Ex. 4 L5 Ca+ Homeostasis (39) Flashcards
What cells are responsible for incorporating Ca2+ into bone
Osteoblasts
(osteoblasts - build bone
Osteoclasts - tear down bone
Osteocytes - direct)
99% of calcium in the body is
In the bones and teeth
-Other 1% is in extracellular fluid and cellular cytoplasm
Calcium is an important
signaling molecule
Most of the calcium in cells is stored in
ER or mitochondria - very small amount of calcium is free within cell cytoplasm
-Low free calcium because calcium is a 2nd messenger
detriments of calcium are based on
Total calcium
Diffusible calcium
Total calcium
All of it - ionized, complexed, protein bound
(about 2x diffusible)
Diffusible calcium
Ionized and complexed only
Calcium in bone is a crystalline form:
Hydroxyapatite [Ca10(PO4)6(OH)2]
-Inorganic
-Makes rigid structure of bone
-Can be accessed by osteoclastic activity to bring calcium and phosphate out of bone and into EC fluids
(^Role of osteoclasts^)
Bone remodeling
Moving Ca2+ and Phosphorus in and out of bone:
-A continuous balance
Osteoblasts - Bone FORMING cells
-Incorporate Ca2+ and PO4 from plasma into bone
Osteoclasts - Bone resorption cells
-Release Ca2+ and PO4 from bone into plasma
Osteoporosis cause
Imbalance of osteoblasts and osteoclasts
Osteoclasts outnumber osteoblasts = continue to take minerals aways from bone = wears bone away
Osteocytes: Canaliculi
Extend filaments of actin - touch each other to reach out to other osteocytes
-Allows osteocytes to sense load/pressure on bone
Do not just touch each other - also have gap junction Connections to communicate electrically with each other
-Allow ion flux
Osteocytes release _ when they sense load/pressure
(BMD Increase)
-Osteonectin
-Nitric oxide
-dentin matrix protein 1
(Positive osteoblastic activity; increase in bone mineral density)
Osteocytes release _ when they do not sense load/pressure
(BMD Decrease)
-Sclerostin
-DKK-1
-RANKL
(Lead to net decrease in bone density; these factors can be upregulated, particularly in women going through menopause because they are being suppressed by estrogen)
PTH - parathyroid hormone
Peptide hormone (84 aa) secreted from the parathyroid gland
Cleaved from a 155aa precursor
aa 1-34 have full activity
deletion aa 1&2 eliminates activity
-PTH glands - 4 bean shaped things in back of throat
What does PTH do?
Increases Ca2+ in extracellular fluid
Increased Ca2+ reabsorption from collecting tubules (ECaC1/TRPV5)
Increased Ca2+ resorption from bone (Increase osteoclast # and activity)
Increased PO4 loss in urine
-Suppresses transporters that reabsorb phosphate
Increased 1,25 (OH)2 D3 production by kidney
PTH secretion triggered by ;ow serum Ca++ levels, GPCR that binds Ca2+ CSR (Calcium sensing receptor)
Calcium levels and PTH secretion
Low calcium - permits PTH secretion
Elevated calcium - will cause binding of calcium to GPCR of CSR = shut down PTH secretion
Important interaction between PTH and Vitamin D
Cholecalciferol (Vitamin D3) can be obtained in the diet via exposure to sun light
-Also in milk
-very important in upregulating the ability of the intestine to absorb calcium
Vitamin D synthesis steps
1). Conversion of 7-dehyrocholesterol (Provitamin D) into Cholecalciferol (Vitamin D3) via UV radiation of skin
2) Vitamin D3 converted by Vit D 25-hydroxylase to turn into 25 hydroxyvitamin D3 in the liver
3) 25 hydroxyvitamin D3 transported to kidney via 2 paths - Hydroxylation with 1a-hydroxylase, (produces 1,25 dihydroxy Vit.D3 calcitriol under PTH control) or Hydroxylation with 24-hydroxylase (produces 24,25 dihydroxy vit. D3 secalciferol)) (secondary option, don’t know what it does)
Actions of Vitamin D
1). Increased Ca2+ and PO43- absorption from small intestine
-a direct (rapid) effect on brush border of intestinal mucosal cells (ECaC2/TrpV6)
2). Increases Ca2+ and PO43- reabsorption
3). Indirect (slow) effects on cells
-Calbindins, vitamin D binding protein
4). Feedback inhibition of PTH
1,25(OH)2D3
Absorption of Ca2+ from the intestine
Within enterocyte, rapid insertion of TRPV6 channels into the brush border cells
-Upregulation of proteins:
Calbindin-D9K
TrpV6
Ca2+ -ATPase
-Work to move calcium from the lumen of the intestine into the enterocyte, and then out of the enterocyte and eventually into the _
-Cell will spend a lot of energy to maintain low free calcium levels
Role of Calbindin B9K
Will bind the calcium that comes in through TrpV6 channels and present it to the calcium ATPase to pump it out of the enterocyte and eventually into the bloodstream
Fibroblast Growth Factor 23
32 kDa protein
Secreted by osteocytes and osteoblasts in response to elevated serum phosphate
Stimulates phosphate excretion
Inhibits PTH secretion
Inhibits 1,25(OH)2D3 synthesis
Auto/paracrine effect on osteocytes inhibits bone mineralization
High levels of FGF23 correlate with poor prognosis in patients with CKD on dialysis
-Diagnostic marker
-Protease-resistant mutant of FGF23
-Causes autosomal dominant Hypophosphatemic rickets
Regulation of PTH secretion: 1,25,-(OH)2 Vit D3-
Inhibits PTH secretion
Regulation of PTH secretion: FGF23-
Inhibits PTH secretion
Regulation of PTH secretion: Low Ca2+
Stimulates PTH secretion
Regulation of PTH secretion: High Ca2+
Inhibits PTH secretion
Calcitonin
Secreted by C-cells in thyroid gland- 32 aa peptide
a Negative regulator of serum (extracellular) Ca2+
Calcitonin functions:
-Inhibits Osteoclastic bone resorption
-Increases Ca2+ and PO4 loss in urine (less is reabsorbed)
-Stimulated by high serum calcium levels
Paget’s disease:
Uncontrolled osteoclastic bone resorption and secondary bone formation (2° formation is poorly organized)
Paget’s disease characteristics
1.Bone pain
2. Bone deformities
3. Loss of hearing, hypercalcemia
4. May be caused by a slowly acting virus
Progression of Paget’s in the humerus
-
Oateoporosis: Postmenopausal
Decrease in estrogen levels causes a decreased bone mass
Shift in bone remodeling balance toward resorption (More osteoclasts)
Spontaneous or minimal trauma fractures (Hip, vertebrae, ribs)
Osteoporosis: Aging
Caused by: age related decrease in osteoblast activity in both men and women
Osteoporosis: Background
Systemic skeletal disease characterized by low bone mass and microarchitectural deterioration, with a consequent increase in bone fragility with susceptibility to fracture
Vertebral complications of osteoporosis
-Fragility fracture
-Pain
-Height loss
Kyphosis (Exaggerated, forward rounding of the upper back)
-Activity limitations
-Restrictive lung disease
-Psychological symtpoms
Postmenopausal acceleration of bone Loss
Peak bone mass - age ~20 years
Menopause hits at 50 - see decrease
Fracture threshold -RELISTEN
Risk factors for osteoporosis:
-Physical inactivity
-age
-Low Ca2+ intake in early years
-Long term glucocorticoid therapy
Hypercalcemia: Two parts
Hyperparathyroidism
Malignant tumors
Hyperparathyroidism
Increased bone resorption and decreased Ca2+ excretion
Malignant tumors
Some produce a peptide with PTH activity
(Causes CNS symptoms - depression, coma)
Hypocalcemia:
- Hypoparathyroidism
- Vit. D deficiencies
-Causes neuromuscular disturbances paresthesias, tetany, muscle cramps
Vit. D deficiency - Rickets
Weight bearing bone deformities in children
hypocalcemia - adults
Vitamin D: preparations
Cholecalciferol Vit D3 (OTC)
Calci(fe)diol 25 (OH) Vit D3 (Calderool)
Calcitriol 1,35(OH)2 Vit D3 (Rocaltrol)
Ergocalciferol (Vitamin D2) isolated from UV irradiated yeast
Vitamin D mechanism of action
Increased Ca++ and PO4 absorption from gut
Increased Ca++ and PO4 reabsorption in renal tubules
