Calcium Homeostasis

1. Calcium Homeostasis By Dr. Khurram Irshad Department of Physiology

2. Calcium HomeostasisKey Players 1. Parathyroid Hormone 2. Calcitonin 3. and Vitamin D3

3. Calcium homeostasis Key Organs Involved • Parathyroid Gland • Intestines • Bone • Kidneys • And Skin

4. Physiological importance of Calcium • Calcium salts in bone provide structural integrity of the skeleton • Calcium ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processes • Neuoromuscular excitability • Blood coagulation • Hormonal secretion • Enzymatic regulation

5. Regulation of Calcium Concentration • The important role that calcium plays in so many processes that its concentration, both extracellularly and intracellularly, be maintained within a very narrow range. • This is achieved by an elaborate system of controls

6. Extracellular Calcium • When extracellular calcium falls below normal, the nervous system becomes progressively more excitable because of increase permeability of neuronal membranes to sodium. • Hyperexcitability causes tetanic contractions • Hypocalcemic tetany

7. Extracellular Calcium • Three definable fractions of calcium in serum: • Ionized calcium 50% • Protein-bound calcium 41% • 90% bound to albumin • Remainder bound to globulins • Calcium complexed to serum constituents 9% • Citrate and phosphate Ca2+ normally ranges from 8.5-10 mg/dL in the plasma.(9.4 mg/dL or 2.4 mmol/L)

8. Calcium and phosphorous? • Calcium is tightly regulated with Phosphorous in the body. • Phosphorous is an essential mineral necessary for ATP, cAMP second messenger systems, and other roles

9. Calcium turnover

10. Calcium and bone • 99% of Calcium is found in the bone. Most is found in hydroxyapatite crystals. Very little Ca2+ can be released from the bone– though it is the major reservoir of Ca2+ in the body.

13. Bones cells

14. Calcium turnover in bones • 80% of bone is mass consists of cortical bone– for example: dense concentric layers of appendicular skeleton (long bones) • 20% of bone mass consists of trabecular bone– bridges of bone spicules of the axial skeleton (skull, ribs, vertebrae, pelvis) • Trabecular bone has five times greater surface area, though comprises lesser mass. • Because of greater accessibility trabecular bone is more important to calcium turnover

15. Bones • 99% of the Calcium in our bodies is found in our bones which serve as a reservoir for Ca++ storage. • 10% of total adult bone mass turns over each year during remodeling process • During growth rate of bone formation exceeds resorption and skeletal mass increases. • Linear growth occurs at epiphyseal plates. • Increase in width occurs at periosteum • Once adult bone mass is achieved equal rates of formation and resorption maintain bone mass until age of about 30 years when rate of resorption begins to exceed formation and bone mass slowly decreases.

16. Bone cell types • There are three types of bone cells: Osteoblasts are the differentiated bone forming cells and secrete bone matrix on which Ca++ and PO precipitate. • Osteocytes, the mature bone cells are enclosed in bone matrix. • Osteoclasts is a large multinucleated cell derived from monocytes whose function is to resorb bone. Inorganic bone is composed of hydroxyapatite and organic matrix is composed primarily of collagen.

17. Bone formation • Active osteoblasts synthesize and extrude collagen • Collagen fibrils form arrays of an organic matrix called the osetoid. • Calcium phosphate is deposited in the osteoid and becomes mineralized • Mineralization is combination of CaP04, OH-, and H3CO3– hydroxyapatite.

18. Control of bone formation and resorption? • Bone resorption of Ca++ by two mechanims: osteocytic osteolysis is a rapid and transient effect and osteoclasitc resorption which is slow and sustained. • Both are stimulated by PTH. CaPO4 precipitates out of solution id its solubility is exceeded. The solubility is defined by the equilibrium equation: Ksp = [Ca2+]3[PO43-]2. • In the absence of hormonal regulation plasma Ca++ is maintained at 6-7 mg/dL by this equilibrium.

19. Osteocytic osteolysis? • Transfer of calcium from canaliculi to extracellular fluid via activity of osteocytes. • Does not decrease bone mass. • Removes calcium from most recently formed crystals • Happens quickly.

20. Bone resorption? • Does not merely extract calcium, it destroys entire matrix of bone and diminishes bone mass. • Cell responsible for resorption is the osteoclast.

21. Calcium, bones and osteoporosis • The total bone mass of humans peaks at 25-35 years of age. • Men have more bone mass than women. • A gradual decline occurs in both genders with aging, but women undergo an accelerated loss of bone due to increased resorption during perimenopause. • Bone resorption exceeds formation.

22. Calcium, bones and osteoporosis • Reduced bone density and mass: osteoporosis • Susceptibility to fracture. • Earlier in life for women than men but eventually both genders succumb. • Reduced risk: • Calcium in the diet • habitual exercise • avoid drinking carbonated soft drinks

23. Vertebrae of 40- vs. 92-year-old women Note the marked loss of trabeculae with preservation of cortex.

24. Hormonal control of bones

25. Vitamin D • Vitamin D, after its activation to the hormone 1,25-dihydroxy Vitamin D3 is one of the principal regulator of Ca++. • Vitamin D increases Ca++ absorption from the intestine and Ca++ resorption from the bone .

26. Synthesis of Vitamin D • Humans acquire vitamin D from two sources. • Vitamin D is produced in the skin by ultraviolet radiation and ingested in the diet. • Vitamin D is not a classic hormone because it is not produce and secreted by an endocrine “gland.” Nor is it a true “vitamin” since it can be synthesized de novo. • Vitamin D is a true hormone that acts on distant target cells to evoke responses after binding to high affinity receptors

27. Synthesis of Vitamin D • Vitamin D3 synthesis occurs in keratinocytes in the skin. • 7-dehydrocholesterol is photoconverted to previtamin D3, then spontaneously converts to vitamin D3.

28. Synthesis of Vitamin D • PTH stimulates vitamin D synthesis. In the winter or if exposure to sunlight is limited (indoor jobs!), then dietary vitamin D is essential. • Vitamin D itself is inactive, it requires modification to the active metabolite, 1,25-dihydroxy-D. • The first hydroxylation reaction takes place in the liver yielding 25-hydroxy D. • Then 25-hydroxy D is transported to the kidney where the second hydroxylation reaction takes place.

29. Synthesis of Vitamin D • The mitochondrial P450 enzyme 1a-hydroxylase converts it to 1,25-dihydroxy-D, the most potent metabolite of Vitamin D. • The 1a-hydroxylase enzyme is the point of regulation of D synthesis. • Feedback regulation by 1,25-dihydroxy D inhibits this enzyme. • PTH stimulates 1a-hydroxylase and increases 1,25-dihydroxy D. • Phosphate inhibits 1a-hydroxylase and decreased levels of PO4 stimulate 1a-hydroxylase activity

30. Vitamin D promotes intestinal calcium absorption • Vitamin D acts via steroid hormone like receptor to increase transcriptional and translational activity • One gene product is calcium-binding protein (CaBP) • CaBP facilitates calcium uptake by intestinal cells

31. Vitamin D action • The main action of 1,25-(OH)2-D is to stimulate absorption of Ca2+ from the intestine. • 1,25-(OH)2-D induces the production of calcium binding proteins which sequester Ca2+, buffer high Ca2+ concentrations that arise during initial absorption and allow Ca2+ to be absorbed against a high Ca2+ gradient

32. 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.

33. Vitamin D and Bones • Proper bone formation is stimulated by 1,25-(OH)2-D. • In its absence, excess osteoid accumulates from lack of 1,25-(OH)2-D repression of osteoblastic collagen synthesis. • Inadequate supply of vitamin D results in rickets, a disease of bone deformation

34. Parathyroid Hormone Parathyroid Hormone is essential for life

35. Parathyroid Hormone • PTH is synthesized and secreted by the parathyroid gland which lie posterior to the thyroid glands. • The blood supply to the parathyroid glands is from the thyroid arteries. • The Chief Cells in the parathyroid gland are the principal site of PTH synthesis.

36. Synthesis of PTH • PTH is translated as a pre-prohormone. • Cleavage of leader and pro-sequences yield a biologically active peptide of 84 aa. • Cleavage of C-terminal end yields a biologically inactive peptide.

37. Calcium regulates PTH

38. Regulation of PTH? • PTH secretion responds to small alterations in plasma Ca2+ within seconds. • When Ca2+ falls, cAMP rises and PTH is secreted. • A unique calcium receptor within the parathyroid cell plasma membrane senses changes in the extracellular fluid concentration of Ca2+. • This is a typical G-protein coupled receptor that activates phospholipase C and inhibits adenylate cyclase—result is increase in intracellular Ca2+ via generation of inositol phosphates and decrease in cAMP which prevents exocytosis of PTH from secretory granules.

39. Calcitonin plays a role in skeletal integrity in pregnancy or breast feeding Gastrointestinal hormones Negative feed back loops

41. Calcium regulates PTH secretion

42. PTH action • The overall action of PTH is to increase plasma Ca++ levels and decrease plasma phosphate levels. • PTH acts directly on the bones to stimulate Ca++ resorption and kidney to stimulate Ca++ reabsorption in the distal tubule of the kidney and to inhibit reabosorptioin of phosphate (thereby stimulating its excretion). • PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D synthesis.

43. Primary Hyperparathyroidism • Calcium homeostatic loss due to excessive PTH secretion • Due to excess PTH secreted from adenomatous or hyperplastic parathyroid tissue • Hypercalcemia results from combined effects of PTH-induced bone resorption, intestinal calcium absorption and renal tubular reabsorption • Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D.

44. Hypercalcemia of Malignancy • Underlying cause is generally excessive bone resorption by one of three mechanisms • 1,25-(OH)2-D synthesis by lymphomas • Local osteolytic hypercalcemia • 20% of all hypercalcemia of malignancy • Humoral hypercalcemia of malignancy • Over-expression of PTH-related protein (PTHrP)

45. PTH receptor defect • Rare disease known as Jansen’s metaphyseal chondrodysplasia • Characterized by hypercalcemia, hypophosphotemia, short-limbed dwarfism • Due to activating mutation of PTH receptor • Rescue of PTH receptor knock-out with targeted expression of “Jansen’s transgene”

46. Hypoparathyroidism • Hypocalcemia occurs when there is inadequate response of the Vitamin D-PTH axis to hypocalcemic stimuli • Hypocalcemia is often multifactorial • Hypocalcemia is invariably associated with hypoparathyroidism • Bihormonal—concomitant decrease in 1,25-(OH)2-D

47. Hypoparathyroidism • PTH-deficient hypoparathyroidism • Reduced or absent synthesis of PTH • Often due to inadvertent removal of excessive parathyroid tissue during thyroid or parathyroid surgery • PTH-ineffective hypoparathyroidism • Synthesis of biologically inactive PTH

48. -Carpopedal Spasm -Rickets

49. Pseudohypoparathyroidism • PTH-resistant hypoparathyroidism • Due to defect in PTH receptor-adenylate cyclase complex • Mutation in Gas subunit • Patients are also resistant to TSH, glucagon and gonadotropins

50. Calcitonin • Calcitonin acts to decrease plasma Ca++ levels. • While PTH and vitamin D act to increase plasma Ca++-- only calcitonin causes a decrease in plasma Ca++. • Calcitonin is synthesized and secreted by the parafollicular cells of the thyroid gland. • They are distinct from thyroid follicular cells by their large size, pale cytoplasm, and small secretory granules.