. 41% of plasma Ca bound to plasma proteins and not filtered by glomerular capillaries. Rest is combined with anions like PO4 or ionized (50%) and filtered in glomeruli a. Renal tubules reabsorb 99% of filtered Ca and 100mg/day excreted in urine b. 90% of Ca is reabsorbed in proximal tubules, loops of henle, distal tubules c. In late tubules, reabsorption depends on levels in the blood d. When Ca is low, reabsorption is great and almost no Ca is lost in urine e. Minute increase in blood Ca increases Ca excretion a lot, controlled by PTH f. Renal phosphate excretion is controlled by an overflow mechanism; when PO4 is below critical value of 1mm/L, all PO4 in glomerular filtrate is reabsorbed and no phosphate is lost i. Above this value, rate of PO4 loss is directly proportional to additional increase ii. Kidneys regulate phosphate concentration in extracellular fluid by altering rate of phosphate excretion in accordance with plasma concentration iii. PTH can greatly increase phosphate excretion by kidneys Bone and its relation to extracellular Ca and PO4 – bone is tough organic matrix enhanced by Ca -compact bone is 30% matrix and 70% salts Organic Matric of Bone – 95% collagen fibers and gelatinous ground substance to give tensile strength; ground substance composed of extracellular fluid + proteoglycans of chondroitin sulfate and hyaluronic acid Bone Salts – crystalline salts deposited in organic matrix are Ca and PO4; combination is called hydroxyapatite Ca10(PO4)6(OH)2 -Mg, Na, K, and CO3 are also present in bone salts, conjugated to crystals -radioactive substances can conjugate and stay, can cause osteosarcoma Tensile and Compressional Strength of Bone – arrangement of collagen and hydroxyapatite bonding prevents “shear” in bone; prevents slipping out of place to provide strength in bone and Ca provides great compression strength Precipitation and Absorption of Ca and PO4 in Bone – Equilibrium with Extracellular Fluids 1. Hydroxyapatite does not precipitate in EC fluid despite supersaturation of Ca and PO4 – inhibitors are present in body to stop hydroxyapatite from precipitating, such as pyrophosphate 2. Mechanism of Bone Calcification – initial stage is secretion of collagen molecules and ground substance by osteoblasts, which polymerize to form fibers to become an osteoid, similar to cartilage but Ca deposits can precipitate -as osteoid is formed, osteoblasts are entrapped and become quiescent, becoming osteocytes -Ca begins to precipitate on collagen fibers that multiple to become hydroxyapatite precursors -over time, amorphous salts converted to hydroxyapatite crystals over weeks or months -amorphous salts can be absorbed when body needs calcium Precipitation of Ca in Nonosseous Tissues under Abnormal Conditions – Ca never precipitates in tissues besides bone unless under abnormal conditions, such as atherosclerosis Ca exchange between bone and extracellular fluid – importance of exchangeable Ca in bone is that it provides rapid buffering mechanism to keep extracellular Ca concentration in extracellular fluids from rising to excessive levels Deposition and Absorption of Bone – bone is deposited by osteoblasts and absorbed by osteoclasts (osteoblasts found on outer surfaces of bones) -osteoclasts are monocyte derived, bone absorbing cells controlled by PTH -osteoclasts send out villus-like projectionstoward bone and secrete proteolytic enzymes and acids (citric acid and lactic acid) -enzymes digest/dissolve matrix and acid dissolves bone salts -PTH binds to receptors on adjacent osteoblasts causing them to release osteoprotegerin ligand (OPGL), also called RANK ligand, which activates receptors on osteoclast precursor -Osteoblasts also secrete osteoprotegerin (OPG) also called osteoclastogenesis inhibitory factor (OCIF), a cytokine which inhibits bone resorption -OPG opposes bone resorption activity of PTH -Vitamin D and PTH stimulate osteoclast through inhibiting OPG production and stimulating OPGL formation; estrogen stimulates OPG production -bone deposition and resorption are in equilibrium so total mass becomes constant -bone is deposited in circles (lamellae) until tunnel is filled; leaving haversian canal -bone adjusts in strength depending on degree of bone stress (thicken with heavy loads) -shape of bone can adjust, and because old bones are weak and brittle, remodeling is important -repair of fracture activates osteoblasts Vitamin D – potent effect increases Ca absorption from intestine and effects deposition/resorption; vitamin D converted to active form 1,25-dihydroxycholecalciferol 1. cholecalciferol (vitamin D3) if formed in the skin – vitamin D3 is formed in skin as a result of irradiation of 7-dehydrocholesterol by UV 2. cholecalciferol converted to 25-hydroxycholecalciferol in liver – has a feedback inhibitory step on conversion, important because it regulates concentration of 25hydroxycholecalciferol in plasma to promote excessive action of vitamin D, and also, controlled conversion of vitamin D conserves it in liver for future use 3. Formation of 1,25-dihydroxycholecalciferol in kidneys and control by PTH – occurs in proximal tubules to form the most active form of vitamin D, it requires PTH 4. Ca Ion concentration controls formation of 1,25-dihydroxycholecalciferol – plasma concentration of 1,25(OH)D3 is inversely affected by plasma Ca, because Ca ion itself has influence on preventing conversion of 25 hydroxycholecalciferol 1,25(OH)D3, and even more important, PTH is greatly suppressed when Ca concentration is high a. When PTH is high, 25-hydroxycholecalciferol 24,25-dihydroxycholecalciferol which has no Vitamin D effect -active vitamin D increases absorption of Ca and PO4 in extracellular fluid and contributes to negative feedback -vitamin D receptors are on most cells in nuclei, and has hormone/DNA binding domains -vitamin D receptor forms complex with retinoid-X receptor, which binds DNA and activates transcription -in some cases, vitamin D inhibits transcription; vitamin D receptor has 1000x more affinity for 1,25(OH)D3 than 25-hydroxycholecalciferol Hormonal effect of Vitamin D to promote instestinal Ca absorption – 1,25(OH)D3 is a hormone that promotes intestinal absorption of Ca by forming calbindin, a Ca binding protein on epithelial receptors on brush borders that functions in transport into cell cytoplasm -rate of Ca absorption directly proportional to quantity of CALBINDIN -also upregulates calcium-stimulated ATPase and Alkaline phosphatase in epithelial cells Vitamin D promotes phosphate absorption by intestines – normally PO4 easily absorbed, but it is enhanced with vitamin D from direct effect of 1,25(OH)D3 Vitamin D decreases renal Ca and PO4 excretion – decreases substances in urine Effect of Vitamin D on Bone and PTH – administration of vitamin D causes absorption of bone, and in absence of vitamin D, PTH associated bone absorption is reduced/prevented -in small quantities, vitamin D promotes bone calcification Parathyroid Hormone – regulates intestinal absorption, renal excretion, and exchange between extracellular gluid and bone of these ions Anatomy of Parathyroid Glands – 4 parathyroid glands behind thyroid gland -removal of 1 or 2 of these causes no major anomalies, but removal or 3-4 causes hypoparathyroidism, and a small portion of the gland can hypertrophy to take over function -parathyroid gland contains chief cells (PTH secretion) and oxyphil cells (not known function) Effect of Parathyroid Hormone on Ca and PO4 concentrations – causes Ca concentration to rise and PO4 concentration to fall faster -PTH increases Ca and PO4 absorption from bone and decrease excretion of Ca by kidneys PTH increases Ca and PO4 absorption from bone – two effects on bone to cause absorption: 1. Rapid phase (osteolysis) begins in minutes and increases for several hours and results from activation of already existing bone cells to promote Ca and PO4 absorption a. Occurs in the bone matrix in vicinity of osteocytes in bone, and also in vicinity of osteoblasts along bone surface b. Osteocytic Membrane system composed of osteoblasts and osteocytes separates bone from extracellular fluid c. Bone fluid – between osteocyte membrane and bone, where Ca is pumped from bone into this fluid creating Ca concentration in bone 1/3 of EC fluid. Activation of osteocytic pump reduces concentration in bone even more, called osteolysis d. Cells express receptors for PTH, which can activate Ca pump and cause rapid removal of CaPO4 salts from amorphous bone i. Stimulates pump by increasing Ca permeability of bone fluid side of osteocytic membrane, allowing Ca to diffuse into membrane cells from bone fluid 2. Slower phase taking weeks and results from proliferation of osteoclasts and followed by osteoclastic resorption of the bone itself a. PTH has better known effect by activating osteoclasts, but osteoclasts do not have receptor for PTH; believed that osteoblasts send secondary signal TO osteoclasts called osteoprotegerin ligand which activates receptors on preosteoclastcells and transforms them into mature osteoclasts b. Occurs in 2 steps: immediate activation of osteoclasts and formation of new osteoclasts (takes several days of excess PTH for osteoclastic system to become well developed) c. A few months of excess PTH can cause weakened bones and secondary stimulation of osteoblasts to correct weakened state Parathyroid hormone deceases Ca excretion and increases PO4 excretion by kidneys – also increases rate of reabsorption of Na, K+, and amino acids -inceased Ca absorption occurs in late distal tubules, collecting tubules and early collecting ducts -without PTH, continual loss of Ca would deplete both extracellular fluid and bone Ca Parathyroid Hormone increases intestinal absorption of Ca and PO4 – does this by increasing formation of 1,25-OH2D3 from Vit D -cAMP mediates effects of PTH – after few minutes of PTH administration, cAMP increases in osteocytes, osteoclasts, and other cells, which is responsible for osteoclastic secretion of enzymes and acids to cause bone reabsorption and formation of 1,25-OH2D3 Control of Parathyroid Secretion by Ca Ions – slightest decrease in Ca concentration in EC fluid causes parathyroid glands to increase rate of secretion, and cause hypertrophy if persists -parathyroids become enlarged in rickets and pregnancy, greatly enlarged in lactation -parathyroids decrease in size with increases in Ca concentration such as excessive Ca in diet, increased vitamin D in diet, bone absorption other than PTH -changes in EC fluid are detected by calcium-sensing receptor (CaSR) in parathyroid cell membranes (G-protein stimulated by Ca2+ activates inositol triphosphate and diacylglycerol which increases Ca from intracellular stores to DECREASE PTH -decreased EC fluid Ca inhibits these pathways and stimulates PTH secretion Summary – PTH stimulates bone resorption causing release of Ca into EC fluid, PTH increases reabsorption of Ca and decreases PO4 reabsorption from kidneys, leading to decreased excretion of Ca and increased excretion of PO4, and PTH is necessary for activating Vitamin D Calcitonin – peptide hormone secreted by the thyroid gland DECREASES plasma Ca and has opposite effects to PTH -synthesis of calcitonin occurs in parafollicular cells or C cells in interstitial fluid between follicles of thyroid gland, and are remnants of ultimobranchial glands of lower animals Increased plasma Ca stimulates Calcitonin secretion – contrasts to PTH secretion, stimulated by decreased calcium concentration Calcitonin DECREASES plasma calcium in two ways: 1. decreases absorptive activities of osteoclasts and osteolytic effect of osteocytic membrane throughout bone, shifting balance in favor of Ca deposition 2. decreased formation of new osteoclasts; because osteoclastic resorption of bone leads to osteoblastic activity, decreased of osteoclasts followed by decreased numbers of osteoblasts, and long term effect is LITTLE on Ca concentration -Calcitonin has WEAK effect on plasma concentration in adult human – reasons for weak effect is 3-fold 1. any initial reduction in Ca ions caused by calcitonin leads to powerful PTH effect 2. When thyroid gland is removed and no more calcitonin is present, little effect on long term blood concentration is noted 3. Daily rates of absorption and deposition of Ca are small, even after rate of absorption is slowed by calcitonin 4. Calcitonin is more prominent in children, when bone remodeling is greatest -Paget Disease – osteoclastic activity is greatly increased, calcitonin has much more powerful effect on reducing calcium absorption Buffer Function of Exchangeable Calcium in Bones – First line of Defense – exchangeable Ca in bones are the amorphous calcium compounds which cause immediate exchange upon increases or decreases of concentration Hormonal Control of Ca Ion Concentration – Second Line of Defense – at the same time that exchangeable calcium is buffering, both parathyroid and calcitonin hormonal effects are at play -within few minutes of increase in Ca ion concentration, rate of PTH secretion decreases, calcitonin increases -only PTH mechanism seems to be important in maintaining normal plasma Ca Pathophysiology of PTH, Vitamin D, and Bone Disease 1. Hypoparathyroidism – with insufficient PTH, osteocytic resorption and exchangeable Ca decreases and osteoclasts become inactive -calcium reabsorption from bones is depressed that level of Ca in body fluids decreases, bone usually remains strong -when parathyroids are removed, Ca in blood falls and can cause tetany of laryngeals -treatment of hypoparathyroidism is usually with PTH and Vitamin D 2. Primary Hyperparathyroidism – abnormality of parathyroids causes excess PTH secretion usually do it a tumor; causes extreme osteoclastic activity in the bones and elevates Ca in the EC fluid while depressing concentration of phosphate because of increased renal excretion -Bone disease in Hyperparathyroidism – severe disease cause osteoclast absorption to exceed osteoblast deposition, and bone may be eaten away entirely. Cystic bone disease of hyperparathyroidism is called osteitis fibrosa cystica -osteoblastic activity increases greatly to try to make up for this, and secrete alkaline phosphatase, causing high levels of AlkPhos in the blood -Effects of hypercalcemia in Hyperparathyroidism – depression of CNS, muscle weakness, ab pain, peptic ulcer, lack of appetite, and depressed relaxation of heart -Parathyroid poisoning and Metastatic Calcification – when extreme PTH levels secreted, level of Ca in body fluids rises rapidly, causing supersaturation of Ca and PO4 in the blood, so CaPO4 crystals begin to deposit in alveoli of lungs, kidney tubules, thyroid, stomach -Formation of Kidney Stones in hyperparathyroidism – excess Ca and PO4 absorbed by intestines must be excreted by kidneys, causing proportionate increase in urine, causing precipitation in kidney to form kidney stones -CaOxalate stones can develop as well Secondary Hyperparathyroidism – high levels of PTH occur as compensation for hypocalcemia and not as a result of overactive parathyroids secreting PTH -can be caused by vitamin D deficiency or chronic renal disease which causes insufficient active vitamin D production -vitamin D deficiency leads to osteomalacia and high levels of PTH cause absorption of bones Rickets caused by Vitamin D deficiency – in children, Ca or PO4 deficiency in EC fluid causes rickets due to lack of vitamin D -exposure to sun converts 7-dehydrocholesterol to vitamin D3 to preven rickets -Plasma Ca and PO4 decreases in rickets – plasma Ca in rickets is only slightly depressed, but PO4 is greatly depressed because parathyroids prevent Ca level from falling by promoting bone absorption every time Ca levels fall -no good regulatory mechanism for preventing a falling level of phosphate -Rickets weakens the bones – marked compensatory increase in PTH secretion causes extreme osteoclastic absorption of bone to cause bone to become progressively weaker and imposes marked stress on bone and causing extreme osteoblastic activity as well, which builds osteoid without calcium, causing uncalcified, weak osteoid to replace older bone being reabsorbed -tetany in rickets – doesn’t occur in early stages of rickets because parathyroids continually stimulate osteoclastic absorption of bone, but when bones become exhausted of Ca, level of calcium falls rapidly, to cause tetany -treatment of rickets – treatment of rickets depends on supplying adequate Ca and PO4 in diet and also large amounts of vitamin D -Osteomalacia (adult rickets) – serious deficiencies of vit d and Ca occur as a result of steatorrhea (failure to absorb fat) because vitamin D is fat-soluble and Ca tends to form insoluble soaps with fat, both passing into feces. Doesn’t cause tetany, but causes severe bone disability -Osteomalacia and Rickets Caused by Renal Disease – prolonged kidney damage causes failure of kidney to form 1,25(OH)D3, and if it is damaged, renal rickets is severe -congenital hypophosphatemia – results from congenitally reduced reabsorption of phosphates by renal tubules and must be treated with phosphate compounds instead of Ca and vitamin D, also called vitamin D-resistant rickets -Osteoporosis – most common of all bone diseases and results from diminished organic bone matrix rather than poor bone calcification -osteoblastic activity is low, and rate of bone osteoid deposition is less -main causes are: lack of physical stress on bones, malnutrition, lack of vitamin C (necessary for secretion of intercellular substances by all cells such as osteoid), postmenopausal lack of estrogen secretion because estrogens decrease number and activity of osteoclasts, old age, where growth hormone and factors diminish, and cushing’s syndrome – because massive glucocorticoids are secreted in this disease to cause decreased deposition of protein throughout the body and increased catabolism of protein and have specific effect of depressing osteoblastic activity Physiology of Teeth – teeth grind, cut, and mix food; upper sets of teeth fit with lower set, called occlusion Enamel – outer layer of enamel created by ameloblasts; once erupted and covers surface of tooth, no more enamel is made. Enamel is hard, much harder than dentin, makes it resistant to acids, enzymes, and other corrosive agents Dentin – main body of tooth composed of dentin, which is strong and bony; made up of hydroxyapatite crystals similar to bone but much denser inside collagen fibers -made by odontoblasts -calcium salts in dentin make it resistant to compressional forces Cementum – bony substance secreted by peridontal membrane lining tooth socket. Cementum holds teeth in place, and when teeth are exposed to excessive strain, cementum becomes thicker and stronger Pulp – pulp cavity is filled with pulp, composed of connective tissue with an abundant supply of nerve fibers, blood vessels, and lymphatics -lined by odontoblasts which secrete dentin, but also encroach onto pulp as we age -dentinal tubules are projected into dentin and involved in exchange of Ca, PO4, and other minerals Dentition – humans develop 2 sets of teeth; first is called deciduous teeth, and have 20 in number; permanent teeth occur later Formation of Teeth – invagination of oral epithelium into dental lamina followed by development of tooth-producing organ; epithelial cells above form ameloblasts, and below form odontoblasts Eruption of Teeth – growth of bone shoves tooth upward Development of permanent teeth – a tooth-forming organ develops in deeper dental lamina for each permanent tooth that will be needed after deciduous teeth are gone and slowly form for the first 6-20 years of life -permanent tooth pushes forward and erodes the root of deciduous tooth to cause it to loosen and fall out Metabolic Factors Influence Development of Teeth – accelerated by thyroid and growth hormones, and deposition of salts in early forming teeth affected by Ca and PO4 in diet and vitamin D present, and rate of PTH secretion Mineral exchange in teeth – salts of teeth are composed of hydroxyapatite with associated ions, and are constantly being deposited while old salts are being reabsorbed from teeth -deposition and reabsorption occur mainly in dentin and cementum to limited extent, occur mainly through exchange of minerals with saliva by diffusion -rate of absorption and deposition of minerals in cementum is equal to that of surrounding bone of jaw, where is deposition and absorption of minerals in dentin is 1/3 that of bone -continual mineral exchange happens in dentin and cementum Dental Abnormalities – most common are caries (erosion of teeth) and malocclusion (failure of projections of upper and lower teeth to interdigitate properly) Caries and the rold of bacteria and ingested carbs – most common bacteria in caries of tooth is streptococcus mutans; first event is deposit of a plaque (film of precipitated products of saliva and food on teeth) -large numbers of bacteria inhibit plaque and available to cause caries -these bacteria depend on carbs for their food -they form acids and proteolytic enzymes, which cause caries because calcium salts of teeth are slowly dissolved in high acidic medium; once salts have been absorbed, the matrix is rapidly digested by enzymes -enamel of teeth is primary barrier to development of caries; once carious process has passed enamel, to dentin, process proceeds rapidly -high carb diet causes more frequent caries Role of Fluorine in Preventing Caries – fluorine does not make enamel harder, but does replace OH ions in hydroxyapatite when makes enamel less soluble, and fluorine may be toxic to bacteria -fluorine is believed to promote deposition of CaPO4 to heal enamel surface when pits develop from caries Malocclusion – caused by hereditary abnormality that causes teeth of one jaw to grow to abnormal positions, and teeth do not interdigitate properly and cannot perform normal grinding action -results in abnormal placement of lower jaw in relation to upper jaw and cause undesirable effects such as pain in mandibular joint and deterioration of teeth