Hormonal Regulation of Calcium Metabolism Flashcards
1
Q
Extracellular Calcium Pools
A
- Three fractions of extracellular calcium exists which are in dynamic equilibrium
- Ionized free calcium - 50%
- Bound to proteins - 40%
- In complexes with anions such as citrate and phosphate - 10%
- Distribution affected by various factors:
- Changes in blood pH
- Alkaline blood pH favors more protein bound calcium
- Acidic blood pH does the opposite
- Concentrations of citrate and phosphate
- Changes in blood pH
2
Q
Calcium
Concentration Gradient
A
- Extracellular [Ca2+] ~ 2.3-2.6 mM and intracellular [Ca2+] ~ 100 nM which is a 20,000x difference.
- Extracellular calcium is close to its saturation point so any increase can lead to precipitation.
- Allows for a rapid flow into cell when Ca2+ channels open.
- High intracellular [Ca2+] is toxic
- Cells use pumps and exchangers to move calcium out
- Some stored in ER and mitochondria
3
Q
Calcium Homeostasis
A
Significant fluctuations in [Ca2+] detrimental for the body.
To maintain constant [Ca2+] daily absorption and excretion must be equivalent.
- GI tract absorbs 50% of dietary calcium via Vit D regulated mechanism
- Remainder lost in stool
- GI absorption balanced by equal [Ca2+] loss from urinary tract
- Skeleton stores 98% of body’s total Ca2+ in combination with phosphate as hydroxyapatite crystals
- Skeletal/GI Ca2+ in dynamic balance with ECF which contains ~ 0.9 g of calcium
- Ca2+ exchange between ECF and skeleton is a net zero in young adult
- More calcium enters skeleton in childhood
- More calcium levels skeleton in old age
- Skeleton can mobilize Ca2+ into ECF to prevent hypocalcemia for months to years.
- May produce deleterious long-term effects
- PTH raises [Ca2+] short-term
- Vit D raises [Ca2+] long-term
4
Q
Phosphate Equilibrium
A
- Phosphorus and calcium form hydroxyapatite crystals present in mineralized bone
- 85% of the 600g phosphorus in an adult stored in skeleton
- ECF phosphate [HPO22- and H2PO4-] between 2.8-4 mg/dL
- Close to saturation so excess may lead to formation of precipitates resulting in calcification
- Phosphorous pools in soft tissues and ECF in equilibrium with the bone
5
Q
Phosphorus Homeostasis
A
- Typically 1,400 mg/day of dietary phosphorus intake
- Majority (~1,300 mg) absorbed from GI tract mostly as inorganic phosphate.
- Resorption from bone ~ 200 mg/day
- 300 mg/day eliminated through feces
- Results in total uptake of 1,100 mg/day
- Control of phosphorus pools relies heavily on modulating kidney filtration and subsequent excretion mechanisms
- Influenced by parathyroid hormone
6
Q
Parathyroid Hormone
Synthesis & Metabolism
A
- Synthesized and secreted by chief cells of the 4 parathyroid glands
- First synthesized as a prepro-PTH
- Removal of signal sequence produces mature peptide hormone PTH
- PTH rapidly metabolized by the liver and kidney
- Has a half-life of 2-4 minutes
7
Q
Parathyroid Hormone
Secretion
A
-
Induction of PTH secretion
- Most important stimulating factor is reduction in circulating free [Ca2+]
- Magnesium acts similarly to calcium and inhibits release
- Lithium stimulates release
- Aluminum inhibits release
-
Mechanism
- Ca2+ binds to the Calcium Sensing Receptor (CASR) on the chief cell
- Family of GPCR’s
- Activation of the GPCR acts via IP3/DAG secondary messengers to inhibit PTH release
- So when [Ca2+] high less PTH released
- Ca2+ binds to the Calcium Sensing Receptor (CASR) on the chief cell
- Vit D exerts a negative feedback on PTH
- PTH stimulates the production of Vit D
- Vit D inhibits on the gene expression of PTH
- Avoids excessive production of PTH
8
Q
Effects of PTH
A
PTH increases plasma calcium levels via 3 direct mechanisms.
- Increased bone resorption
- Increasing renal reabsorption of calcium in the distal tubule of kidney
- Decreasing phosphate reabsorption in the kidney from the proximal and distal tubules
PTH also increases the synthesis of active Vit D.
9
Q
PTH Mechanism
A
- PTH functions through G-protein coupled receptors
- Increases in both cAMP and IP3 → increase in Ca2+ required for cellular signaling of PTH
10
Q
PTH-hormone Related Protein
(PTHrP)
A
- Shorter form of PTH released by tumor cells from certain cancers including renal and breast carcinomas
- Able to bind the PTH receptor and facilitate bone turnover
- Promotes skeletal dissemination of cancer clls
- Promotes adaption of the cancer cells to the bone microenvironment in metastasis
11
Q
Activity of PTH
On Bone
A
- PTH binds to its G-protein coupled receptors on osteoblasts.
- Osteoclasts do not have receptors for PTH.
- Stimulated osteoblasts produces cytokines including RANK-L and IL-6.
- These cytokines stimulate the maturation of osteoclasts leading to bone-resorption.
- Intermittent increases in PTH stimulates osteoblasts to produce bone matrix.
- Chronic elevations in PTH inhibits bone formation activity of osteoblasts.
Controlled production of PTH under normal physiological conditions will stimultaneously promote bone formation and resorption.
12
Q
Activity of PTH
On The Kidney
A
- PTH stimulates calcium reabsorption in the distal tubule.
- Leads to a much faster increase in [Ca2+}
- 90% of the Ca2+ recovered daily is collected from the proximal convoluted tubule but PTH does not regulate this process
- PTH decreases phosphate reabsorption in the proximal and distal tubules.
- Largely compensates for the increase in phosphate levels caused by bone resorption
- Prevents formation of hydroxyapatite crystals between calcium and phosphate
- PTH stimulates 25-hydroxyvitamin D-1α-hydroxylase which is found in the mitochondria of cells in the proximal tubule
- Enzyme converts Vit D to its most active metabolite.
13
Q
Synthesis of D Vitamins
A
- Pro-Vitamin D (7-dehydrocholesterol) is converted in the epidermis into Vit D3 (cholecalciferol) by UV light.
- 30-120 min/day sufficient.
- Vit D2 or D3 supplementation can also be given
- Both can undergo the same biosynthetic steps.
- Inactive Vit D3 circulates bound to binding proteins.
- Hydroxylated in the liver to 25-Hydroxycholecalciferol (25-(OH) D3) which can be stored in adipose and skeletal muscle.
- To become biologically active it needs to be further hydroxylated in the kidney by 25-(OH)- D-1α-Hydroxylase to form active Calcitriol (1,25(OH)2D3)
- Enzyme is stimulated by:
- PTH
- Estrogen
- Prolactin
- Growth Hormone
- Enzyme is stimulated by:
14
Q
Vit D Mechanism
A
- Vit D is a steroid hormone which utilizes a Type 2 intracellular intranuclear receptor.
- Vit D binds the Vitamin D receptor (VDR)
- Complex interacts with retinoic acid X receptor (RXR) to form a heterodimeric transcription factor.
- Enhances or suppresses specific genes by binding to Vitamin D response elements (VDREs)
15
Q
Vit D
Modulation of [Ca2+]
A
- Modulates calcium levels by three principal mechanisms:
- Increasing the intestinal absorption of dietary calcium and phosphate.
- Stimulating the maturation of osteoclast progenitor cells.
- Inhibiting the synthesis of PTH.
- Has a weak postive effect on the reabsorption of calcium and phosphate in the kidney.
16
Q
Vit D
Effects on the Intestine
A
- Increases the absorption of calcium in the duodenum from 10% to 70%.
- Causes direct opening of calcium channels present on the surface of intestinal cells
- Via stimulation of gene expression of calbindin
- Regulates the transport of calcium from the lumen, through the cell, and into the blood circulation
- Causes direct opening of calcium channels present on the surface of intestinal cells
17
Q
Vit D
Effects on Bone Metabolism
A
- Stimulates osteoblasts to produce cytokines which promote the maturation of osteoclasts’ progenitors
- Stimulates bone-degradation activity of mature osteoclasts
- Stimulates osteoblast’s synthesis of several proteins involved in bone matrix formation:
- Osteopontin
- Osteocalcin
Vit D responsible for maintaining a metabolically active and healthy skeleton.
18
Q
Vit D
Negative Feedback Mechanisms
A
- Vit D exerts negative feedback and inhibits expression of PTH
- Chief cells have VDREs present on the PTH gene which gets suppresed by the binding of Vit D to VDR.
- Increasing concentrations of Calcitriol (1,25-(OH)2D3) stimulates the activity of 25-(OH)-D-24-Hydroxylase and induces the biodegradation of Vit D via negative feedback of itself
19
Q
Summary of PTH Actions
A
20
Q
Summary of Vit D Actions
A
21
Q
Calcitonin
Synthesis and Regulation
A
- Peptide hormone produced by thyroid parafollicular C-cells
- Functions to reduce circulating levels of calcium and phosphate
- C-cells express the same calcium-sensing receptor as the parathyroid chief cells.
- Increase in [Ca2+] inhibits PTH secretion while stimulating calcitonin secretion.
22
Q
Actions of Calcitonin
A
- Functions to decrease circulating levels of calcium and phosphorus
- Directly inhibits bone resorption by osteoclasts
- Increases excretion of calcium and phosphate from the kidney
- Along with sodium, potassium, and magnesium
- Effects are commonly observed with exogenous calcitonin therapy such as for osteoporosis
- The physiological absence of calcitonin has no effects on calcium levels or bone metabolism.
23
Q
Osteoporosis
A
A reduction in the total bone mass affecting both mineral bone and organic matrix equally.
- Several causes:
- Long-term deficiency of dietary calcium
- Vit C deficiency
- Reduction in mechanical stress
- Advanced age (most common)
- Accelerated loss in bone calcium content observed in older females as compared to males.
- Attributed to the decline in estrogen that occurs after menopause
24
Q
Abnormal Plasma [Ca2+]
A
