Parathyroid Hormone, Calcitonin, and VItamin D Flashcards
What is cortical bone?
Compact bone that forms the cortex or outer shell of most bones
What is the medullary cavity?
Central cavity of bone shafts where red bone marrow and or yellow bone marrow
What is osteoid?
Provides sites for nucleation of hydroxyapatite crystals
What is the main protein in osteoid?
Type I collagen
What is the fundamental functional unit of compact bone?
Osteon or Haversion system
When it comes to metabolic function versus structural function of bone what has priority?
Metabolic to maintain homeostasis
What does absence of weight-bearing lead to?
Promotes demineralization of bone leading to increased plasma Ca2+ levels, decreased PTH, increased urinary Ca2+
What is the large bulge of osteoblastic tissue and new bone formation at the point of a break called?
Callus
What does alkalosis cause?
Decreases free Ca plasma levels
What does acidosis cause?
Increased free Ca plasma levels
How does alkalosis and acidosis affect calcium?
Be baring the amount bound to proteins
What are the forms of Ca2+ found in plasma?
Ionized Ca2+
Protein-bound Ca2+
Calcium complexed to anions
What does hypocalcaemia lead to?
Neuron depolarizing spontaneously that can lead to tetany and seizures
What does hypercalcemia cause?
Depresses the nerve and muscle activity,
Sluggish CNS and reflexes, Decreased QT
Lack of appetite
Constipation
When does bone deposition occur?
When [Ca2+] x [PO4-] > solubility product
When [Ca] is elevated what sensor is activated?
Calcium-sensing receptors (PT gland)
What are calcium-sensing receptors and what do they do?
G-protein (q) receptors that bind extracellular calcium; increased calcium binding to the receptors activates Gq (PIP2-> IP3 and DAG) the calcium released intracellularly will lead to calcium inhibiting fusion and release of PTH from vesicles
What effect does vitamin D have on PTH?
Inhibits PTH transcription
How does vitamin D mediate its effects on PTH?
Binds Vit-D-VDR to the VDR response element leading to decreased rate of PTH transcription
What cell in the PT gland releases PTH?
Chief cells
What is the stronger stimulus for calcium regulation in adults?
PTH not calcitonin
What causes familial hypercalcemic hypocalciuria?
Ca receptor in patients is mutated resulting in [Ca] being higher than normal
What occurs in FHH?
Calcium levels must be higher in the plasma before inhibiting PTH secretion resulting in normal PTH but elevated [Ca]
Mode of inheritance in FHH?
Autosomal dominant disorder
What drug is used for parathyroid cancer and hyperparathyroidism?
Calcimetrics
How does calcimetrics work?
It is a CaSR agonist mimicking Calcium
What is the key action of PTH?
Promote Ca reabsorption in TAL and DCT
Reduce reabsorption of PO4 in PCT and DCT
What inhibits osteoclast action?
Calcitonin
Estrogen
What is the PTH-1R coupled to?
Both Gs and Gaq receptors
Effect of PTH-1R Gaq when stimulated?
Reduces Pi absorption
Effect of Gs coupled with PTH-1R?
Secretion of M-CSF/RANK-L/IL-6 by osteoblasts
What does M-CSF (macrophage colony stimulating factor) cause?
Osteoclast precursors to proliferate and form mature multinucleated osteoclasts
What does RANK-L protein cause?
Stimulated pre-osteoclasts to become osteoclasts
What do glucocorticoids increase the production of in osteoblasts?
RANK-L
What proteins are needed for osteoclasts to attach to bone matrix?
Integrin on the membrane attach to vitronectin in bone matrix
What inhibits differentiation of osteoclast precursor into mature osteoclasts?
Osteoprotegrin
What is osteoprotegrin?
A decoy receptor for RANK-L
What is tartrate-resistant acid phosphatase (TRAP)?
Decreases osteoclast activity (mechanism not known) causing osteopetrosis (thick brittle bones)
Three main effects of PTH?
- ) Promotes Ca2+ reabsorption
- ) Inhibits PO43- reabsorption
- ) Promotes hydroxylation of 25-hydroxyviatmin D activating vitamin D
PTH half-life:
1-84 PTH rapidly cleared by kidneys
Smaller fragments have full activity and takes several hours
What does vitamin D directly cause on bone?
Bone demineralization (breakdown)
How does vitamin D indirectly cause deposition of bone?
It causes Ca/PO4 reabsorption from both smooth muscle and the kidney raising Ca/PO4 plasma levels and causing deposition in bones (deposition overshadows the bone demineralization by the direct affect of vitamin D)
What does Ca2+ and PO4 ingestion cause in PTH and Vit D respectively?
Ca: PTH and Vit D decrease
PO4: PTH and Vit D increase
What does increased phosphorus ingestion cause?
Lower Ca levels and increase Ca/PO4 ratio promoting bone mineralization
What cells secrete calcitonin?
C cells (parafollicular cells) in the thyroid
Cellular mechanism of calcitonin action?
Receptors on osteoclasts are coupled to both cAMP-PKA and Ca2+ PKC mediated signaling pathways
CT effect on osteoclasts?
Decreased activity decreasing bone reabsorption
What diseases is CT useful in treating?
Paget’s disease
Severe hypercalcemia
Osteoporosis
Four ways calcitonin lowers blood Ca2+ levels:
- ) Inhibits Ca2+ absorption in intestines
- ) Inhibits osteoclast activity
- ) Stimulates osteoblast activity
- ) Inhibits renal tubular reabsorption of Ca2+
CT half-life?
50-80 minutes; degraded in the kidneys
What is PTHrP?
PTH-related peptide (they don’t know anything about it really)
Where is PTHrP synthesized?
In normal and malignant tissues
What does PTHrP receptor in kidney and bone cause?
Produces the actions of PTH aka hypercalcemia
When is PTHrP released?
In lactating breast to promote mobilization of calcium from maternal bone during milk production
What causes rickets?
Vitamin D deficiency in children causing reduced rigidity of bones and bowing of long bones
What is osteomalacia?
Vitamin D deficiency in adults leading to brittle bones but not bowing of long bones
Why does bowing of long bones occur in rickets but not osteomalacia?
Because rickets is in children before closure of their growth plates where osteomalacia only occurs in adults after the closure of growth plates
What is osteoporosis?
Loss of bone mass and density
What is osteopetrosis?
Increase in bone mass and density
What causes osteopetrosis?
Malfunctioning in osteoclasts resulting in a deficiency in carbonic anhydrase encoded by the gene CA2 (needed for breakdown of bone)
What is Paget’s disease?
Excessive breakdown and formation of bone leading to disorganized bone remodeling
What bones does Paget’s disease affect?
Pelvis, femur, lumbar vertebrae
What is the first manifestation of Paget’s disease?
Elevated alkaline phosphatase in blood
What is seen in the facial bones of Paget’s disease?
Grossly over thickening and deformation
What is affected in FHH?
Mutation in Ca2+ receptor on PT chief cells
