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

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
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
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
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
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
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
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
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
