1. Calcium and its significance in the bone metabolism Romana Šlamberová, MD PhD Department of Normal, Pathological and Clinical Physiology

2. CALCIUM  2% of body weight  99% in bones  1% in body fluids  Plasma (Extracellular fluid) 2.25 – 2.75 mmol/l  Cell (Intracellular fluid) 10 -8 – 10 -7 mol/l = 10 -5 – 10 -4 mmol/l

3. PLASMA CALCIUM diffusible  48% (50%) Ca 2+ ionized  6% (10%) combined with anions (citrate, phosphate) – non-dissociated nondiffusible  46% (40%) combined with plasma proteins  combination with proteins depends on pH 0.2 mmol/l Ca 2+ on each pH unit

4. ROLE OF CALCIUM  excitability of cell membranes  neuromuscular transmission and muscle contraction  releasing of transmitters from synapses  “second messenger”  stimulates secretory activity of exocrine glands and releasing of hormones  contractility of myocard  blood coagulation

5. PHOSPHATES  80% bones and teeth  10% blood and muscles  10% different chemical complexes  Plasma (ECF) 0.65 – 1.62 mmol/l  Cell (ICF) 65 mmol/l (including organic P)

6. PHOSPHATES (2)  calcium phosphate, hydroxyapatite (bone)  inorganic anions: HPO 3 2-, H 2 PO 3-  organic:DNA, phospholipids  ATP, cAMP, creatinphosphate molecules with metabolic significance  Ca, P rates of intake 1g/day

7. Bones – reservoir of calcium  99% of skeletal calcium forms stable bone (not exchangeable with the Ca in extracellular fluid)  1% is in the form of releasable pool of Ca  Balance of deposition and resorption  Osteoblasts – bone-forming cells responsible for bone deposition Secrete type I collagen Differentiate into osteosytes  Osteoclasts – “bone-eating” cells that resorb the previously formed bone

8. Regulation of osteoblasts function  Stimulation PTH (fast reaction - activation of calcium pump ? – pumping Ca to ECF) 1,25 Dihydrocholecalciferol IL-1 T3, T4 hGH, IGF-1 (insuline-like growth factor) PGE 2 (prostaglandine) TNF (tumor necrosis factor) Estrogens ?  Inhibition Corticosteroids

9. Regulation of osteoclasts function  Stimulation PTH (not directly – through stimulation of osteoblasts) 1,25 Dihydrocholecalciferol (not directly – through stimulation of osteoblasts) IL-6, IL-11  Inhibition Calcitonin (directly – receptors) Estrogens (by inhibiting production of certain cytokines) TGF-β (tranforming growth factor) PGE 2 (prostaglandine)

10. Bone structure From Ganong Due to Copyright rules it is impossible to publish pictures that were used in this lecture. Therefore, all slides that contained pictures are blank. Thank you for understanding.

11. Sex differences From Ganong

12. Thyroid and Parathyroid glands

13. Calcium metabolism From Guyton and Hall

14. Regulation of calcium metabolism 1. Parathyroid hormone 2. Calcitonin 3. Vitamin D

15. PARATHORMON  Parathyroid glands  polypeptide of 84 amino acids  stimulus for secretion – low plasma calcium  function – to INCREASE plasma calcium activation of osteoclasts – stimulates absorption of Ca, P from bones decreases excretion of Ca by kidneys increases excretion of P by kidneys stimulates conversion of vitamin D to calcitriol (vitamin D hormon) in kidneys

16. Relation - plasma Ca 2+ concentration x hormones

17. CALCITONIN  Parafollicular cells of thyroid gland (C-cells)  peptide of 32 amino acids  stimulus for secretion – high plasma calcium (food intake – gastrin, CCK, glucagon)  function – to DECREASE plasma calcium and phosphates inhibits osteolysis – decreases absorption of Ca, P from bones stimulates incorporation of Ca, P to bones decreases absorption of Ca, P in kidneys decreases the effect of PTH on bones – PTH antagonist

18. CALCITRIOL vitamin D hormone  Skin: preprovitamin D (7-dehydrocholesterol ergosterol) - UV irradiation: cholecalciferol (D3), ergocalciferol (D2) - Liver:25- hydroxycholecalciferol - Kidneys:1,25- dihydroxycholecalciferol (conversion is mediated by PTH)  function – to INCREASE plasma calcium increases absorption of Ca in intestines stimulates formation of calcium-binding protein in epithelial cells promotes bone calcification and deposition inhibits secretion of PTH

19. CALCITRIOL vitamin D hormone (2)

20. Changes in Ca 2+ plasma level Hypocalcemia  Muscle tetany carpopedal spasm  Dilatation of heart  Increased cell membrane permeability  Impaired blood clotting Hypercalcemia  Depression of nervous system, reflex activity,  Increased heart contractility  Formation of calcium phosphate crystalls

21. Carpopedal spasm From Guyton and Hall

22. Changes in PTH plasma level Hypoparathyroidism  Muscle tetany Hyperparathyroidism  Decalification of bones  Multiple fractures (Osteitis fibrosa cystica)  Kidney stones

23. Changes in vitamine D plasma level Hypovitaminosis  RICKETS (rachitis)– children  OSTEOMALACIA - adults Attention! – Osteoporosis is decrease of bone mass (matrix and minerals) Hypervitaminosis  Tissue and organs calcification  Lost of body weight  Kidney function failure

24. Basic functions of plasma membrane 1. Transport 2. Membrane potential 3. Ion channels 4. Mechanism of secretion

25. Structure of the plasma membrane

26. Ionic composition of ICF and ECF IonECF mmol/l ICF mmol/l Nernst equilibrium potential Na + 136-14620+53 mV K+K+ 3.8-5.4150-97 mV Ca 2+ 2.05-2.65c. 10 -4 +120mV Cl - 97-1093-97 mV HCO 3 - 22-2610-30 mV