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37 Cards in this Set

  • Front
  • Back
Calcium is essential for what biochemical processes?

Inorganic Phosphate?
Ca2++: Blood coagulation, enzymes activity, apoptosis, membrane/action potential, exocytosis

Pi: ATP, backbone of nucleic acids, Phosphorylation/Dephosphorylation of proteins, lipids, second messengers that are regulatory steps in metabolic reactions and signaling pathways.
Acid-base balance regulation (phosphate buffer)
Where and in what form is Calcium primarily stored in the body?
As Calcium salts in bone (this accounts for 99% of Calcium in our body). This is primarily in the form of hydroxyapatite crystals (calcium and phosphate).
The total plasma Calcium consists in what three fractions?
Bound to protein (40-45%)
Bould to multiple organic and inorganic anions such as sulfate, phosphate, lactate, and citrate (5-10%)
Free ionized, aka active (50%)
Besides the blood what are other three organs mainly involved in regulation of calcium homeostasis?
Bone, Kidney, Intestine
What are the major hormones that regulate calcium and phosphate homeostasis?
Vitamin D (1,25 OH2 D3)
Parathyroid Hormone
Calcitronin
Describe how each of the following affects calcium and phosphate homeostasis:
Vitamin D
Parathyroid Hormone
Calcitonin
Vitamin D increases plasma Ca, and increases plasma phosphate

Parathyroid hormone increases plasma Ca and decreases plasma Pi

Calcitonin decreases Plasma Ca and decreases Pi
How does Vitamin D increase calcium concentration?
The active form of Vitamin D, Calcitriol acts on the kidneys to increase reabsorption and decrease excretion of calcium. It also acts on the INTESTINE to stimulate increased absorption of calcium, and it acts on bone to increase resorption.
What cells are responsible for secreting PTH?
Chief cells of the parathyroid gland
Explain how PTH secretion is regulated by plasma calcium
Ca is the principle physiological regulator of PTH secretion.
An increase in plasma Ca allows it to bind to Ca-sensing receptors on the parathyroid. The bound receptor triggers a cascade effect, activating phospholipase A2, and increasing leukotrienes. Leukotrienes will subsequently increase PTH degradation.
Low plasma Ca allows the G protein Ca receptor to relax and PTH secretion can occur.
Explain how PTH secretion is regulated by Vitamin D
Vitamin D can inhibit PTH secretion directly by acting on the PH glands and blocking gene expression of PTH.
It can also act indirectly via a negative feedback mechanism
Where can you find PTH receptors?
In bone (osteoblasts)
In the kidney

There is NO direct PTH effect in the intestine
What are the effects on PTH on its target cells?
In bone (Osteoblasts):
PTH increases Ca mobilization from bone ca salts

In the kidney (the proximal and distal tubules):
PTH increases calcium reabsorption
PTH decreases phosphates resbsorption
Stimulates synthesis of 1,25(OH)2D3
Vitamin D is classified as what kind of hormone?

What is the active form of Vitamin D called?

How is Vitamin D transported in the blood?

What are the main organs Vitamin D affects?
1,25(OH) 2D3 is classified as a steroid hormone

The active form of Vitamin D is calcitriol (Calcitriol - 1,25(OH)2D3)

1,25(OH)2D3 and its metabolites circulate in the blood bound to plasma proteins (~99.6%) and in free forms (~0.4%)

Vitamin D-binding protein (DBP) in primarily transport protein

1,25(OH)2D3 has several effects on the INTESTINE, kidneys, and bones
What enzyme catalyzes the major step in vitamin D production?
1 alpha hyroxylase
List dietary sources of vitamin D.

What is the desirable concentration of 25 (OH) D3?
Dietary supplements
D2 (ergocalciferol)
D3 - (cholecalciferol) more effective than D2
The desirable concentration of 25(OH) D3 is  30 ng/mL ( 75 nmol/L)
What are stimulatory and inhibitory factors of vitamin D synthesis?
Stimulatory Factors:
- PTH
- Low ECF [Ca2+]
- Low ECF [Pi]


Inhibitory Factors:
- Vit D inhibits its own production via negative feedback
- High ECF [Ca2+] suppress the stimulators of its production in a classical negative feedback manner
What are the actions of Vitamin D?
Essential for acquiring adequate amounts of Ca2+ and Pi from the diet
Increases plasma [Ca2+] and plasma [Pi]
Regulates processes of bone resorption and deposition
Inhibits PTH secretion
How does active Vitamin D increase Ca absorption in the small intestine?
Ca2+ is absorbed from the duodenum and jejunum via transcellular (active) and paracellular (passive) route
1,25(OH)2D3 increases absorption of Ca2+ in the intestine by stimulating synthesis of calcium binding protein (calbindin, “shuttle” protein), channels, pumps, exchangers which function to increase transcelluar Ca2+ transport
Increases Pi absorption
How does Vitamin D act on Bone?
Calcitriol promote bone calcification (synthesis):
Indirectly through increased Ca2+ and Pi absorption from the intestine (bone calcification is a passive process)
Directly stimulating osteoblasts
Extreme quantities of Vit D causes resorption of bone
admonish
v. warn reprove. When her courtiers questioned her religious beliefs, Mary Stuart admonished them, declaring that she would worship as she pleased.
What is the effect of Calcitonin on Calcium and Pi levels?
Calcitonin causes a rapid and dramatic decrease in plasma [Ca2+] and [Pi]
Not a major physiological regulator of calcium or phosphate homeostasis in humans
How does Calcitonin act on bone?
Calcitonin decreases plasma [Ca2+] by:
Inhibiting osteoclast activity (major effect)
Promoting Ca2+ deposition in the exchangeable (soluble) bone Ca2+salts
Calcitonin decreases formation of new osteoclasts
What are the three main types of bone cells and what do they do?
Osteoblasts
Promote the formation of bone
Are developed from mesodermally-derived cell
Have the PTH receptor
Recruit osteoclasts into bone resorption process
Maturate into osteocytes


Osteocytes
Are differentiated cells (“retired osteoblasts”)
Form “osteo-internet”: connected by gap- junction with other osteocytes, lining cells
Regulate ions, nutrients, cytokines, and metabolites (“wastes”) movement into/out of the canalicular fluid
Mobilize osteoblasts for bone repare


Osteoclasts
Promote the resorption of bone
Are developed from bone marrow cells (monocyte/macrophages lineage)
Preosteoclasts and o-clasts have the RNK receptor
Describe the composition of bone
Organic Matrix:
90-95% collagen and 5-10% ground substance (proteoglycans) that are produced by osteoblasts
Salts:
Hydroxyapatite (crystalline salts), Mg, Na, K, etc
Cells:
Osteoblasts, Osteoclasts, Osteocytes
Why do hydroxyapatites not precipitate in normal tissues and plasma?

Are there any exceptions?
Precipitation is inhibited by pyrophosphate in all tissues of the body
The DO precipitate in bone
What two mechanisms is calcium exchanged between bone and ECF?

Describe each one of them
1. Rapid response: Bone fluid exchange with soluble bone salts
Soluble bone Ca2+ salts exchange between bone fluid and the ECF

Lacunae and canaliculi are filled with ECF that is in equilibrium with soluble bone salts within the bone matrix

2. Slow response: Bone remodeling
Ca2+ ions are mobilized from the crystalline (insoluble) Ca2+ salts by bone remodeling process
Bone remodeling process is a constant cycle of degradation and resynthesis involving osteoblasts, osteocytes, and osteoclasts
Normally bone resorption and synthesis processess are balanced in healthy mature bone
Bone mass varies with stages of life

The goal is to maintain normal plasma calcium levels
Describe the process of Bone Remodeling
1. Osteocytes detect structural weakness
- Osteocytes act as mechanosensors
2. Then, osteocytes send activating signals (cytokines) to lining cells or resting osteoblasts through fluid-filled canaliculi and syncytial processes
3. Osteoblasts recruit osteoclasts for bone resorption via paracrine cytokine signals
4. After a suitable amount of bone has been resorbed, another set of osteoblasts is recruited to fill in the resorption cavity with new strong bone. New osteoblasts synthesize and release osteoid at the site, forming a new soft not mineralized matrix. The new matrix is mineralized with calcium and phosphorous (precipitation). Active OSTEOBLASTS secretes enzymes alkaline phosphatase and osteocalcin. (An increased plasma level of alkaline phosphatase and osteocalcin indicates bone formation process)

5. The (~4%) osteoblasts differentiate into osteocytes within the new mineralized bone
How do osteoblasts recruite osteoclasts in the third step of bone remodeling?
Osteoblasts synthesize and release factors that induce osteoclast differentiation (by M-CSF) from the precursor cell and activation (by Receptor Activator of NF-kB Ligand; RANKL)
Osteoblasts also produce a factor (osteoprotegrin, OPG) that terminate RANKL effect
negative feedback control
Osteoclasts form villus-like projections forming a ruffled border adjacent to the bone
Osteoclasts release proteolytic enzymes and acids (citric, lactic) from villi into a cavity, called a resorption pit
Ca2+ can be transported from the resorption pit into the blood
Products of collagen degradation (i.e., hydroxyproline and hydroxylysine) are released into circulation and excreted in the urine
Osteoclasts then undergo apoptosis
Growth Hormone is essential for bone growth in children. What are the effects of GH on the intestine and kidney?
Increases Ca2+ absorption in the intestine
Increases renal phosphates reabsorption
What are the effects of TH on development and serum calcium levels?
THs are essential for the development, growth and maturation of the skeleton in infants and children
Low THs level causes delayed ossification of cartilaginous bone

Excess of TH increases bone resorption and increases the serum [Ca2+]
What are the results of chronically excessive Glucocorticoids?
When GCs are chronically present in excess this:
Decreases renal tubular calcium reabsorption
Decreases intestinal Ca absorption
Stimulates bone resorption and inhibits bone formation
What are the causes and effects of Tetany?
Hypocalcaemia (causes depolarization of somatic neurons) increases the excitability of nerves → more Ach released → more skeletal muscle contraction
Treatment: Calcium
What are the hormonal responses to hypocalcemia?
Rapid Response - Primarily via action of PTH:
- Inhibition of Ca2+ excretion from in the urine
- Stimulation of soluble bone salts mobilization
Slow Response
PTH activates calcitriol synthesis in the kidney
Cacitriol increases Ca2+ absorption from the GI tract
PTH stimulates bone resorption by osteoclasts
What are the results of primary hyperparathyroidism?
1° HYPERparathyroidism - ↑PTH, ↑Serum [Ca2+], ↑Alkaline phosphatase, ↓Serum [Pi]

Hypercalcemia
Muscle weakness, fatigue, bradycardia, constipation, nausea, CNS depression

Bone Effects
Net bone resorption, weakened bone, bone pain

Renal Effects
Kidney stones
What are the results of primary hypoparathyroidism?
1° HYPOparathyroidism - ↓PTH, ↓Serum [Ca2+], ↑Serum [Pi]

Hypocalcemia, mostly neuromuscular, TETANY
What are the causes, clinical features, and treatment of rickets?
Failure of osteoid to calcify (“soft” bones)
in a growing person - Rickets
Commonly caused by a deficiency in Vitamin D production and activation, availability in the diet, or action at target cells
in the adult - Osteomalacia
Serious deficiencies of vitamin D and calcium
In patients with chronic renal failure
Clinical Features
Bone weakness
Short stature
Bowed legs
Tetany
Treatment
Calcium and phosphate supplementation
Vitamin D supplementation
Describe Osteoporosis and list etiologies/risk factors?
Characterized by progressive loss of bone matrix
Most common of all metabolic bone diseases with immense morbidity and significant mortality
1.3 million fractures per year
Vertebral body, forearm, hip
Etiologies/Risk Factors
Gender
Aging
Race
Sex hormone deficiency
Hereditary
Lifestyle and habits
Nutrition