Mineral Homeostasis Flashcards by J L

Bones
• 99% of the ____ in our bodies is found in our bones which serve as a reservoir for Ca2+ storage.
• ____% of total adult bone mass turns over each year during remodeling process
• During growth, rate of bone formation exceeds resorption and skeletal mass increases.
• ____ growth occurs at epiphyseal plates.
• Increase in width occurs at ____
• Once adult bone mass is achieved, equal rates of formation and resorption maintain bone mass until age of about ____ years when rate of resportion begins to exceed formation and bone mass slowly decreases.

calcium
10
linear
periosteum
30

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There are 3 major types of bone cells:
____are the differentiated bone forming cells and secrete bone matrix on which Ca2+ and PO43- precipitate.
____, the mature bone cells are enclosed in bone matrix.
Osteoclasts is a large ____ cell derived from ____ whose function is to resorb bone.

osteoblasts
osteocytes
multinucleated
monocytes

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Bone Formation and Mineralization
• Active ____ synthesize and extrude collagen
• Collagen fibrils form arrays of an organic matrix called the ____.
• ____ is deposited in the osteoid and becomes mineralized
• Dependent on ____
• Alkaline phosphatase and osteocalcin play roles in
bone formation
• Their ____ levels are indicators of osteoblast activity.

osteoblasts
osteoid
calcium phosphate
vitamin D
plasma

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How does bone transfer calcium? -Canaliculi

• Within each bone unit, there are fluid-containing channels called the ____.
• Canaliculi traverse the mineralized bone.
• Interior osteocytes remain connected to surface
cells via syncytial ____.
• This process permits transfer of calcium from enormous surface area of the interior to extracellular fluid.

canaliculi

cell processes

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Control of Bone Formation and Resorption

Bone resorption of Ca2+ by two mechanisms: ____ is a rapid and transient effect and ____ which is slow and sustained.
Bone formation and resorption are ____ by PTH.

osteocytic osteolysis
osteoclastic resorption
stimulated

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Osteocytic Osteolysis
• Transfer of ____ from canaliculi to extracellular fluid via activity of osteocytes.
• Does not decrease ____.
• Removes calcium from most ____ formed crystals
• Happens ____.

calcium
bone mass
recently
quickly

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Bone Resorption
• Does not merely extract calcium, it ____ entire matrix of bone and ____ bone mass.
• Cell responsible for resorption is the osteoclast.

destroys

diminishes

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How to maintain mineral homeostasis?

Build and maintain a healthy skeleton and dentition
Maintain the ____ and intracellular ____ at a fixed level
Maintain cellular and extracellular [PO4 ]
Prevent ____ calcification

The mechanisms of mineral homeostasis are designed to satisfy all these needs

blood
[Ca++]
ectopic

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Mineral homeostasis

Adult organisms try to maintain ____ (intake = output)
Calcium and phosphate ions can combine to form insoluble salts, the concentrations of these ions in cells and body fluids is precisely regulated to prevent inappropriate precipitation
Mineral balance is achieved by ____ control of Ca and P transport into and out of ____, ____ and ____

mineral balance
hormonal
intestine
kidney
bone

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Why is Calcium important?

Ca salts in bone provide structural integrity of the skeleton.
____ is the most abundant mineral in the body.
The amount of Ca is balanced among intake, storage, and excretion.
This balance is controlled by transfer of Ca among 3 organs: ____, ____, ____.

• Ca ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processes
ü Neuoromuscular excitability and signal transduction
ü ____ coagulation
ü Hormonal secretion
ü ____ regulation
ü Neuron excitation

Calcium
intestine
bone
kidneys
blood
enzymatic

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Intake of Calcium
• About ____ mg of Ca is ingested per day.
• About ____ mg of this is absorbed into the body.
• Absorption occurs in the ____, and requires ____ (stay tuned….)

1000
200
small intestine
vitamin D

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Storage of Calcium

An adult human contains ~ ____ g of Ca++
~ ____% is in the skeleton in the form of hydroxyapatite Ca10(PO4)6(OH)2 and ____% is in blood and body fluids intracellular calcium
Extracellular Ca++ concentration is ~ ____ (~10 mg/dL)
The concentration of Ca2+ in the cytosol is ~ ____

• This ____ concentration gradient across the plasma membrane has important biological implications

1000
99
1
10-3 M
10-7 M
steep

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Regulation of Calcium

The important role that calcium plays in so many processes dictates that its ____, both extracellularly and intracellularly, be maintained within a very ____ range.
This is achieved by an elaborate system of controls

concentration

narrow

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Regulation of Intracellular Calcium

Control of cellular Ca homeostasis is as carefully maintained as in extracellular fluids
[Ca2+]cyt is approximately ____ of extracellular concentration
Stored in ____ and ____
____ transport systems control [Ca2+]cyt
Calcium ____ into cytosolic compartment and is actively pumped into storage sites in organelles to shift it away

1/1000th
ER
mitochondria
"pump-leak"
leaks

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Extracellular Calcium
•Ca2+ normally ranges from ____ mg/dL in the plasma.
• Three definable fractions of calcium in serum:
• Ionized calcium 50% (Only free, ionized Ca2+ is
biologically ____).
• Protein-bound calcium 40%
—• 90% bound to ____
—• Remainder bound to ____
• Calcium complexed to serum constituents 10%
—____ and ____

8.5-10
active
albumin
globulins
citrate
phosphate

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Intake of Phosphate
• About ____ mg of phosphate is ingested per day.
• About ____ mg of this is absorbed into the body.
• Phosphate is absorped in the ____, stored in the ____ and excreted by the ____

1000
450
small intestine
skeleton
kidneys

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Storage of Phosphate

• An adult human contains approximately ____ g of phosphorus
- ~ ____% of this is present in crystalline form in the skeleton
- ~ ____% is present in the extracellular fluids (~ 1 mM)
- The concentration in cells is ~ ____ mM
• These concentrations are ____ rigidly maintained than that of calcium

700
85
15
5
less

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Phosphorous in Blood and Bone

PO4 normal plasma concentration is ____ mg/dL. 87% is ____, with 35% complexed to different ions and 52% ____.
13% is in a ____ protein bound state. 85- 90% is found in bone.
The rest is in ATP, cAMP, and proteins

3.0-4.5
diffusible
ionized
non-diffusible

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Regulation of Pi homeostasis

Cells require adequate Pi for energy metabolism and nucleic acid synthesis
Cells take up Pi from the blood using ____ (____ transport)
Absorption and reabsorption of Pi occur primarily in the ____ and ____
Pi is regulated by ____, ____ and ____

Na/Pi co-transporters
active
intestine
kidney
PTH
vitamin D
FGF23

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Hormonal Control of Ca2+

• The major hormones involved in plasma calcium homeostasis are:
ü 1,25(OH)2 vitamin D3 acts on ____, ____ and ____

ü Parathyroid hormone (PTH) acts on ____ and ____

ü Calcitonin (CT) acts ____ and ____
• Vitamin D and PTH ____ blood calcium
• CT ____ blood calcium.
• Many other hormones effect calcium homeostasis

intestine
kidney
bone

kidney
bone

bone
kidney

increase
decreases

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Vitamin D

Vitamin D is the precursor of the hormone 1,25(OH)2 vitamin D3, one of the hormones controlling mineral metabolism

• Two natural forms of Vitamin D:
- ____, derived from the plant steroid ergosterol = ____
- ____, derived from cholesterol = ____
• Both forms must be further ____ to be effective 1,25-(OH)2-vitamin D.
• Dietary Vitamin D is usually ____.

vitamin D2
ergocalciferol
vitamin D3
cholecalciferol
hydroxylated
D2

Vitamin D action
v The active form of Vitamin D, 1,25(OH)2-D3, is synthesized in the ____

v The rate of this conversion is controlled by ____

v The major target organs for 1,25(OH)2-D3 are
____, ____ and ____

v Increased levels of 1,25-(OH)2-D lead to:
• Increased Ca++ and Pi absorption by ____
• Increased Ca++ reabsorption in ____
• Increased resorption of ____
• Similar to effects of PTH

kidney
PTH
intestine
kidney
bone
small intestine
kidney
bone

What do the range of serum 25OH vitamin D conincide with?

< 30 nmol/L, < 12 ng/mL = ____
>= 50 nmol/L, >=20 ng/mL = ____
> 125 nmol/L, >50 ng/mL = ____

vitamin D deficincey
considered healthy and adequate bone health
adverse effects

Look up the target genes of vitamin D

Know this table!

OKAY

Mechanism of vitamin D action • The vitamin D receptor (VDR) belongs to the ____ hormone receptor superfamily • The VDR binds cooperatively to these vitamin D response elements (VDREs) as a ____ with another member of the family, the ____

steroid/thyroid heterodimer retinoid X receptor (RXR)

``` Vitamin D-dependent Ca2+ Absorption • ____>____>____ • Absorption is greater at ____ pH • The pH of the stomach is about 2 • Peak absorption at the beginning of the ____ ```

``` dudenum jejunum ileum low duodenum ```

Vitamin D action * The main action of 1,25-(OH)2-D is to ____ absorption of Ca2+ from the intestine. * 1,25-(OH)2-D induces the production of ____ proteins which sequester Ca2+, buffer high Ca2+ concentrations that arise during initial absorption and allow Ca2+ to be absorbed against a high Ca2+ gradient

calcium binding

Vitamin D Actions on Bones * Another important target for 1,25-(OH)2-D is the ____. * ____, but not ____ have vitamin D receptors. * In its absence, excess ____ accumulates from lack of 1,25-(OH)2-D repression of osteoblastic collagen synthesis. * 1,25-(OH)2-D acts on osteoblasts which produce a ____ signal that activates osteoclasts to resorb ____ from the bone matrix. * 1,25-(OH)2-D also stimulates ____.

``` bone osteoblasts osteoclasts osteoid paracrine Ca2+ osteocytic osteolysis ```

What factor(s) regulate Vitamin D? * PTH increases ____ activity, increasing production of active form. * This increases calcium ____ from the intestines, increases calcium ____ from bone, and ____ loss of calcium through the kidney. * As a result, PTH secretion ____, decreasing 1- hydroxylase activity (negative feedback). • Low ____ concentrations also increase 1- hydroxylase activity (vitamin D increases phosphate reabsorption from the ____).

``` 1-hydroxylase absorption release decreases decreases phosphate urine ```

Vitamin D deficiency caused skeletal diseases • Vitamin D-dependent rickets type ____ in children - a softening of bones potentially leading to fractures and deformity (defective mineralization or calcification of bones) • ____ – adult form of rickets • Vitamin D-resistant rickets (mutation in ____) - Hypophosphatemic rickets – hereditary disease of ____ metabolism (____ mutation) - Pseudo-deficiency rickets – genetic defects in ____ metabolism (CYP27B1 ____ of function)

``` II oseomalacia VDR phosphate PHEX vitamin D loss ```

Parathyroid hormone • PTH is an 84 amino acid monomeric polypeptide hormone • Only the first ____ amino acids are essential for activity • A related hormone, PTHrP (PTH-related peptide), • has significant ____ to PTH

34 | homology

Parathyroid Hormone * PTH is synthesized and secreted by the ____ which lie ____ to the thyroid glands. * The blood supply to the parathyroid glands is from the ____ arteries. * The ____ in the parathyroid gland are the principal site of PTH synthesis. * It is THE MAJOR of ____ homeostasis in humans.

``` parathyroid gland posterior thyroid chief cells Ca++ ```

Actions of PTH - Fine tunes Ca2+ levels in blood - -- ____ Ca2+ - -- ____ Pi - PTH acts directly on ____ to stimulate resorption and release of Ca2+ into the extracell space (____) - -- Gs protein-coupled receptors in osteoblasts increase ____ and activate ____ - -- ____ osteoblast function - -- occurs when PTH is secreted ____; the opposite occurs when it is given ____ by injection

``` increases bone slow cAMP PKA inhibits continuously once daily ```

Actions of PTH - Two effects in kidney - - PTH acts directly on kidney to ____ calcium reabsorption and phosphate excretion (____) - -- Gs protein-coupled receptors - -- PTH acts on ____ - -- Calcitonin ____ - Stimulate transcription of ____ for vitamin D activation in kidney - -- Vitamin D ____ calcium and phosphate absorption

kidney rapid distal tube inhibits 1-alpha hydroxylase increases

Parathyroid hormone receptor PTH1R • Highly Expressed in ____ and ____. • Also exressioned in many other tissues, particularly in growth plate ____ • In tissues other than kidney and bone, PTH1R mediates the paracrine/autocrine actions of ____, rather than the endocrine actions of ____

``` kidney bone chondrocytes PTHrP PTH ```

The PTH paradox * Recent evidence shows that PTH can also have an ____ effect on bone * The choice between anabolic and catabolic effects of the hormone depends on the ____ of hormone application * ____ administration of PTH may be useful in the treatment of osteoporosis and periodontal disease

anabolic kinetics intermittent

How is PTH regulated? • The dominant regulator of PTH is ____. • Secretion of PTH is ____ related to [Ca2+]. • Maximum secretion of PTH occurs at plasma Ca2+ below ____ mg/dL. • At Ca2+ above ____ mg/dL, PTH secretion is maximally inhibited.

plasma Ca2+ inversely 3.5 5.5

Calcium-sensing receptor - The CaSR is a cell surface ____ capable of detecting small changes in serum [Ca2+] - CaSR is also expressed in ____, chondrocytes, and ____

GPCR kidney tubules osteoblasts

``` Calcitonin • Product of ____ cells of the thyroid • 32 aa • ____ osteoclast mediated bone resorption • This ____ serum Ca2+ • Promotes renal ____ of Ca2+ ```

parafollicular C inhibits decreases excretion

Calcitonin • The major stimulus of calcitonin secretion is a rise in ____ levels • Calcitonin is a physiological ____ to PTH with regard to Ca2+ homeostasis • The target cell for calcitonin is the ____. • Calcitonin acts via increased ____ concentrations to inhibit osteoclast motility and cell shape and inactivates them, resulting in decreased bone resorption. • The major effect of calcitonin administration is a rapid ____ in Ca2+ caused by inhibition of bone resorption.

``` plasma Ca2+ antagonist osteoclast cAMP fall ```

Influences of Growth Hormone * Normal GH levels are required for skeletal growth. * GH increases intestinal ____ absorption and renal ____ resorption. * Insufficient GH prevents normal bone production. * Excessive GH results in bone abnormalities (____ of bone formation AND ____).

calcium phosphate acceleration resorption

Effects of Glucocorticoids • Normal levels of glucocorticoids (____) are necessary for skeletal growth. • Excess glucocorticoid levels ____ renal calcium reabsorption, interfere with intestinal calcium ____, and ____ PTH secretion. • High glucocorticoid levels also interfere with ____ production and action, and ____ production. • Net Result: rapid ____

``` cortisol decrease absorption stimulate growth hormone gonadal steroid osteoporosis (bone loss) ```

Influence of Thyroid Hormones * Thyroid hormones are important in skeletal growth during ____ and ____ (____ effects on osteoblasts). * Hypothyroidism leads to ____ bone growth. * Hyperthyroidism can lead to ____ bone loss, suppression of ____, decreased ____ metabolism, decreased ____ absorption. Leads to ____.

``` infancy childhood direct decreased increased PTH vitamin D calcium osteoporosis ```

Effects of diets * ____ are essential nutrients which cannot be made by the body, so they need to be ingested. * Increasing dietary intake of Ca may prevent osteoporosis in ____ women. * Excessive ____ intake in diet can impair renal Ca reabsorption, resulting in ____ blood Ca and ____ PTH release. Normally, PTH results in increased absorption of Ca from the GI tract (via vitamin D). But in aging women, vitamin D production decreases, so Ca isn’t absorbed, and PTH instead causes increased ____.

``` biominerals postmenopausal Na lower increased bone loss ```

Effects of diets * High ____ diet may cause loss of Ca from bone, due to acidic environment resulting from ____ metabolism and decreased reabsorption at the kidney. * Intake of carbonated beverages has been associated with ____ excretion and loss of ____

protein protein increased calcium

Effects of Exercise * Bone cells respond to ____ gradients in laying down bone. * Lack of weight-bearing exercise decreases bone ____, while increased exercise helps form ____. * Increased bone resorption during immobilization may result in ____

pressure formation bone hypercalcemia

``` Disorders of bone mineral homeostasis • ____-senile, postmenopausal • Chronic ____ failure • Primary hyperparathyroidism • Hypoparathyroidism • ____- nutritional vitamin D dependent, vitamin D resistant • ____ osteodystrophy • Hypercalcemia/hypocalcemia •Hyperphosphatemia/hypophosphatemia • Idopathic hypercalciuria • ____ disease ```

``` osteoporosis renal rickets intestinal pagets ```

Osteoporosis • Osteoporosis is characterized by a significant ____ in bone mineral density compared with age- and sex-matched norms • There is a decrease in both bone ____ and bone ____ • Osteoporosis is the most ____ 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 ____ 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

``` reduction mineral matrix common postmenapausal ```

Vitamin D Deficiency: Rickets * Inadequate intake and absence of ____ * The most prominent clinical effect of Vitamin D deficiency is ____, or the defective mineralization of the bone matrix * Vitamin D deficiency in children produces ____ * A deficiency of renal 1α-hydroxylase produces ____ rickets * Sex linked gene on the ____ chromosome * Renal tubular defect of ____ resorption * Teeth may be ____ and eruption may be ____

``` sunlight osteomalacia rickets vitamin D-resistant X phosphate hypoplastic retarded ```

Rickets •Thining (____) or decreased mineralization (____) of the enamal •____ teeth •Minimal caries can produce ____; periapical abscesses are thus common

hypoplasia hypocalcification hypoplastic pulpitis