CALCIUM HOMEOSTASIS
Bone, 3 hormones (PTH, Vitamin D and Calcitonin)
Calcium in the body
1.1– 1.3 kg of Ca++ in body
-99% = skeletal
-0.9% is intracellular
-0.1% is extracellular
Typical plasma concentration = 9-11mg/dL, 2.5mM
-50% bound to albumins (binding is pH dependent, acute alkalosis increases binding), globulins, phosphate and citrate
-50% free, biologically active
Intracellular concentration = 100nM
-Massive chemical transmembrane gradient
-Found mostly as protein complexes in membrane or ER
derived from dietary sources
Importance of calcium
-Calcium phosphate salts in bone provide structural integrity of the skeleton
-Ions in extrac and intrac fluids are essential for normal function of several biochemical processes e.g. neuromuscular excitability, blood coagulation, hormonal secretion, enzymatic regulation
e.g. Neuromuscular excitability
- Hypocalcemia
-Increased membrane Na+ permeability
-Nerves & muscles overexcitable
-Tetany – involuntary muscular spasms
-Larngospasms – airway constriction
- Hypercalcemia
-Decreased neuromuscular sensitivity
-Groans, constipation
-Bone pain
-Kidney stones
-Cardiac arrhythmias
Importance of phosphate
-Essential for normal function of several cellular processes e.g. signal transduction
-Important structural role in the cell e.g. DNA/RNA, membrane phospholipids, complex carbohydrates
Ca++ homeostasis – minute to minute monitoring/adjustment of plasma levels to maintain them within the normal range
Ca++ balance – long term, refers to relative rates of Ca++ bone deposition or resorption
Bone
Bone is an NB reservoir of Calcium storage (99% total body). In bone remodeling, about 10% of total adult bone turns over each year.
In growth, rate of bone resorption exceeds resorption and skeletal mass increases. Linear growth occurs at epiphyseal plates while width increases at periosteum.
At about 30 years, rate of absorption begins to exceed formation and bone mass slowly decreases.
Structure and cells:
Osteoblasts (bone formation) – differentiated bone forming cells which secrete bone matrix/collagen on Ca++ and phosphate precipitate
Osteocytes (bone maintenance) –osteoblasts/mature bone cells enclosed in matrix
Osteoclasts (bone resorption) – large multinucleated cell derived from monocytes
Osteogenic cells – immature bone stem cells that proliferate to give osteoblasts
Bone remodeling – resorption and formation
- Dynamic tissue
- Rates of resorption and formation normally in EQ
- Differential activity of osteoblasts/clasts determine bone formation/loss
- These cells are targets for several endocrine and paracrine regulators of Ca++ homeostasis
Osteoblasts and their role in osteoclast development
- Produce 2 NB mediators for osteoclast development
- RANKL (receptor activator of NFκβligand)
-TNF cytokine family
-Binds to RANK on macrophages and promotes differentiation into osteoclasts and suppression of apoptosis
-Increased resorption
- Osteoprotegrin
-Inhibitor/decoy receptor for RANK
-Decreases resorption
mechanism of resorption:
- Osteocyticosteolysis (rapid exchange)
-Ca++ is moved from labile pool in bone fluid into plasma by PTH activated Ca++ pumps
-Pumps located in osteocytic-osteoblastic bone membrane (filmy intercytoplasmis projections of the 2 cells)
- Osteoclasticresorption (slow exchange)
-Ca++ moved from stable pool in mineralized bone into plasma via PTH induced dissolution of the bone by osteoclasts
Hormonal control of Ca++ by Calcitrophic Hormones
Ca++ resorption, reabsorption and absorption is regulated in bone, kidney and intestine by PTH, Vitamin D3 and calcitonin
Parathyroid Hormone
What is it? Calcitrophic hormone, peptide
Where is it made?
-Secreted by the parathyroid gland which lies posterior to the thyroid gland
-The chief/principal cells are Ca++ sensing
Synthesis
-Pre-prohormone in RER
-Cleavage of leader and pro-sequences in the golgi apparatus give biologically active peptide
-Proteolysis of PTH generates C terminal protein fragments that are inactive. This is NB for modulating amount of active PTH released
-Stored in secretory granule
Regulation of secretion
-Plasma free/ionized Ca++ is the main regulator
-Secretion is inversely related to Ca++ conc
-Max secretion when Ca++ is less than 3.5mg/dL
-Other regulators = catelcholamines, Mg++
Parathyroid calcium sensing receptor
-G protein coupled receptor on chief cells
-Gqα – increases IP3 (phospholipase C)
-Giα– decreases cAMP
-If ECF concentration increases, cAMP decreases and IP3 increases, PTH secretion decreases
Targets & Physiological role?
-To increase plasma Ca++ levels (& moderately decrease plasma phosphate)
-It acts directly on bones to increase resorption (2 mechanisms above)
-On the kidney to increase Ca++ reabsorption and phosphate excretion
-Indirectly on intestine by stimulating 1,25-(OH)2-D synthesis
-Ca++ feedback loop suppresses PTH
Association with any diseases?
-Inactivating mutations…hypocalciurichypercalcemia
-Activating mutations…hypoparathyroidism/hypercalcuria/hypocalcemia
Vitamin D (Cholecalciferol):
What is it? Not a classic hormone as it is not produced and secreted by an endocrine gland. But it is a true hormone because it has an endocrine mode of action of distant target via binding to high affinity receptors.
Where is it made?
- derived from photodependent production in keratinocytes
- ingested in the diet
skin: 7-dehydrocholesterol converted to Vitamin D3
liver: Vit D3 hydroxylated by P450C25 to 25(OH)D3/calcidiol
kidney: 2nd hydroxylation reaction catalysed by 1α hydroxylase to produce calcitriol/1,25(OH)2D3
1α hydroxylase activity is regulated via feedback inhibition, PTH, hypophosphatemia and prolactin
target tissue?intestine, bone, parathyroid, immune cells and some remains in kidney
Physiological role?
- Promotes intestinal calcium absorption
Approximately 200mg of Ca++ is absorbed per day. The major site for absorption is the duodenum.
Vesicular, transcellular and paracellular transport are all Vit D dependent
-Facilitated/active transport of Ca++ into enterocyte
-bound by a Vit D inducing high affinity Ca++ binding protein called calbidin
-some Ca++ is stored in cell organelles while some is pumped out of cell by ATP dependent pump thus increasing Ca++ in the ECF
- Actions on Bones
-Osteoblasts have Vitamin D receptors
-Stimulates release of RANKL from osteoblasts enhancing osteoclast differentiation and proliferation
-Increases resorption
Diseases?
Vitamin D deficiency causes rickets
Familial Vitamin D deficiency caused by mutation in vitamin D receptor
Calcitonin
What is it? Belongs to evolutionary conserved family of hormones that includes isletamyloid precursor protein, calcitonin gene related peptide, adrenomedullin
Where is it made?
- Produced in thyroid C cells (parafollicular cells)
- Different from follicular cells due to large size, pale cytoplasm, and small secretory granules
Regulation? Secreted in response to increased plasma Ca++ levels
Physiological role?
- Minor role in calcium homeostasis and aims to decrease plasma levels
- Functional anatagonist to PTH
- Inhibit osteoclastic activity in bone
- Inhibit reabsorption at kidney