Vitamin D and Calcitonin

•     How Does “D” Compare To Hormones?

•     Vitamin D3 is not secreted by a classical endocrine gland, the active form of the hormone is released from the kidney and acts at distant sites or locally.

•     Each of the forms of vitamin D is hydrophobic, and is transported in blood bound to carrier proteins.

•     To Make Me D, Warm Me Up and Hydroxylate Me..3X!

•     Vitamin D

•     Vitamin D, after its activation to the hormone 1,25-dihydroxy Vitamin D₃ is a principal regulator of Ca⁺⁺. 

•     Vitamin D increases Ca⁺⁺ absorption from the intestine and Ca⁺⁺ resorption from the bone as well as bone mineralization.

•     So..Exposure to Sun and Then, Fortified Foods….Give Us the D We Need

•     Functions of Vitamin D in Calcium homeostasis

•     Functions as a hormone to maintain                      blood calcium within normal range:

–     Enhances intestinal absorption of calcium and phosphorus.

–     Promotes renal calcium retention.

–     Mobilizes calcium from bone (resorption) as needed.

–     Promotes bone mineralization.

Holick MF, 1996   

•     Site of Action of Vitamin D

•     1,25(OH)₂D helps to maintain calcium and phosphate in serum by its action on intestine, bone, kidney, and the parathyroids

•     In small intestine, 1,25(OH)₂D stimulates calcium absorption , primarily in duodenum and phosphate absorption by jejunum and ileum

•     At high concentrations, 1,25(OH)₂D increases bone resorption

•     In the kidneys, 1,25(OH)₂D inhibits its own synthesis and stimulates its metabolism

•     1,25(OH)₂D acts directly on the parathyroids to inhibit the synthesis and secretion of PTH

•     1,25(OH)₂D exerts its action by associating with a specific nuclear vit D receptor analogous to steroid receptors

•    



How Does Vitamin D Facilitate Calcium Absorption in the Intestines??

•     IN THE INTESTINE

•     The vitamin D  form 1,25-dihydroxycholecalciferol [1,25(OH)₂D₃],

  

1. stimulates the synthesis of the epithelial calcium channels  in the plasma membrane, calcium pumps , and

2. induces the formation of the calbindins.

•          

           Once joined with ingested vitamin D, facilitate increased serum calcium levels .

    Shows Expressed Calbindins  and How they facilitate transport of  Calcium through the Membranes

•     Calcium Absorption Enhanced by Carrier Protein  Calbindin

•      

      Calcium absorption is a transport across the epithelial cell, which is greatly enhanced by the carrier protein calbindin, the synthesis of which is totally dependent on vitamin D

•     Vitamin D Actions on Bones

•     Another important target for 1,25-(OH)₂-D is the bone. 

•     Osteoblasts, but not osteoclasts have vitamin D receptors. 

•     1,25-(OH)₂-D acts on osteoblasts which produce a paracrine signal that activates osteoclasts to resorb Ca⁺⁺ from the bone matrix. 

•     1,25-(OH)₂-D also stimulates osteocytic osteolysis.  

•     Calcitriol Raises Blood Calcium in 3 Ways:

1. Increases Ca⁺⁺ absorption by the small intestine.

2. Increases Calcium (and Phosphate ) resorption from the skeleton.  It binds to hematopoietic stem cells and causes differentiation of  osteoclasts.

3.    Weakly promotes the reabsorption of Calcium ions by the kidney cells (less calcium excreted)

•     But, I thought Vitamin D HELPED US retain Calcium?

•        Yes, It does. So, although there is some  proliferation of osteoclasts, the

           NET RESULT  IS:

•     CALCIUM ABSORPTION and REMODELING….Outweighs RESORPTION…. Because…

 Vitamin D has also been shown to play an important part in regulating the proliferation and differentiation of both types of bone remodeling cells - those responsible for bone breakdown and those that reform the bone a new…and more.  

•     Vitamin D– Mode of Action

•     Vitamin D is a lipid soluble hormone that binds to a typical nuclear receptor, analogous to steroid hormones. 

•     Because it is lipid soluble, it travels in the blood bound to hydroxylated a-globulin.

•     There are many target genes for Vitamin D.

•     Mode of Action of Vit D

•     Small hydrophobic signal molecules diffuse directly across the plasma membrane of target cells and bind to intracellular receptor proteins, eg. Steroid hormones, thyroid hormones, retinoids and vitamin D

•     When these signal molecules bind to their receptor proteins, they activate the receptors , which bind to DNA to regulate the transcription of specific genes

•     CALCITONIN

•     Calcitonin

•     32 amino acids

•     C cells or the parafollicular cells of the thyroid gland

•     Action

–   Inhibits bone resorption

–   Decrease blood calcium

–   Increase Na⁺, Ca⁺⁺ and phosphate excretion in the urine

–   Decrease gastric acid secretion

•     Antagonist to PTH

•     Sites and mode of action:

•     Acts on both bone and kidney

•     Calcitonin:

–   Reduces plasma calcium in three ways

1. Decrease the activity of the osteoclast

2. Increase the osteoblastic activity

3. Prevent formation of new osteoclast from osteoprogenitor cells

–   Increase both urinary calcium and phosphate clearance

•     Calcitonin

What happens…….

1. Action on bones:

–   Calcitonin inhibits resorption of bones by osteoclasts; thus reduces mobilization of Ca and inorganic PO₄ from bones into blood

–   Stimulates influx of phosphates in bones

–   Promotion of bone formation is UNCERTAIN BUT it increases osteoblasts cells

•     Calcitonin

2. Action on kidneys:

–   Acts on distal tubule and ascending loop of Henle; Decreases tubular reabsorption of both calcium and inorganic phosphate PRODUCING calcinuria and phosphaturia

–   Inhibits α-1-hydroxylase and inhibits synthesis of Vit D3 thus decreasing calcium absorption from intestine

–   Mechanism of Action

1. Role of cyclic AMP

–   Calcitonin binds to specific calcitonin receptors on the plasma membrane of bone osteoclasts and renal tubular  epithelial cells à activates adenyl cyclase which increases cAMP which mediates the cellular effects of hormone

2. Cellular shift

–   Calcitonin in vitro and in vivo produced a cellular shift  in which the number of osteoclasts decreased

3. pH change

–   Calcitonin regulates pH at cellular level producing more alkaline medium which diminishes resorption

•     Control of calcitonin secretion

•     Regulated by the extracellular concentration of ionized calcium.

•     Elevated blood calcium levels strongly stimulate calcitonin secretion

•     Secretion is suppressed when calcium concentration falls below normal

•     Effect: lowers the circulating Ca⁺⁺ and phosphate level