Regulation of calcitonin secretion

• Elevation of blood calcium– Response greater in male– Affected by age

• Declines as one ages

• Secretion by GI tract– Gastrin

• Stimulator of acid secretion

– Cholecystokinin

• Response to calcium– Calcium receptors

• Increased calcium, increased calcitonin secretion

Physiological roles

• Bone mineral metabolism– Prevention of hypercalcemia

• After meals

– Mineralization of bones in neonates– Protection against calcium loss

• Pregnancy• Lactation

• Satiety factor– Regulation of food intake

• Inhibition of food intake• Inhibition of calcium-induced hunger

• Vitamin D regulation– Stimulation of vitamin D metabolism

• Direct stimulation• Decreased blood calcium level

Mechanism of action

• Receptors for calcitonin– Skeletal tissue, kidneys, and Leydig cells

• Coupled with adenylate cyclase• Coupled with different types of G proteins

– Gs, Gi, and Gq– Depending on the cell cycle– Trigger different responses (activation of different

sigaling pathway)

Vitamin D• Cholesterol

derivative– Contain sterol ring

• Two substances– Cholecalciferol– Ergocalciferol

• Not really vitamin– Precursor for steroid-

like hormones• Produced by specific

tissues

Synthesis

• Vitamin D2 (ergocalciferol)– Precursor

• Ergosterol– Plant origin

• Vitamin D3 (cholecalciferol)– Produced by skin

• 7-dehydrocholesterol– UV light as energy source (thermal isomerization)– Production of inert metabolites (lumisterol and

tachysterol) when exposed to sun for a prolonged period

– Transported into the blood• Vitamin D3 only• Binding protein

– Transcalciferin

• Vitamin D3– Requires further conversion

• 25-hydroxyvitamin D3– Liver

• 1,25-dihydroxyvitamin D3– Kidneys– Hormonal form of vitamin D3– Bound to plasma protein (transcalciferin)

• 24,25-dihydroxyvitamin D3– Inactive form in mammals– Kidneys and other organs

• 1,24,25-trihydroxyvitamin D3– Unknown origin and function

Vitamin D metabolism• Blood calcium level

– Production of 1,25 dihydroxyvitamin D3• Increased when low blood calcium level• Decreased when high blood calcium level• Regulated by PTH

• Production of 24,25 dihydroxyvitamin D3– Increased when 1,25 dihydroxyvitamin D3

decreases• Inhibited by PTH

• Activity of renal 1alpha-Ohase– Regulation

• Vitamin D level (inverse)• PTH (stimulation)

– Inhibited by 1,25 dihydroxvitamin D3

• Increased phosphate excretion (stimulation)– PTH-induced

• Conversion of 25-hydroxyvitamin D to 24,25 dihydroxyvitamin D– Inactivation of 25-hydroxyvitamin D

• Secretion of 1,25 dihydroxyvitamin D3– Hormonal regulation

• Insulin• GH• Prolactin

Physiological roles

• Absorption of calcium– Intestine

• Increased phosphate translocation• Increased calcium transport

– From mucosa to serosa via cytosolic calcium binding protein

– Bones• Paradox

– Essential for normal bone growth– Causes demineralization

• Absorption of calcium – Kidneys

• Tubular reabsorption• Retention of phosphate by proximal tubule

• Regulation of PTH secretion– Negative feedback

• Long-feedback system– Blood calcium level

• Short-feedback system– 1,25

dihydroxyvitamin D3

• Proliferation and differentiation of cells– Hematopoetic stem cells– Keratinocytes– Myoblasts

• Immune reaction

Mechanism of action

• Receptor– Nuclear receptor

• Similar to steroid receptor– Ligand binding domain– DNA binding domain

• Interaction with hormone responsive element– VDRE

• Delayed action (2 hours)– Protein synthesis

Hormonal integration in calcium homeostasis

• Calcitonin– Inhibition of PTH and vitamin D action on

osteoclasts• Not on osteoblasts

Hormonal integration in calcium homeostasis

• Calcitonin– Inhibition of bone resorption by

multinucleated osteoclast• Alteration of morphology• Activity of osteoclast activity

– Reduced lysosomal enzyme release

• Stimulates detachment of osteoclasts• Inhibit motility• Reduction of lifespan

• PTH– Elevation of blood calcium level

• cAMP mediated• Stimulation of osteoclast activity• Inhibition of osteoblast activity

– Osteoblast• Target cells• Indirectly affect osteoclast function

• PTH– Stimulates secretion of osteoclast differentiation-

inducing factors• Cytokines

– IL-6

– Increased differentiation of precursor cells into multinucleated osteoclasts

• Morphological changes• Secretion of lysosomal contents• Result in increased release of calcium and phosphate

• Regulation– Short-term

• Parathyroid gland– PTH

– Long-term• Kidney

– 1,25-dihydrovitamin D

• Intestinal calcium absorption• Decreased skeletal calcium turn-over

• Other hormones– Estrogens

• Crucial for maintenance of bone density in women

– Inhibition of IL-6 secretion

– GH• Greater bone mass in African-Americans