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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?

Elements of the Body (Table 2-1)

Overview
Calcium (Ca2+) 99% 1.3 mM (ionized) Carefully controlled 104-105
Cell signaling and 2nd messenger Neurotransmitter and hormone release Exocytosis of proteins Muscle contraction Blood clotting Biomineralization

Characteristic Body total in bone/teeth Plasma concentration of ionic form Normal variation of ionic form [extracellular]/[intracellular]

Phosphate (HPO42-) 85% 1.3 mM Within 50% 10

Regulatory roles

Nil

Important conclusion, calcium is an important regulator

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)

Sutherland Second Messenger Hypothesis

Understand this key concept

Second Messengers

Fig. 19-4

More Second Messenger

Three Forms of Circulating

2+ Ca

Intake = output Negative calcium balance: Output > intake


Neg Ca2+ balance leads to osteoporosis

Calcium Balance

Positive calcium balance: Intake > output


Occurs during growth

Calcium is essential, we cant synthesize it

Calcium and the Cell

Translocation across the plasma membrane Translocation across the ER and mitochondrion; Ca2+ ATPase in ER and plasma membrane

Anatomy and Feedback Inhibition

Synthesized in the 4 parathyroid glands PreProPTH 115 aa precursor giving a 90 aa prohormone Cleaved at -6/-7 84 residues in the mature peptide Regulator of Ca2+ homeostasis

Parathyroid Hormone Structure

Parathyroid Hormone Biosynthesis

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

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

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

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

Parathyroid Hormone Receptor


7 TM GPCR

G-Protein Cycle (Fig. 19-10)

Regulation of Adenylyl Cyclase (Fig. 19-11)

7 and 12 TM segments

Cyclic AMP Metabolism (Fig. 19-12)

Know each step involved in the generation of cAMP by PTH (words, not structures)

Inorganic (67%)

Bone

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

Bone Composition

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

Osteoblast and Osteoclast Function


Osteoblasts Bone formation Synthesis of matrix proteins
Type I collagen Osteocalcin Others

Osteoclasts Bone resorption


Degradation of proteins by enzymes Acidification

Mineralization Activation of osteoclasts via RANKL production

RANK is activated by RANKL, and this leads to cells differentiation to osteoclasts

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

PTH and Osteoblastogenesis

Osteoclast Mediated Bone Resorption

Osteoclastogenesis: RANKL, RANK, and OPG


Osteoblasts activate osteoclasts, formation of a multinuclear cell The molecular participants in this pathway are the membraneassociated 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

RANK and RANKL

Osteoclastogenesis

PTH and Kidney

PTH acts on the distal tubule

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+

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

Vitamin D Metabolism

Transport and Metabolic Sequence of Activation of Vitamin D

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

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

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 1-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

Rickets

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, 25dihydroxyD3

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

PTHrP; Parathyroid Related Protein

Causes of Hypocalcemia
Hypoparathyroid
Postoperative

Nonparathyroid
Vitamin D deficiency

PTH Resistance
Pseudohypoparathyroidism

Idiopathic Post radiation

Malabsorption Liver disease


Kidney disease Vitamin D resistance

Sequence of Adjustments to Hypocalcemia

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

Pseudohypoparathyroidism

Pseudohypoparathyroidism

Elfin facies, short stature, enamel hypoplasia

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

Causes of Hypercalcemia
Common
Malignant disease, e.g. some lung cancers Hyperparathyroidism Vitamin D toxicity (excessive intake)

Uncommon
Renal failure Sarcoidosis Multiple myeloma

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)

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

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

Hyperparathyroidism

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

Lamina Dura

Tooth sockets are bounded by a thin radiopaque layer of dense bone Lamina dura: hard layer

Congenital Hypoparathyroidism

Hypoplasia of the teeth, shortened roots, and retarded eruption

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

Bisphosphonates

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

Normal and Osteoporotic Bone

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)

Sequelae of Osteoporosis

Osteoporosis

Bone Density as a Function of Age

FDA Approved Rxs 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

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

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) Raloxifenes 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

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

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 Rxs
Sodium fluoride
Considered a possibility for years Adoption seems unlikely

Strontium ranelate
NEJM 350 (2004) 459-468.

Calcium Content of Foods

http://www.nal.usda.gov/fnic/foodcomp/Data /SR16/wtrank/wt_rank.html

Selected Web Sites

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

Transport and Metabolic Sequence of Activation of Vitamin D

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

Sequence of Adjustments to Hypocalcemia