Lecture 8 (75) : Parathyroid

Question 1

State the general functions of Calcium. (8)

What range is it tightly regulated in?

mM and mg/dL

Answer 1

1. Most abundant cation

2.Tightly regulated range in plasma (2.2 - 2.6 mM)
(or 8.8 - 10.3 mg/dL)

3. Membrane stability and cell function
4. Neuronal transmission
5. Bone structure/formation
6. Blood coagulation
7. Muscle function
8. Hormone secretion

Question 2

State the general functions of Phosphate. (8)

What range is it typically found it?
mM and mg/dL

Answer 2

1. Cellular energy metabolism (ATP)
2. Intracellular signaling pathways
3. Nucleic acid backbone
4. Bone structure
5. Enzyme activation/deactivation
6. 8 1.45 mM or 2.4 - 4.1 mg/dL

Question 3

What is the main affect of HYPERPHOSPHATEMIA?

Answer 3

Hyperphosphatemia:
- result of severe tissue injury “crush”

-10-fold more Pi than Ca2+ in soft tissue

Question 4

Most calcium is free or protein bound?

Most phosphate?

What is a good indicator of free calcium availability?

Answer 4

both are FREE

2. Calcium bound to albumin -

albumin levels good indicator of free calcium availability

Question 5

What are the 4 main affects of HYPOCALCEMIA?

HYPERCALCEMIA?(4)

Answer 5

Hypocalcemia:

1. muscle failure
2. tetany
3. convulsions
4. death

tetany = depolarization threshold is lower = EASIER TO DEPOLARIZE when less calcium in Extracellular space

Hypercalcemia:

1. renal dysfunction
2. calcification of soft tissues
3. muscle weakness
4. coma

• RENAL dysfunction
• kidney overwhelmed and cannot filter the calcium deposits in the soft tissues!!

Question 6

What are the 2 primary regulators of Calcium?

What is the 3rd, but potentially not important for humans?

Answer 6

Two primary regulators of calcium :

1. Parathyroid hormone (PTH)
2. Vitamin D = Calcitriol (skin,diet)
3. Calcitonin (thyroid) *potentially not important

Question 7

What are the 2 primary cell types in the Parathyroid Gland?
(what is their function)

Where is it located?

Answer 7

1. Chief Cells (also called Principal cells) – synthesize PTH
2. Oxyphil Cells – no known function, increase with age and chronic kidney disease
   - Paired glands (4 total) located at posterior borders on lateral lobes of thyroid gland (usually embedded in capsule)

Question 8

What directs processing to the ER?

______ is highly homologous to PTH 1-34 AA.

What is the only active portion of PTH?

Answer 8

1. Signal Peptide
2. PTHrP is highly homologous
3. Only N terminal 1-34 is ACTIVE - binds to PTH receptor

Question 9

What fragment of PTH has a longer half life?

What portion is clinically important with a half life of 4 min?

Answer 9

C-terminal fragment 35-84 has longer half-life than other fragments – inactive

Intact 1-84 fragment: half-life of 4 min. Clinically important measurement
- need full PTH to measure how much PTH is in the blood

Question 10

_______Mimics action of PTH in bone and kidney.

Normally at very low concentrations; not a regulator of _____ .

Many tumors produce it (renal, bladder, lymphoma, head/neck) resulting in _____

Answer 10

1. PTH rP
2. plasma Ca2+
3. hypercalcemia.

Question 11

Are PTH and PTHrP structurally similar?

What are they similar in?

Answer 11

NO

Equal binding to PTH–> activate the same receptor equally well

Question 12

What is the primary PTh receptor?

Where is it located? (2)

What type of receptor? (2 subdivisions)

Which fragment of PTh does it bind?

Does it bind both PTH and PTHrp?

Answer 12

1. PTH 1R – primary receptor
2. Located in osteoblasts and kidney (bone & kidney - where PTH acts)
3. G-protein coupled receptor
   a) Gαs —- adenylyl cyclase/cAMP pathway
   b) Gαq —- PLC/IP3/DAG
4. Binds 1-34 fragment, 1-84, PTHrP
5. binds both PTH & PTHrP

Question 13

What is the role of PTH 2R?

Answer 13

physiological importance in humans unclear

Binds 1-34

Does not bind PTHrP

• BUT can be a therapeutic target

Question 14

What are the net affects of PTH?

Answer 14

1. Increase plasma Ca2+

2. Decrease plasma Pi

Question 15

Osteoblasts:

1. What is their function?
2. High expression of _____
3. Derived from what type of stem cells?

Answer 15

1. Bone formation and mineralization

• extrude calcium & phosphate from inside bone where they are stored into EXTRACELLULAR space
• nucleation = hardening bone

2. High expression of PTH receptors
3. Derived from mesenchymal stem cells

Question 16

Osteoclasts:

1. Function
2. Derived from?
3. Express/do not express PTH receptors?

Osteocytes:

1. Function
2. Terminally differentiated from____.

Answer 16

Osteoclasts:
1. Bone reabsorption

2. Derived from hematopoietic stem cells
3. Do not express PTH receptors

Osteocytes:
1. Make up most of the bone matrix

2. Terminally differentiated from osteoblasts

Question 17

PTH stimulates _____ in osteoblasts which stimulates the differential of osteoclast precursors.

PTH stimulation of osteoclasts is direct or indirect?

PTH also stimulates _____ which leads to the maturation of osteoclast & bone reabsorption.

Answer 17

1. M - CSF

(Macrophage colony stimulating factor)

2. INDIRECT
3. RANK ligand
   - Bone degradation releases Ca2+ and Pi to systemic circulation

Question 18

Osteoblasts export Ca2+ and Pi where and for what purpose?

It is the major factor maintaining what?

Answer 18

1. into extracellular space for bone mineralization

2. Major factor in maintaining plasma calcium homeostasis.

Question 19

What is the antagonist of RANK ligand?

What stimulate and what inhibits it?

How is this related to osteoporosis and stress?

Answer 19

Osteoprotegerin (OPG) antagonist of RANK ligand.

Estrogens stimulate and Cortisol inhibits OPG

-pre-menopausal protected from osteoporosis due to HIGH ESTROGEN
post = excessive RANK stimulation of RANK ligand!!!

• stress = more cortisol released –> increased bone resorption

Question 20

What is the function of PTH in the kidney?

What gene does it stimulate?

Which enzyme does it encode and what does this convert?

It also stimulates _____ insertion onto apiece membrane of what part of the nephron?

Answer 20

Stimulates CYP1α –

encodes 1α-hydroxylase which converts active form of Vitamin D

Stimulates Ca2+ channel insertion in apical membrane of DISTAL tubule (Thick ASCENDING LIMB)

• phosphate reabsorption is mostly blocked at Proximal Tubule

Question 21

What is the primary regulator of PTH?

Answer 21

Plasma calcium concentration!!!!

Question 22

PTH REGULATION:

Where are Calcium - Sensing Receptors (CaSR) located? (3)

What do they bind?

What do they inhibit?

What do they degrade?

Answer 22

1. Located in
   - chief cells
   - kidney tubules
   - C cells (of thyroid)
2. Binds ionized (free) Ca2+
3. Inhibits PTH synthesis at promoter level

Stimulates degradation of preformed PTH

Question 23

Vitamin D binds ____.

What is its DIRECT affect on PTH?

INDIRECT affect?

Answer 23

Binds nuclear receptor - VDR

1. DIRECT: Inhibits PTH synthesis at PROMOTER level (like CaSR)
2. INDIRECT: Stimulates CaSR gene transcription

Question 24

State the calcium type responsible for the following functions:

1. Vitamin D2 – dietary from vegetables - NOT FROM CHOLESTEROL
2. general term for vitamin D and other natural structural analogs.
3. 1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxy-cholecalciferol (this is the active form)
4. specifically refers to vitamin D3 (from animal tissues). - derived from cholesterol
5. 25-hydroxy-vitamin D (25-D) = 25-hydroxy-cholecalciferol (immediate precursor)

Answer 24

1. Ergocaliferol
2. Calciferol
3. *Calcitriol = calcifitriol
4. Cholecaciferol
5. Calcidiol = calcifidiol
   - BINDS RECEPTOR + high abundance compared to active form - plays a role in mediating calcium homeostasis

Question 25

Vitamin D synthesis: 1. Derived from? 2. What type of receptor? 3 Active form? 4. Bound in plasma or not? If yes, to what?

Answer 25

1. Derived from cholesterol – steroid hormone 2. Nuclear Receptor = VDR 3. Active form = 1,25-dihydroxycholecalciferol 4. Bound in plasma to vitamin D-binding protein

Question 26

How is Vitamin D transported to the LIVER? (2 ways) What happens in the liver? Where is it converted to the active form? What enzyme does it require for this?

Answer 26

1. Chylomicrons via lymphatics 2. Portal Vein - in the liver it is converted to 25-OH- D3 by 25-Hydroxylase 3. KIDNEY --> by 1 alpha-hydroxylase

Question 27

What is Vitamin D said to have pleotropic effects?

Answer 27

Deficiency linked to: 1. Multiple Sclerosis 2. Asthma 3. Cardiovascular disease 4. Type II Diabetes mellitus 5. Colorectal/breast cancer

Question 28

What are the 3 targets of Vitamin D?

Answer 28

3 targets: Bone Gut Kidney

Question 29

What are the DIRECT affects of Vitamin D on bone? INDIRECT?

Answer 29

1. Direct: Mobilize Ca2+ from bone Osteoblasts and osteoclasts have VDRs Vitamin D stimulates osteoclast proliferation/differentiation (NEW bone formation) 2. Indirect: Increases plasma Ca2+ which promotes bone mineralization - primary role is BONE FORMATION by braking down OLD bone to make NEW bone

Question 30

What are the DIRECT affects of Vitamin D on INTESTINE? 3 for Calcium & 1 affect for Phosphate

Answer 30

1. Increases transcellular Ca2+ absorption in duodenum - by increasing TRYP5 channels - increasing cal binding - increasing Ca-ATPase 2. Stimulates Pi reabsorption from small intestine

Question 31

Describe the process of Calcium Homeostasis.

Answer 31

1. Low blood calcium sensed: 2. increase PTH (CaSR in chief cells) 3. Long term: stimulate CYPa to convert inactive to active Vitamin D 4. Short turn: increase bone turnover by osteoclast 5. increase calcium reabsorption and phosphate excretion of kidney (fast) 6. NEGATIVE FEEDBACK on PTH a) shut off the promoter b) more CaSR (sensing receptors)

Question 32

Clinical Disorders: HYPERPARATHYROIDISM: 1. Primary problem 1b. Secondary 2. Causes 3. How is it related to Vitamin D?

Answer 32

Primary: hyperplasia, carcinoma of parathyroid gland Hypercalcemia, kidney stones 1b. Secondary: - due to chronic renal failure (no Vitamin D activated = too much PTH synthesis since vitamin D not inhibiting) Reduced Vitamin D leads to excess PTH synthesis

Question 33

Clinical Disorders: Osteoporosis: 1. Main problem 2. Causes 3. Treatment

Answer 33

1. Reduced bone density – mainly trabecular bone*** 2. Causes: genetic, menopause (low estrogen – loss of OPG), - glucocorticoid therapy/chronic stress, - low dietary Ca2+ 3. Treatment: - estrogens - calcitonin - biphosphonates (inhibit bone resorption) - Vitamin D

Question 34

Clinical Disorders: HYPOPARATHYROIDISM: 1. Main problem 2. What is a symptom? What is this called? Rickets (children)/Osteomalacia (adults) 1. Main problem 2. Symptoms (2)

Answer 34

1. Hypocalcemic tetany (reducing threshold for depolarization) 2. Chvostek sign: twitching of facial muscles in response to tapping of facial nerve 1. Unmineralized bone due to Vitamin D deficiency 2. “bowing” of long bones (children) & Decreased bone strength

Question 35

Clinical Disorders: Pseudohypoparathyroidism Congenital defect where? Generalized resistance to what? (4) Clinical signs? (4)

Answer 35

1. G protein that associates with PTHR1 2. PTH, TSH, LH, and FSH ``` 3. Clinical signs: low Ca++, high phosphate, elevated PTH short stature ``` ** no issue with thyroid gland itself**

Question 36

Tubular reabsorption of phosphate (TRP) _____ as phosphate excretion increases. Urinary hydroxyproline shows what?

Answer 36

DECREASES enhanced bone resorption

Question 37

Calcitonin: 32 -amino acid peptide produced in the ______ of what gland? possible function? Why is the normal physiological importance unclear?

Answer 37

1. C-cells of thyroid gland. 2. Inhibits calcium reabsorption in bone? ``` 3. Complete thyroidectomy (with parathyroids left intact) does not alter NORMAL physiological range of Ca2+. ``` 2. C-cell tumors – extremely high calcitonin – does not affect Ca2+ levels.

Question 38

What is the therapeutic use of Calcitonin? What is the net affect? What is it used to treat?

Answer 38

1. inhibits osteoclast reabsorption of and slows bone turnover 2. net effect: hypocalcemic action 3. Used to treat Paget disease: (one part of bone resorped too quickly)

Question 39

What is Paget Disease?

Answer 39

excessive localized regions of bone resorption and reactive sclerosis. Very high bone turnover Cause is unknown.

Question 40

What is the ESCAPE phenomenon in regards to Calcitonin treatment?

Answer 40

“Escape” phenomenon – rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours making this a less effective treatment option. - receptors for CALCITONIN downregulate = NOT A LONG TERM FORM OF TREATMENT (have to stop and start)