Regulation of Mineral Homeostasis 2022.pptx

Mineral

1. Mineral H omeostasis: Calcium and Phosphorus

2. Parathyroid Hormone (PTH) PTH effect on bone Vitamin D Parathyroid Hormone-related Peptide ( PTHrP ), Calcitonin, Phosphatonins Mineral homeostasis: Calcium and Phosphorus

3. Parathyroid gland Parathyroid Hormone

4. Hormone synthesis PTH is 84 amino acid polypeptide Active hormone is sequence 1-34 Parathyroid Hormone

5. Hormone release Parathyroid Hormone S. Ferrè al, Kidney International, Vol 82, Pg 1158

6. Acts via cAMP and PLC Kidney Stimulation of Ca reabsorption Stimulation of vitamin D synthesis (stimulates alpha 1 hydroxylase ) Stimulation of phosphate excretion (as well as bicarbonate) by removing Phosphate (and bicarbonate) transporter from the apical surface of the proximal tubule Bone Stimulation of bone resorption and Ca release Can be anabolic – bolus injections increase bone mineralization! Effects – prevents hypocalcemia Parathyroid Hormone

7. Key Concepts: PTH defends against hypocalcemia Decreased plasma calcium increases PTH release and vitamin D decreases PTH release PTH increases plasma calcium levels by: Increasing Ca reabsorption in kidney Increasing phosphate (and bicarbonate) excretion by kidney Release of calcium from bone Activation of vitamin D to increase calcium absorption from intestine PTH injected intermittently can increases bone mineralization Parathyroid Hormone

8. Parathyroid Hormone (PTH) PTH effect on bone Vitamin D Parathyroid Hormone-related Peptide ( PTHrP ), Calcitonin, Phosphatonins Mineral homeostasis: Calcium, and Phosphorus

9. PTH Effect on Bone Calcified bone RANK (Cytokine receptor) Lysosome ATP H + Collagen fibers Osteocyte Bone cells: Osteocytes, Osteoclasts and Osteoblasts

10. ATP H + RANK (Cytokine receptor) Lysosome resorption lacuna (pit) Calcified bone H + H + H + PTH Effect on Bone Bone cells: Osteocytes, Osteoclasts and Osteoblasts

11. PTH Effect on Bone Bone cells: Osteocytes, Osteoclasts and Osteoblasts Tim Arnett ( [email protected] ) & Javier Manzano , UCL

12. Calcified bone PTH Effect on Bone Bone cells: Osteocytes, Osteoclasts and Osteoblasts

13. Calcified bone PTH Effect on Bone Bone cells: Osteocytes, Osteoclasts and Osteoblasts

14. Calcified bone PTH Effect on Bone Bone cells: Osteocytes, Osteoclasts and Osteoblasts

15. Calcified bone PTH Stem cells M-CSF Osteoclast precursors Mononuclear osteoclast PTH Effect on Bone PTH releases Ca from bone PTH binds to its receptor on stromal cells in the bone (including osteoblasts) leading to release of M-CSF M-CSF stimulates differentiation of new osteoclasts

16. Calcified bone PTH Effect on Bone PTH releases Ca from bone Osteoclasts are activated by RANK ligand a cytokine from TNF superfamily that activates RANK (cytokine receptor) RANK ligand (RANK-L) is released as a cytokine by lymphocytes, RANK-L is expressed on bone stromal cells as membrane-bound molecule

17. Calcified bone PTH Effect on Bone PTH releases Ca from bone Osteoclasts are activated by RANK ligand a cytokine from TNF superfamily that activates RANK (cytokine receptor) RANK ligand (RANK-L) is released as a cytokine by lymphocytes, RANK-L is expressed on bone stromal cells as membrane-bound molecule

18. Calcified bone PTH PTH Effect on Bone Osteoblasts can counter activation of osteoclasts via osteoprotegrins : Osteoprotegrins bind and sequester cytokines (RANK ligands)

19. Calcified bone PTH Effect on Bone Estrogen and androgen effects in bone Bone cells: Both increase osteoblast differentiation and lifespan Both decrease osteoclast differentiation and lifespan of osteoclasts ER-alpha increases bone density in response to mechanical stress (independent of estrogen binding!) Lymphocytes: Estrogens decrease expression of RANK-L

20. Calcified bone PTH Effect on Bone Glucocorticoid effects in bone Initial effect: Increased bone breakdown Increase RANK-L and M-CSF (increase number of osteoclasts) Longer term effect: Decreased bone formation Decreased differentiation and increased apoptosis of osteoblasts and osteocytes; decreased OPG production

21. Key Concepts: PTH acts on bone via receptors expressed on osteoblasts, osteoblasts precursors and osteocytes PTH stimulates osteoblasts and osteocytes to pump calcium in circulation PTH stimulates osteoclast differentiation, activation and prolongs the life of osteoclasts RANK-L binding to osteoclast RANK activates them Osteoblasts release osteoprotegrins to bind RANK-L and decrease activation of osteoclasts Estrogens and androgens increase differentiation and lifespan od osteoblasts and induce apoptosis of osteoclasts; estrogens decrease RANK-L Cortisol increases differentiation (via M-CSF) and activity (via RANK-L) of osteoclasts and apoptosis of osteoblasts and osteocytes; decreases production of osteoprotegrins PTH Effect on Bone

22. Which of the following could be a strategy to design a drug to prevent osteoporosis: Screen for an antagonist specific for the osteoclast RANK receptor. Inhibit production of osteoprotegrins . Stimulate PTH receptors expressed in bone Generate an antibody that specifically binds RANK Ligand All of the above could be good strategies

23. Parathyroid Hormone (PTH) PTH effect on bone Vitamin D Parathyroid Hormone-related Peptide ( PTHrP ), Calcitonin, Phosphatonins Mineral homeostasis: Calcium, and Phosphorus

24. Synthesis Vitamin D

25. Synthesis Vitamin D Regulated: PTH h Phosphate i 1,25 (OH) D i Liver Kidney

26. mRNA RXR prom Cellular mechanism of action Vitamin D

27. Kidney Stimulation of Ca, phosphate reabsorption Inhibition of alpha 1 hydroxylase (negative feedback) Parathyroid Inhibits PTH synthesis and release Inhibits parathyroid growth Intestine Stimulation of Ca, phosphate absorption Bone Stimulation of bone resorption and Ca, phosphate release via immature osteoblasts ( this is direct effect, however, because of the effects on parathyroid and increase of Ca and phosphate net effect is anabolic!!!) Effects – bone mineralization Vitamin D

28. Key Concepts: Vitamin D is a steroid hormone responsible for bone mineralization Vitamin D achieves this by inhibition of PTH release, absorption of Ca and phosphate in the intestine and reabsorption of Ca and phosphate in the kidney Vitamin D precursor is synthesized in skin and it is in two steps: 1) liver and 2) alpha 1 hydroxylation in kidney PTH promotes kidney activation of vitamin D and plasma phosphate and vitamin D inhibit it. Vitamin D

29. Parathyroid Hormone (PTH) PTH effect on bone Vitamin D Parathyroid Hormone-related Peptide ( PTHrP ), Calcitonin, Phosphatonins Mineral homeostasis: Calcium, and Phosphorus

30. Thyroid parafollicular cells - histology Calcitonin

31. Synthesized by “C” ( parafollicular ) cells in thyroid 32 Amino acid Released in response to elevated Ca Synthesis Calcitonin

32. Via G-protein coupled receptor elevates cAMP Bone Inhibits osteoclasts Kidney Phosphaturia , Calciuresis , Natriuresis Effects – prevents hypercalcemia * Calcitonin

33. Shares sequence homology and the receptor with PTH Same effects as PTH except no effect on alpha 1 hydroxylase Synthesized by many tissues (cartilage, bone, heart, kidney, brain…) Critical for development of bone and cartilage in fetus Varitey of tumors synthesize it – malignancy-induced hypercalcemia Function and origins Parathyroid hormone-related peptide ( PTHrP )

34. Several different molecules – FGF 23 one of them Regulate phosphate – elevated phosphate stimulates synthesis Act in kidney  phosphaturia Function – prevent hyperphosphatemia Phosphatonins

35. Key concepts PTHrP – effects same as PTH except no vitamin D activation in kidney PTHrP primarily a paracrine, but acts as a hormone when secreted by a tumor Calcitonin – decreases calcium concentration by inhibiting osteoclasts, calciuria , phosphaturia Phosphatonins – decrease phosphate concentration by stimulating phosphaturia Calcitonin, PTHrP , Phosphatonins