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Slide 1-

Study Guide for Calcium and Phosphate Metabolism The most important first messengers for Dental Biochemistry include parathyroid hormone, calcitonin, insulin, and glucagon Name common second messengers and how they operate Define calcium balance Describe the properties and mechanism of action of parathyroid hormone (PTH) including G-protein function Review the composition of bone, and know what bone mineral is What are the two main functions of parathyroid hormone in kidney? Describe the metabolic activation of vitamin D What are the actions of vitamin D? What is osteomalacia? Rickets? Hyperparathyroidism? Pseudohypoparathyroidism? What is osteoporosis? Describe physiological ways to establish and maintain maximum bone density What foods are good sources of dietary calcium?
Slide 2-

Elements of the Body (Table 2-1)
Slide 3-

Overview
Slide 4-

Regulation of Calcium Metabolism Minerals; serum concentration Calcium (Ca2+); 2.2-2.6 mM (total) Phosphate (HPO42-); 0.7-1.4 mM Magnesium (Mg2+); 0.8-1.2 mM Organ systems that play an import role in Ca2+ metabolism Skeleton GI tract Kidney Calcitropic Hormones Parathyroid hormone (PTH) Calcitonin (CT) Vitamin D (1,25 dihydroxycholecalciferol) Parathyroid hormone related protein (PTHrP)
Slide 5-

Sutherland Second Messenger Hypothesis Understand this key concept
Slide 6-

Second Messengers Fig. 19-4
Slide 7-

More Second Messenger
Slide 8-

Three Forms of Circulating Ca2+
Slide 9-

Calcium Balance Intake = output Negative calcium balance: Output > intake Neg Ca2+ balance leads to osteoporosis Positive calcium balance: Intake > output Occurs during growth Calcium is essential, we can’t synthesize it
Slide 10-

Calcium and the Cell Translocation across the plasma membrane Translocation across the ER and mitochondrion; Ca2+ ATPase in ER and plasma membrane
Slide 11-

Anatomy and Feedback Inhibition
Slide 12-

Parathyroid Hormone Structure Synthesized in the 4 para-thyroid glands PreProPTH 115 aa precursor giving a 90 aa prohormone Cleaved at -6/-7 84 residues in the mature peptide Regulator of Ca2+ homeostasis
Slide 13-

Parathyroid Hormone Biosynthesis
Slide 14-

Regulation of PTH Secretion and Biosynthesis Extracellular Ca 2+ regulates secretion of PTH Low Ca 2+ increases High Ca 2+ decreases Ca2+ also regulates transcription High levels of 1,25 dihydroxyvitamin D3 inhibit transcription
Slide 15-

Calcium Sensing Receptor (CaSR) Parathyroid chief cells contain a Ca2+ sensing receptor (CaSR) 7 transmembrane segments (We will see a lot of 7 TM receptors) mM affinity for Ca2+ GPCR of the GPLC and GI varieties Generates inositol 1,4, 5-trisphosphate which  increases intracellular Ca2+ There are two paradoxes The receptor responds to decreasing concentrations of agonist Low extracellular Ca2+ increases intracellular Ca2+ Also found in thyroid C cells (calcitonin), kidney, and brain
Slide 16-

Circulating Forms of PTH Intact, active PTH of 84 aa Inactive carboxyterminal fragments lack the 1-34 active domain PTH t1/2 (half life) is 2-3 min Liver (2/3rds) and kidney (1/3rd) are major sites of fragmentation
Slide 17-

Actions of Parathyroid Hormone Fine tunes Ca2+ levels in blood It increases Ca2+ It decreases Pi Parathyroid hormone acts directly on bone to stimulate resorption and release of Ca2+ into the extracellular space (slow) Gs protein-coupled receptors in osteoblasts increase cAMP and activate PKA Inhibits osteoblast function This occurs when PTH is secreted continuously; the opposite occurs when it is given once daily by injection Two effects in kidney Parathyroid hormone acts directly on kidney to increase calcium reabsorption and phosphate excretion (rapid) Gs protein-coupled receptors Parathyroid hormone acts on distal tubule Calcitonin inhibits Stimulates transcription of 1-alpha hydroxylase for Vitamin D activation in kidney Vitamin D increases calcium and phosphate absorption
Slide 18-

Parathyroid Hormone Receptor 7 TM GPCR
Slide 19-

G-Protein Cycle (Fig. 19-10)
Slide 20-

Regulation of Adenylyl Cyclase (Fig. 19-11) 7 and 12 TM segments
Slide 21-

Cyclic AMP Metabolism (Fig. 19-12) Know each step involved in the generation of cAMP by PTH (words, not structures)
Slide 22-

Bone Inorganic (67%) Hydroxyapatite 3 Ca10(PO4)6(OH)2 There is some amorphous calcium phosphate Organic (33%) component is called osteoid Type I collagen (28%) Non-collagen structural proteins (5%) Proteoglycans Sialoproteins Gla-containing proteins (gamma carboxyglutamate) Phosphoproteins Bone specific proteins: osteocalcin, osteonectin Growth factors and cytokines (Trace) Bone undergoes continuous turnover or remodeling throughout life About 20% of bone is undergoing remodeling at any one time
Slide 23-

Bone Composition
Slide 24-

Calcium and the Skeleton A, absorption is stimulated by Vit D; S, secretion GF, glomerular filtration; TR, tubular reabsorption of Ca2+ is stimulated by PTH
Slide 25-

Osteoblast and Osteoclast Function Osteoblasts Bone formation Synthesis of matrix proteins Type I collagen Osteocalcin Others Mineralization Activation of osteoclasts via RANKL production Osteoclasts Bone resorption Degradation of proteins by enzymes Acidification RANK is activated by RANKL, and this leads to cells differentiation to osteoclasts
Slide 26-

Bone Remodeling Osteoclasts dissolve bone Large multinucleated giant cells Osteoblasts produce bone Have receptors for PTH, CT, Vitamin D, cytokines, and growth factors Main product is collagen When osteoblasts become encased in bone, they become osteocytes
Slide 27-

PTH and Osteoblastogenesis
Slide 28-

Osteoclast Mediated Bone Resorption
Slide 29-

Osteoclastogenesis: RANKL, RANK, and OPG Osteoblasts activate osteoclasts, formation of a multinuclear cell The molecular participants in this pathway are the membrane-associated protein named RANKL (receptor activator of nuclear factor kappa B ligand,) a member of the tumor necrosis factor family of cytokines Its cognate receptor is RANK; TRAF, TNF receptor associated factors Mediates activation of NF-kappa-B by unknown mechanism OPG (osteoprotegerin) is a soluble "decoy" receptor for RANKL RANKL is expressed on the surface of osteoblastic stromal cells By binding to RANK, its receptor, on osteoclast precursors, RANKL enhances their recruitment into the osteoclastogenesis pathway in the physiology of bone metabolism RANKL also activates mature osteoclasts to resorb bone RANKL is a factor through which osteoblasts regulate osteoclasts, and bone formation is coupled to bone resorption
Slide 30-

RANK and RANKL
Slide 31-

Osteoclastogenesis
Slide 32-

PTH and Kidney PTH acts on the distal tubule
Slide 33-

Calcitonin Product of parafollicular C cells of the thyroid 32 aa Inhibits osteoclast mediated bone resorption This decreases serum Ca2+ Promotes renal excretion of Ca2+
Slide 34-

Calcitonin Probably not essential for human survival Potential treatment for hypercalcemia 7 transmembrane segment receptor Stimulates cAMP production in bone and kidney
Slide 35-

Vitamin D Metabolism
Slide 36-

Transport and Metabolic Sequence of Activation of Vitamin D
Slide 37-

Proposed Mechanism of Action of 1,25-DihydroxyD3 in Intestine
Slide 38-

Vitamin D-dependent Ca2+ Absorption Duodenum>jejunun>ileum Absorption is greater at low pH The pH of the stomach is about 2 Peak absorption at the beginning of the duodenum
Slide 39-

Vitamin D Deficiency: Rickets Inadequate intake and absence of sunlight The most prominent clinical effect of Vitamin D deficiency is osteomalacia, or the defective mineralization of the bone matrix Osteoblasts contain the vitamin D receptor Vitamin D deficiency in children produces rickets A deficiency of renal 1α-hydroxylase produces vitamin D-resistant rickets Sex linked gene on the X chromosome Renal tubular defect of phosphate resorption Teeth may be hypoplastic and eruption may be retarded
Slide 40-

Rickets
Slide 41-

Vitamin D-Resistant Rickets Above: Hypoplastic teeth Below: Minimal caries can produce pulpitis; periapical abscesses are thus common Lack 1-hydroxylase in kidney Rx: Respond well to 1, 25-dihydroxyD3
Slide 42-

PTHrP; Parathyroid Hormone related Protein It is synthesized as 3 isoforms as a result of alternative splicing (139, 141, 173 aa) Can activate the PTH receptor Plays a physiological role in lactation, possibly as a hormone for the mobilization and/or transfer of calcium to the milk May be important in fetal development May play a role in the development of hypercalcemia of malignancy Some lung cancers are associated with hypercalcemia Other cancers can be associated with hypercalcemia
Slide 43-

PTHrP; Parathyroid Related Protein
Slide 44-

Causes of Hypocalcemia
Slide 45-

Sequence of Adjustments to Hypocalcemia
Slide 46-

Pseudohypoparathyroidism Symptoms and signs Hypocalcemia Hyperphosphatemia Characteristic physical appearance: short stature, round face, short thick neck, obesity, shortening of the metacarpals Autosomal dominant Resistance to parathyroid hormone The patients have normal parathyroid glands, but they fail to respond to parathyroid hormone or PTH injections The rise in urinary cAMP after parathyroid hormone fails to occur The cause of the disease is a 50% deficiency of Gs in all cells Symptoms begin in children of about 8 years Tetany and seizures Hypoplasia of dentin or enamel and delay or absence of eruption occurs in 50% of people with the disorder Rx: vitamin D and calcium
Slide 47-

Pseudohypoparathyroidism Elfin facies, short stature, enamel hypoplasia
Slide 48-

Signs and Symptoms of Hypercalcemia Neurologic Lethargy, drowsiness, depression, confusion Can lead to coma and death Neuromuscular Muscle weakness, hyptonia, decreased reflexes Cardiac Arrhythmias Bone Ache, pain, fracture
Slide 49-

Causes of Hypercalcemia
Slide 50-

Causes of Hypercalcemia Primary hyperparathyroidism Most people are asymptomatic Classically affects skeleton, kidneys, and GI tract Triad of complaints: bones, stones, and abdominal groans Renal stones are most common single presenting complaint Usually due to an adenoma (tumor)
Slide 51-

Hyperparathyroidism The disorder is characterized by hypercalcemia, hypercalcuria, hypophosphatemia, and hyperphosphaturia Parathyroid hormone causes phosphaturia and a decrease in serum phosphate Calcium rises and it is also secreted in the urine Most common complication are renal stones made of calcium phosphate Stone chemistries: calcium, phosphate, urate Most serious complication is the deposition of calcium in the kidney tubules resulting in impaired renal function
Slide 52-

Primary Hyperparathyroidism Calcium excretion > calcium intake Large regions of bone are replaced by connective tissue Two lesions: maxilla and forehead
Slide 53-

Hyperparathyroidism Left: Giant Cell Granuloma Right: Loss of lamina dura, pathognomonic oral change in hyperparathyroidism
Slide 54-

Lamina Dura Tooth sockets are bounded by a thin radiopaque layer of dense bone Lamina dura: “hard layer”
Slide 55-

Congenital Hypoparathyroidism Hypoplasia of the teeth, shortened roots, and retarded eruption
Slide 56-

Hypercalcemia of Malignancy Treatment improves quality of life when Ca2+ is elevated but not yet life threatening Treat with bisphosphonates Inhibits osteoclastic activity When serum Ca2+ > 3.00 mM treat with NaCl IV
Slide 57-

Bisphosphonates
Slide 58-

Osteoporosis Osteoporosis is characterized by a significant reduction in bone mineral density compared with age- and sex-matched norms There is a decrease in both bone mineral and bone matrix Osteoporosis is the most common metabolic bone disease Affects 20 million Americans and leads to 1.3 million fractures in the US per year Women lose 50% of their trabecular bone and 30 % of their cortical bone 30% of all postmenapausal women will sustain an osteoporotic fracture as will 1/6th of all men The cost of health care and lost productivity is $14 billion in the US annually
Slide 59-

Normal and Osteoporotic Bone
Slide 60-

Factors that Affect Peak Bone Mass Gender (M>F), males have greater PBM than females Race (Blacks >Whites) Genetics (osteoporosis runs in families and this may be the predominant factor) Estrogen receptor gene Type I collagen gene Vitamin D receptor gene Gonadal steroids (estrogen and testosterone increase bone mass) Growth hormone (increases bone mass) Calcium intake (supplements work) Exercise (increases bone mass)
Slide 61-

Sequelae of Osteoporosis
Slide 62-

Osteo-porosis
Slide 63-

Bone Density as a Function of Age
Slide 64-

FDA Approved Rx’s for Osteoporosis Bisphosphonates (alendronate and risedronate), calcitonin, estrogens, parathyroid hormone and raloxifene are approved by the US Food and Drug Administration (FDA) for the prevention and/or treatment of osteoporosis The bisphosphonates (alendronate and risedronate), calcitonin, estrogens and raloxifene affect the bone remodeling cycle and are classified as anti-resorptive medications Teriparatide, a form of parathyroid hormone, is a newly approved osteoporosis medication. It is the first osteoporosis medication to increase the rate of bone formation in the bone remodeling cycle
Slide 65-

Treatments (Continued) Exercise, activity Calcium intake should be 1000-1500 mg/day Postmenapausal women take in less than 500 mg/day Males and females should take in 1000-1500 mg/day All adults greater than 65 years should take 1500 mg/day Three glasses of milk or three cups of yogurt per day provide 1000-1500 mg/day Estrogen treatment Estrogen inhibits osteoclastic activity Bone density increases 3-5% per year for the first three years after menopause This therapy needs to be individualized Estrogen may increase the incidence of breast cancer, heart attacks, stroke, blood clots That it may exacerbate cardiovascular disease is controversial All the data are not in yet, and estrogen treatment is under review; for more information go to http://www.fda.gov/bbs/topics/NEWS/2003/NEW00863.html
Slide 66-

Treatments (Continued) Raloxifene (Brand name Evista) is a selective estrogen receptor modulator Decreases in estrogen levels after menopause lead to increases in bone resorption and bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. This imbalance between resorption and formation is related to loss of estrogen, and may also involve age-related impairment of osteoblasts or their precursors Raloxifene reduces resorption of bone and decreases overall bone turnover. These effects on bone are manifested as increases in bone mineral density (BMD) Raloxifene’s biological actions, like those of estrogen, are mediated through binding to estrogen receptors. This binding results in the modulation of expression of multiple estrogen-regulated genes in different tissues
Slide 67-

Treatments (Continued) Bisphosphonates inhibit osteroclasts Alendronate (Brand name Fosamax) Risedronate (Brand name Actonel) Calcitonin (Brand name Miacalcin ) From salmon Given intranasaly Probably least effective Rx Vitamin D Most Americans consume less than recommended amount 800 IU per day seems safe and not enough to cause vitamin D toxicity
Slide 68-

Treatments (Continued) Parathyroid hormone (Brand name Forteo) Teriparatide, a form of parathyroid hormone, is approved for the treatment of osteoporosis in postmenopausal women and men who are at high risk for a fracture Chronically elevated PTH leads to bone loss; however, intermittent PTH (once daily bolus injection) leads to new bone synthesis Must be injected daily, a major disadvantage Cost about $7000 per year Future Rx’s Sodium fluoride Considered a possibility for years Adoption seems unlikely Strontium ranelate NEJM 350 (2004) 459-468.
Slide 69-

Calcium Content of Foods http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/wtrank/wt_rank.html
Slide 70-

Selected Web Sites
Slide 71-

Properties of Parathyroid Hormone It is a small protein hormone It acts on its 7 transmembrane segment receptor Gs protein-coupled receptors in osteoblasts increase [cAMP] and activates protein kinase A Parathyroid hormone acts directly on bone to stimulate resorption and release of Ca2+ into the extracellular space (slow) Parathyroid hormone acts directly on kidney to increase calcium reabsorption and phosphate excretion (rapid) Parathyroid hormone acts on distal tubule and stimulates calcium resorption Parathyroid hormone stimulates transcription of 1-alpha hydroxylase for vitamin D activation in kidney Know how 7 transmembrane segment receptors activate or inhibit adenylyl cyclase via the G-protein cycle Know the pathway for the formation of active vitamin D
Slide 72-

Transport and Metabolic Sequence of Activation of Vitamin D
Slide 73-

PTH Biosynthesis PTH is co-secreted with chromogranin A, a protein; significance unknown
Slide 74-

Sequence of Adjustments to Hypocalcemia