Chapter 6 Hormonal Control of Calcium Homeostasis Nam Deuk Kim, Ph.D. 1
1. Calcium and Bone Physiology Plasma Ca 2+ must be closely regulated to prevent changes in neuromuscular excitability Also plays vital role in a number of essential activities Neuromuscular excitability Stimulus-secretion coupling Excitation-contraction coupling in cardiac and smooth muscle Maintenance of tight junctions between cells Clotting of blood Hypercalcemia Reduces excitability Hypocalcemia Brings about overexcitability of nerves and muscles Severe overexcitability can cause fatal spastic contractions of respiratory muscles 2
Endocrine Control of Calcium Metabolism Three hormones regulate plasma concentration of Ca 2+ (and PO 4 3- ) Parathyroid hormone (Parathormone, PTH) Calcitonin Vitamin D 3
Ca ++ : PTH V-D3 Ca ++ : Calcitonin Hydroxyapatite: Ca 10 (PO 4 ) 6 (OH) 2 4
Bone continuously undergoes remodeling. 5
Osteocyte Central canal Lamella Canaliculi Osteon Blood vessel from marrow Central canal Vessel in central canal 6
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Role of osteoblasts in governing osteoclast development and activity 8
Relationship of mineralized bone, bone cells, bone fluid, and the plasma Osteoblast Osteocyte Osteocytic osteoblastic bone membrane Osteoblast Outer surface Mineralized bone Blood vessel Canaliculi Bone fluid Central canal Lamellae 9
Relationship of mineralized bone, bone cells, bone fluid, and the plasma In canaliculi In central canal Mineralized bone: stable pool of Ca 2+ Bone fluid: labile pool of Ca 2+ Plasma Fast exchange Slow exchange (Bone dissolution) = Membrane-bound Ca 2 + pump 10
Endocrine Control of Calcium Metabolism Parathyroid hormone (PTH) Secreted by parathyroid glands Primary regulator of Ca 2+ Raises free plasma Ca 2+ levels by its effects on bone kidneys, and intestines Essential for life Prevents fatal consequences of hypocalcemia Facilitates activation of Vitamin D 11
Fig. 9-1: Posterior (left) and transverse (right) views of the human thyroid with attached parathyroids. 12
2. Parathormone Chief Cells : ( 주세포 ) Parathyroid Hormones (Parathormone, PTH) 혈중칼슘농도증가유지 13
Fig. 9-2: Comparative structures of parathormone (PTH). 14
Synthesis, chemistry, and metabolism of PTH - A polypeptide 84 aa long, derived from a precursor molecule of 115 aa. - Preproparathyroid hormone (115 aa prepropth) 90 aa propth 84 aa PTH Control of PTH secretion - Release of PTH from the gland is controlled by circulating levels of Ca 2+ - Ca 2+ -sensing receptor [calcium-sensing receptor (CaSR)] : a typical seven-spanning membrane G- protein coupled receptor - Human Ca 2+ -sensing receptor: 1,018 aa with 93% sequence similarity to the bovine receptor 15
Parathyroid Chief Cells Pre Pro PTH Rough Endoplasmic Reticulum consitutive synthesis PreproPTH -31-6 1 84 Cisternal space of RER signal peptidase action ProPTH Golgi Apparatus processing Granules packaging PTH Low Ca 2+ Secretion Prepro-PTH and its processing to secreted PTH in the parathyroid chief cells. Negative numbers indicate the number of amino acids prior to the first amino acid in PTH 16
PTH acts to raise plasma Ca 2+ levels - Bone mineral metabolism - Renal reabsorption of calcium - Renal excretion of phosphate - Intestinal absorption of calcium - Control of vitamin D synthesis - Other possible actions of PTH: increases the mitotic rate of red cell progenitors (reticulocytes) and thymic lymphocytes. 17
Interaction between PTH and V-D in controlling plasma calcium 18
3. Parathormone-related Peptide (PTHrP) PTHrP: isolated from human tumor cells or tissues obtained from patients with humoral hypercalcemia of malignancy PTHrP: 139-173 aa resides, depending upon the species. Fig. 9-3: Aligned sequences of the 1 34 region of PTH and PTHrP from various species. Conserved residues are outlined in black. Note the lack of substantial sequence identity between PTH and PTHrP from amino acid residue 14 through the C terminus. 19
Calcitonin 4. Calcitonin Hormone produced by C cells of thyroid gland Negative-feedback fashion Secreted in response to increase in plasma Ca 2+ concentration Acts to lower plasma Ca 2+ levels by inhibiting activity of bone osteoclasts Unimportant except during hypercalcemia Fig. 9-4: Primary structure of human calcitonin. 20
C cell (Calcitonin) 21
Fig. 9-5: Comparative structures of some calcitonins. Three molecular species (isoforms) of salmon CT exist; the structure of salmon I calcitonin is shown, which differs from eel CT at only three residues (eel: 26, Asp; 27, Val; 29, Ala). 22
Calcitonin acts to lower plasma Ca 2+ levels - Bone mineral metabolism: - Calcitonin as a satiety hormone: Subcutaneous (s.c.) injections of CT inhibit the 24-hour food intake of rats and rhesus monkeys. Intracerebroventricular injections of CT in the rat are also inhibitory to feeding. In humans, significant reduction in body weight is observed 24 to 36 hours following a single s.c. injection of CT. - Vitamin D regulation: CT directly stimulates V-D metabolism and indirectly stimulates it by lowering plasma Ca 2+ levels, resulting in the release of PTH, which activates renal vitamin D synthesis and secretion. 23
Negative-feedback Loops Controlling Parathyroid Hormone (PTH) and Calcitonin Secretion 24
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5. Vitamin D Stimulates Ca 2+ and PO 4 3- absorption from intestine Can be synthesized from cholesterol derivative when exposed to sunlight Often inadequate source Amount supplemented by dietary intake Must be activated first by liver and then by kidneys before it can exert its effect on intestines 27
Precursor in skin (7-dehydrocholesterol) Sunlight Dietary vitamin D Vitamin D 3 Hydroxyl group (OH) Liver enzymes 25-OH D 3 Hydroxyl group PTH Plasma Ca 2+ Kidney enzymes + Activation of Vitamin D 1, 25-(OH) 2 D 3 (active vitamin D) Plasma PO4 3- Promotes intestinal absorption of Ca 2+ and PO 3-4 28
Fig. 9-6: Photic stimulation of integumental cholecalciferol (vitamin D 3 ) formation and subsequent transfer to the general circulation by a cholecalciferol-binding protein. 29
Fig. 9-7: Production of ergosterol and ergocalciferol from their precursors. 30
Fig. 9-8: Sequential steps in the biosynthesis of vitamin D. 31
Fig. 9-9: Feedback control of vitamin D biosynthesis. 32
V-D promotes Ca 2+ absorption in the gut and Ca 2+ reabsorption in the kidney. - Intestine: - Bone: - Kidney: - Other putative roles: 33
Interaction between PTH and V-D in controlling plasma calcium 34
Control of plasma phosphate 35
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1) PTH 6. Hormone Mechanisms of Action in Calcium Homeostasis Fig. 9-10: Cell-surface receptors for PTH are coupled to two classes of G proteins. G s mediates stimulation of adenylyl cyclase (AC) and the production of camp, which in turn activates protein kinase A (PKA). G q stimulates phospholipase C (PLC) to form the second messengers inositol-(1,4,5)-triphosphate (IP 3 ) and diacylglycerol (DAG) from membranebound phosphatidyl-inositol-(4,5)-biphosphate. IP 3 increases intracellular calcium (Ca 2+ ) and DAG stimulates protein kinase C (PKC) activity. Each G protein consists of a unique chain and dimer. 37
Regulation of PTH secretion Secretion of parathyroid hormone is controlled chiefly by serum [Ca 2+ ] through negative feedback. Calcium-sensing receptors located on parathyroid cells are activated when [Ca 2+ ] is low. The G-protein coupled calcium receptors (CaR) sense extracellular calcium and may be found on the surface on a wide variety cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, sensation of high concentrations of extracellular calcium result in activation of the Gq G- protein coupled cascade through the action of phospholipase C. This hydrolyzes phosphatidylinositol 4,5- bisphosphate (PIP2) to liberate intracellular messengers IP 3 and diacylglycerol (DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores and a subsequent flux of extracellular calcium into the cytoplasmic space. The effect of this signaling of high extracellular calcium results in an intracellular calcium concentration that inhibits the secretion of preformed PTH from storage granules in the parathyroid gland. In contrast to the mechanism that most secretory cells use, calcium inhibits vesicle fusion and release of PTH. 38
Stimulators of PTH secretion - Decreased serum [Ca 2+ ]. - Mild decreases in serum [Mg 2+ ]. - An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH) Inhibitors of PTH secretion - Increased serum [Ca 2+ ]. - Severe decreases in serum [Mg 2+ ], which also produces symptoms of hypoparathyroidism (such as hypocalcemia). - Hypermagnesemia - Calcitriol In the parathyroids, magnesium serves this role in stimulussecretion coupling. Magnesium: a natural calcium antagonist Hypomagnesia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible. Hypermagnesemia also results in inhibition of PTH secretion when a moderate low calcium concentration is present. 39
Magnesium and the parathyroid Curr Opin Nephrol Hypertens. (2002) 11(4): 403-410. The serum levels of parathyroid hormone and magnesium depend on each other in a complex manner. The secretion of parathyroid hormone by the parathyroid is physiologically controlled by the serum calcium level, but magnesium can exert similar effects. While low levels of magnesium (mild decrease) stimulate parathyroid hormone secretion, very low serum concentrations (hypomagnesemia) induce a paradoxical block. This block leads to clinically relevant hypocalcemia in severely hypomagnesiemic patients. The mechanism of this effect has recently been traced to an activation of the alphasubunits of heterotrimeric G-proteins. Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration Nephrol Dial Transplant (2014) 29: 282 289 Results: I. Increasing Mg concentrations from 0.5 to 2 mm produced a left shift of PTH Ca curves. II. With Mg 5 mm, the secretory response was practically abolished. Mg was able to reduce PTH only if parathyroid glands were exposed to moderately low Ca concentrations; with normal high Ca concentrations, the effect of Mg on PTH inhibition was minor or absent. Conclusions. Mg reduces PTH secretion mainly when a moderate low calcium concentration is present; Mg also modulates parathyroid glands function through upregulation of the key cellular receptors CaR, VDR and FGF23/Klotho 40 system.
2) Calcitonin (CT): Receptors for CT are present in skeletal tissue, kidney, and testicular Leydig cells. Osteoblast Bone constructor Osteoclast Bone destructor PTH G s camp PKA IL-6; other cytokines ODF IL-6 activation inactivation PKA camp G s CT Calcitonin (CT) secreted by thyroid C-cells in response to hypercalcemia. CT gene can yield calcitonin gene-related peptide (CGRP) if processed differently (alternative mrna splicing). CGRP = a potent vasodilator Control of bone remodeling by PTH and calcitonin 41
Receptor for calcitonin The calcitonin receptor, found on osteoclasts, and in kidney and regions of the brain. G protein-coupled receptor, which is coupled by G s to adenylate cyclase and thereby to the generation of camp in target cells. It may also affect the ovaries in women and the testes in men. Uses of calcitonin Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis. Oral calcitonin may have a chondroprotective role in osteoarthritis (OA) How calcitonin affects osteoarthritis (OA)? Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation 42
3) Vitamin D Fig. 9-11: Mechanism of action and general functions of 1,25(OH) 2 D 3 in target cells. 43
7. Hormone Integration in Calcium Homeostasis Fig. 9-12: Generalized model of the role of hormones controlling bone mineralization and demineralization. 44
8. Hormonal Regulation of Intracellular Calcium Fig. 9-13: Primary structure of calmodulin (CaM), an intracellular calcium receptor. The following are one-letter codes for amino acid residues: A, Ala; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; Y, 45 Tyr.
Calcium release in excitation-contraction coupling. 46
Fig. 9-14: Model for the mechanism of action of calmodulin. 47
9. Pathophysiology 1) Hypoparathyroidism results in hypocalcemia. 2) Hyperparathyroidism results in hypercalcemia. 3) Hypercalcemia can accompany some malignancies. 4) Osteomalacia is a condition of inadequate bone mineralization. 5) Paget s disease is characterized by excess osteoclastic activity. 6) Osteoporosis is a condition of decreased bone mineral density. a. Postmenopausal (Type I) osteoporosis b. Senile (Type II) osteoporosis 7) New pharmacological therapies for diseases of Ca 2+ homeostasis are available. a. Bisphosphonates b. Selective estrogen receptor modulators (SERMs) c. Pharmaceutical preparations of vitamin D. d. Dietary calcium and osteoporosis 48
Parathyroid Glands Calcium Metabolism Blood calcium is in equilibrium with calcium in the bone Calcium level is regulated by the parathyroid glands Reduced calcium in blood: tetany (increases neuromuscular excitability, causing spasm of skeletal muscle) Elevated calcium in blood: reduces neuromuscular excitability 49
Calcium Disorders PTH hypersecretion (hyperparathyroidism) Characterized by hypercalcemia and hypophosphatemia PTH hyposecretion (hypoparathyroidism) Characterized by hypocalcemia and hyperphosphatemia Vitamin D deficiency Children rickets Adults osteomalacia 50
Completed Picture of Updated Calcium/Parathyroid Hormone Normogram (http://www.parathyroid.com/hyperparathyroidismdiagnosis.htm, 2014.4.6) 51
Hyperparathyroidism Usually a result of hormone-secreting parathyroid adenoma Blood calcium rises Excessive calcium withdrawn from bone Excessive calcium excreted in urine Treated by removal of tumor 52
원발성부갑상샘기능항진증 (Primary Hyperparathyroidism) : PTH 과다분비 원인 : 1. 샘종 (80%) 2. 원발성증식증 (10~15%) 3. 샘암종 (5% 이하 ) 53
부갑상샘기능항진증조직학적변화 1. Adenoma 2. Primary hyperplasia: Chief cell 3. Primary hyperplasia: Clear cell 4. Secondary hyperplasia 5. Carcinoma 54
부갑상샘기능항진증임상증상 1. 혈중 PTH 상승 2. 고칼슘혈증 3. 저인산염혈증 4. 낭종섬유성골염 5. 신장결석 6. 정서적불안 7. 기억력감퇴 8. 근약화 9. 전이성칼슘침착 10. 위장의소화성궤양 55
고칼슘증감별진단법 1. Hyperparathyroidism 2. Milk-Alkali syndrome 3. V-D intoxication 4. Sarcoidosis 5. Multiple myeloma 6. Metastatic ca. 7. Primary ca, not involving bone 8. Disuse atrophy (osteoporosis) 9. Thyrotoxicosis 56
Hypoparathyroidism Usually result of removal of parathyroid glands during thyroid surgery Blood calcium falls precipitously Leads to neuromuscular excitability and tetany Treated with high-calcium diet and supplementary vitamin D 57
부갑상샘기능저하증 (Hypoparathyroidism) : 혈중저칼슘증발생 1. 갑상샘절제술 2. 특발성 3. 가족성 4. 가성 : PTH 에대한무감응 58
부갑상샘기능저하증 (Hypoparathyroidism) 임상증상 : 저칼슘혈증 근 - 신경흥분성 Trousseau s sign Chvostek s sign Convulsion Laryngeal spasm Choked disk 정서불안 정신병 59
골연화증 / 구루병 골연화증 (Osteomalacia): 새로이형성된뼈기질에미네랄화가부적절한것을특징으로하는성인질환 구루병 (Rickets): 골단이열려있는어린이에서발생하는유사질환 비타민 D 대상의비정상, 인산결핍상태및미네랄화과정자체의결함등 60
골연화증 (Osteomalacia) 구루병 (Rickets) 61
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Paget's disease of bone Paget's disease of the bone (other terms are Paget's disease, osteitis deformans, osteodystrophia deformans): a chronic disorder that typically results in enlarged and deformed bones. The disease is named after Sir James Paget, the British surgeon who first described it in 1877. The excessive breakdown and formation of bone tissue that occurs with Paget's disease can cause bone to weaken, resulting in bone pain, arthritis, deformities, and fractures. Paget's disease is rarely diagnosed in people less than 40 years of age. Women are more commonly affected than men. Prevalence of Paget's disease ranges from 1.5 to 8.0 percent, depending on age and country of residence. Prevalence of familial Paget's disease (where more than one family member has the disease) ranges from 10 to 40 percent in different parts of the world. Because early diagnosis and treatment is important, after age 40, siblings and children of someone with Paget's disease may wish to have an alkaline phosphatase blood test every two or three years. If the alkaline phosphatase level is above normal, other tests such as a bonespecific alkaline phosphatase test, bone scan, or X-ray can be performed. 63
뼈의파제트병 Paget Disease of Bone 64
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Urinary hydroxyproline elevated 66
Osteoporosis Generalized thinning of the bone and dimineralization of the entire skeletal system, porous bones Most common in postmenopausal women Loss of estrogen accelerates rate of bone resorption Also develops in elderly men Remember that osteoporosis is not the same as osteoarthritis Osteoarthritis is the wear and tear degeneration of one or more of the weight-bearing joints 67
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May 4, 2003 골다공증 It was a dramatic end to a 5 1/2- month space station mission for Ken Bowersox, who served as the commander, astronaut Donald Pettit and cosmonaut Nikolai Budarin. Russian spotters carry astronaut Ken Bowersox at the landing site of the Soyuz space capsule that returned him and two others to Earth. 71
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