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