rania ahmed endocrine august 15,2012. objective calcium homeostasis pth structure and function ...
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RANIA AHMEDENDOCRINE
August 15 ,2012
Objective
Calcium homeostasis PTH structure and functionCaSR structure and actions Vitamin D metabolismCalcitonin
CALCIUM HOMEOSTASISSerum calcium concentrations are normally
maintained within the very narrow range that is required for the optimal activity of extracellular and intracellular processes.
Intracellular : secretion ,differentiation , proliferation , motility ,and
cell death.Extracellular: »hormones secretion »excitation-contraction »synaptic transmission »platelet aggregation and coagulation.
Calcium Metabolism40 % bound to plasma proteins , albumin10 % bound to small anions such as
phosphate and citrate 50% Ionized state
Concentration of ionized ca 1.25±0.07mmol/L,
It is the ionized ca that is regulated in extracellular fluid .
Calcium MetabolismBased on a balance between intestinal
absorption, bone mineralization and demineralization, and urinary filtration and reabsorption.
Major direct regulators: Dietary intake Parathyroid hormone (PTH) 1,25 (OH)2-cholecalciferol
Calcitonin.
PTH
EmbryologyThe parathyroid glands develop at 6 weeks.Superior parathyroid glands develop with the
thyroid gland from the fourth branchial pouch and are residing lateral and posterior to the upper pole of the thyroid at the level of the cricothyroid cartilage.
Inferior parathyroid glands descend with the thymus from the third branchial pouch and migrate to the level of the aortic arch or, rarely, fail to migrate, remaining in the high neck
parathyroid glands typically located posterolateral to the thyroid
Anatomy Number of glands: can vary from 4-6 They measure 6 x 4 x 2 mm in maximum diameter
and weigh 25 - 40 mg each. Arterial supply: inferior thyroid artery venous drainage: inferior, middle, superior thyroid
veins Adult parathyroid gland: 50% parenchyma 50% fat cell types: chief cells oxyphil cells Both types make Parathyroid hormone .
Parathyroid Hormone peptide hormonesecreted by chief cells half-life is only 10 minutes. Increased by: low serum calcium Decreased by: high serum calcium, low magnesium, High 1,25 dihydroxy vitamin D
Parathyroid Hormone PTH is synthesized in the parathyroid gland
as a precursor hormone,preproparathyroid hormone, which is cleaved first to proparathyroid hormone and then to the final 84-amino-acid PTH.
Secreted PTH has a half-life of 2 to 4 minutes.
In the liver, PTH is metabolized into the active N-terminal component and the relatively inactive C-terminal fraction
PTH ReceptorsPTH1R expressed in bone and kidney, and also
present in breast ,skin ,heart ,blood vessels and pancreas
PTH1R binds intact PTH and N-terminal residues.Activation of PTH1R activates multiple cellular
pathways and release intracellular calcium stores.
PTH2R expressed in the CNS,CVS ,GIT, lung and testes
PTH2R selectively binds PTH only.
C-PTHRs which present in bone with specificity to carboxyl-terminal region of PTH, PTH 7-84 and shown to possess hypocalcemic activity ,that is reserved by PTH1-34and PTH 1-84.
Action of PTH : CalciumPTH acts to increase the plasma Ca2+
concentration in three ways :1.It stimulates bone resorption, resulting in the
release of calcium phosphate.2.It enhances intestinal Ca2+ and phosphate
absorption by promoting the formation of calcitriol (1,25 dihydroxycholecalciferol)within the kidney.
3.It augments active renal Ca2+ reabsorption.
Regulation of PTH Secretion:Calcitriol & Ions• Calcitriol (1,25-OH-Vit D)
– Binds to the intracellular vitamin D receptor and inhibits PTH gene expression
– Inhibits parathyroid cell proliferation• Magnesium
– Maintains normal parathyroid secretory response– Hypomagnesemia impairs response to PTH and
its release hypocalcemia• Phosphate
– Hyperphosphatemia stimulates PTH secretion• Stimulates parathyroid growth
Effects of PTH on Bone• Increase bone turnover, osteoclastic bone
resorption and new bone formationIntermittent PTH administration has anabolic
activity on boneEnhanced mineralization, recruitment of
osteoblasts and reduction of apoptosisContinous administration/secretion results in
bone resorptionOsteoclast activation occurs secondarily to
osteoblast recruitment
Renal Actions of PTHStimulate Ca reabsorption Inhibits proximal and distal reabsorption
of phosphateStimulate Synthesis of 1,25-OH-Vitamin D
PTH homeostasis
Calcium-ion Sensing Receptor (CaSR)A G-protein coupled
receptorLocated on the cell
surfaces of parathyroid and renal tissues, Also in thyroidal C cells, brain cells & GI tract
Mediates the effects of Ca on target tissues & acts as a first-messenger
Calcium sensing receptorsAllows the parathyroid gland to detect
changes in Ca concentrationActions aim to normalize serum calcium
concentrationDecrease in serum Ca concentration is a
potent stimulus for PTH release
Effects of CaSR on PTHIn hypercalcemia, CaSR acts to:
Increase intracellular calciumDecrease PTH productionDecrease PTH secretionIncrease PTH degradation and promotes
urinary Ca2+ excretionIn chronic hypocalcemia, CaSR affects:
PTH gene expression Parathyroid cell proliferation
Renal Effects of CaSRCaSR expressed heavily in the thick
ascending limb of the Loop of Henle.CaSR also expressed in the
collecting duct.
– Located on the basolateral aspect of cells– Elevated serum Ca inhibits reabsorption of filtered Ca, Mg and NaCl
– Located on the apical aspect of cells– Inhibits ADH action inhibits concentration of urine and results in isotonic polyuria
Disorders with generalized decrease in sensitivity to Ca2+ (affecting all CaSR-expressing tissue)
1. Familial hypocalciuric hypercalcemia (FHH)
2. Neonatal (NHPT) and neonatal severe hyperparathyroidism (SHPT)
3. Familial isolated hyperparathyroidism caused by CaSR mutations
4. Autoimmune hypocalciuric hypercalcemia
Disorders with parathyroid-specific decrease in sensitivity to Ca2+
1. Primary hyperparathyroidism
2. Severe uremic secondary and tertiary hyperparathyroidism
Disorders with generalized increase in sensitivity to Ca2+
1. Autosomal dominant hypoparathyroidism (ADH) due to activating CaSR mutations
2. ADH with features of Bartter's syndrome
3. Hypoparathyroidism due to activating antibodies to the CaSR
Disorders of extracellular calcium-sensing by the calcium-sensing receptor (CaSR)
Inactivating Mutations of CaSR: Familial Hypocalciuric HypercalcemiaAutosomal dominant condition resulting in partial
CaSR function lossAbout 200 mutations have been identifiedMutated CaSR less sensitive to Ca therefore
higher concentrations required to decrease PTH release from parathyroid glands
In the kidney, defect results in increased tubular Ca and Mg reabsorption
Net result is hypercalcemia, hypocalciuria, hypermagnesemia, inappropriately normal or high PTH
Activating Mutations of CaSR: Autosomal Dominant Hypocalcemia • Caused by activating mutation of CaSRCaSR more sensitive to serum calcium levels
therefore PTH release inhibited at lower serum Ca levels
In the kidneys, reabsorption of Ca inhibited at lower serum Ca levels
Net result is hypocalcemia, hypercalciuria and inappropriately low or normal PTH
Vitamin DLipid soluble compounds with a four-ringed
cholesterol backbone.SOURCES — Food and Sunlight. Ultraviolet light photoisomerize provitamin
D to vitamin D3 (cholecalciferol) in the skin from 7-dehydrocholesterol
Vitamin D transported in the blood principally bind to DBP (85%) and albumin (15%).
Vitamin DVitamin D2 is manufactured through the
ultraviolet irradiation of ergosterol, it has a lower affinity than 25-hydroxyvitamin D3 for vitamin D-binding protein. Thus, 25-hydroxyvitamin D2 has a shorter half-life than 25OHD3
Production of 1,25(OH)2D in the kidney stimulated by PTH and IGF-1 and inhibited by FGF23 and high levels of calcium and phosphate.
VIT D Action 1,25-dihydroxyvitamin D binds to intracellular receptors
VDR in target tissues and regulates gene transcription Its most important biological action is to promote
enterocyte differentiation and the intestinal absorption of calcium.
Stimulation of intestinal phosphate absorption, direct suppression of PTH release, regulation of osteoblast function, and allowing PTH-induced osteoclast activation and bone resorption
Production of 1,25(OH)2D in the kidney stimulated by PTH and IGF-1 and inhibited by FGF23 and high levels of calcium and phosphate
Action in Intestine1,25 (OH)2D enhance the efficacy of small
intestine to absorb calcium and phosphorus. Both vitamin D and VDR are required for
optimal absorption of calcium. Vitamin D induce active cellular calcium uptake
and transport mechanisms.Calcium uptake is the rate limiting step in
intestinal calcium absorption, which is highly dependent on vitD.
Vitamin D increase active phosphorus transport.
Action in BoneVitamin D is essential for the development &
maintenance of mineralized skeleton.Osteoblastic bone formation and osteoclastic
bone resorption demand both vitamin D and VDR.1,25(OH)2D VDR system is critical in PTH
induced osteoclastogenesis.1,25(OH)2D VDR increased the expression of
RANKL on the surface of osteoblast ,RANK interaction with its receptor RANKL promotes maturation of osteoclast progenitor cell & mature osteoclast.
Vitamin D ,PTH and prostaglandin stimulate RANKL expression.
Action in KidneyThe kidney expresses VDR, and 1,25 (OH)2D
stimulate Ca²-ATPase in distal tubule as well as 24,25(OH)2D production in the proximal tubule.
1,25 dihydroxyvitamin D decrease its own synthesis through negative feedback and decrease secretion and synthesis of PTH.
1,25 dihydroxyvitamin D increase expression of 25-hydroxyvitamin D-24-hydroxylase to catabolize 1,25(OH)2D to the water-soluble ,biological inactive calcitroic acid .
Denosumab in postmenopausal women with osteoporosisHuman monoclonal antibody to RANK ligand
[RANK-L]) Approved for the treatment of
postmenopausal osteoporosis in June 2010, and is highly effective in reducing the risk of vertebral, nonvertebral, and hip fracture risk.
Mechanism of actionDenosumab binds to osteoblast-produced
RANK-L, thereby preventing RANK-L from binding to the osteoclast receptor, RANK. By preventing RANK-L from binding to RANK, there is less osteoclast differentiation and activity so that bone resorption decreases.
Denosumab'FREEDOM' 5-year data indicates continued
safety and efficacy, and will be extended. Denosumab offers a highly effective and safe
parenteral therapy for osteoporosis and is being studied long term with the extension of the FREEDOM trial, and in other osteoporotic states - in men and glucocorticoid-induced osteoporosis.
Dose of 60 mg by subcutaneous injection every 6 months.
The results of the pivotal registration fracture trial with denosumab versus placebo (‘FREEDOM’). Over 3 years denosumab (60 mg as a subcutaneous injection every 6 months) significantly reduced the incidence of vertebral, nonvertebral and hip fractures compared with placebo [Cummings et al. 2009].
Composite measurement excluding pathological fractures and those associated with severe trauma, fractures of vertebrae, skull, face mandible, metacarpals, fingers and toes.
CAlCITONINCalcitonin is a 32-amino-acid peptide
Calcitonin secreted by parafollicular C cells of the thyroid.
Secretion of calcitonin is under the control of ionized ca.
CaSR expressed on C cell of thyroid ,high extracellular calcium increase secretion of calcitonin.
Hypocalcaemia inhibit calcitonin secretion.
Action of CALCITONIN
Osteoclast and proximal renal tubule cells express calcitonin receptors.
In the bone calcitonin inhibit osteoclastic bone resorption.
In the kidney calcitonin inhibits the reabsorption of PO4 and increase renal excretion of calcium.
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