Calcium and Phosphate Metabolism Lecture VIII PDF

Calcium and Phosphate Metabolism Universit y ofGalway. ie Bone Physiology Function of Bone Structural support Protection of internal organs and soft tissues from damage Locomotion...

Calcium and Phosphate Metabolism Universit y ofGalway. ie Bone Physiology Function of Bone Structural support Protection of internal organs and soft tissues from damage Locomotion 60% inorganic 10% water Mineral storage 30% organic Production of blood cells Endocrine regulation Bone undergoes continuous turnover/remodeling through life About 20% of bone is undergoing remodeling at any Universit time y ofGalway. ie Bone - Inorganic Portion (67%) Hydroxyapatite Crystals Ca10(PO4)6(OH)2 Embedded in collagen matrix Approx. 60–70% dry weight of bone Provides structural strength Facilitates bone regeneration Other Ions Present Na+, K+, Mg2+, CO32-, Ba2+, Zn2+ Reduce the crystallinity of bone minerals Alter solubility Facilitating bone Universit y adaptation ofGalway. ie  Bone – Organic Portion (aka osteoid) (33%) Collagenous Proteins Type I collagen (28%) Ligaments and Tendons Triple helix Structure Provides structural support Contributes to mechanical properties of bone Flexibility Resistance to tensile forces. Also Other forms Type III, IV Universit y ofGalway. ie  Bone – Organic Portion (aka osteoid) (33%) Non-collagen structural proteins Proteoglycans – Macromolecules with core polypeptide and glycosaminoglycan (e.g. Hyaluronic acid) Organization of Bone Extracellular Matrix, Collagen Fibrillogenesis Sialoproteins — highly glycosylated and sulphated phosphoprotein Mineralization and Bone Formation Bone specific proteins Osteocalcin—Bone Formation and Osteoclasts Activity Osteonectin—Modulate GF Activity, Cell adhesion, Mineralization Osteopontin—Regulates Bone Formation, Migration, Adhesion, and Mineralization RANKL (Receptor Activator of Nuclear Factor κ-B Ligand)—Regulation of Bone Resorption Growth factors and cytokines (Trace) Universit y ofGalway. ie Bone Remodeling Osteoclasts dissolve bone Large multinucleated giant cells Osteoblasts produce bone Have receptors for PTH, CT, Vitamin D, cytokines, and growth factors Main product is collagen When osteoblasts become encased in bone, they become osteocytes Universit y ofGalway. ie  Bone Cells Osteoblasts Osteoclasts Bone Formation Bone Resorption Synthesis of matrix proteins Degradation of proteins by Type I collagen enzymes Osteocalcin Acidification OtherBone Proteins Mineralization Activation of osteoclasts via RANKL RANK is activated by RANKL, and production this leads to cells differentiation to osteoclasts Universit y ofGalway. ie Bone Remodeling Universit y ofGalway. ie 2nd Response to Regulating Bone Remodeling Wolff’s Law Bone grows or remodels in response to the forces or stresses placed on it. Appositional growth Growth in diameter is controlled by the amount of mechanical stress and gravity placed on the bone Heavy usage leads to heavy bones; non-use leads to atrophy (bone loss) Astronauts lose bone mineral density as a result of spending time in space Paralysis or prolonged immobilised Universit y ofGalway. ie  Wolffs Laws Law On Bone Explained Piezoelectricity – Tissues Response Whereby: Bone Generates an Electric Charge in Response to Applied Mechanical Stress Action potential Generated Osteocytes Release Factors that Stimulate Osteoblastic Activity Bone growth and Increased Density to Withstand Forces Placed on it Absence of mechanical forces osteoclastic activity increased Weaker and less dense bone Natural Mechanical Stress Applied to Femur Altered after Total Hip Replacement Metal Implant Carries Some of the Load Reducing Stress on Femur Phenomenon is known as Stress Shielding Loss of Bone Mass Through Resorption After Hip Transplant Occur Around the Implant Resulting in a Loosening of the Prosthetic Implant Universit y ofGalway. ie Controlling Bone Remodeling Hormones PTH and Calcitonin Determines whether and when bone remodeling occurs. Mechanical Stress Determines where remodeling occurs. High stress areas grow appositionally. Universit y ofGalway. ie Calcium and Phosphate Universit y ofGalway. ie Phosphate Found in Bone, ATP, cAMP, proteins etc – regulate cell fnc Total body phosphate = 500-800g [85-90% skeleton] Plasma phosphate = 3- 4.5 mg/dl (0.9 -1.3mM) Circulates as Orthophosphate (PO4) Free filtered by kidney – 85% reabsorbed 15% excreted as urinary buffer Absorbed in intestine by Na+ transporter Universit y ofGalway. ie Calcium Total Calcium in body = 1100g (90% in skeleton) Total Plasma Calcium in plasma = 2.2-2.6mmol/L Function Nerve and muscle excitability, Neurotransmission Excitation-contraction coupling in muscle Enzyme co-factor, Bone Second Messenger, Fertilisation, Mitosis Universit y ofGalway. ie  Body Requirements Age (in years) Calcium Requirement 1–3 500mg 4-8 800mg 9 - 18 1300mg 19 - 50 1000mg 51+ 1500mg (Post Menopausal Women) *Pregnant and lactating women are recommended a daily calcium intake of 1000mg. Universit y ofGalway. ie Plasma Calcium Regulation Plasma calcium totals 2.4 mM (9.4 mg/dl) Free calcium is 1.2 mM Free ionised calcium is tightly regulated (5%) Too low = Neuronal hyper-excitability Too high = Neuronal depression Universit y ofGalway. ie Total Calcium Measurement can be Mis-leading Low Albumin: Malnutrition, liver disease, or nephrotic syndrome Total calcium levels might appear falsely low However the levels of ionized calcium remain unchanged Corrected calcium provides a more accurate reflection of calcium status by adjusting for albumin levels Estimate a patient's true calcium levels in the blood, accounting for variations in serum albumin levels Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]) 4.0 -average albumin level: 0.8 - correction factor Universit y ofGalway. ie Calcium Transport in the Blood Ionized fraction depends on pH: protein binding decreases as pH decreases Alkalosis: increased calcium binding to protein; decreased ionised fraction pH 7. 45 Hpocalcaemic effects Each 0.1 decrease in pH increases ionized pH 7.35 calcium by 0.05 mmol/L Acidosis: decreased calcium binding to protein; Universit y increased ionised fraction ofGalway. ie Calcium Homeostasis Three systems: bone, kidney, intestine Three hormones: parathyroid hormone, calcitonin, vitamin D Universit y ofGalway. ie Regulated Tightly Intracellular and ICF - [Ca2+] = 10-7M Extracellular ECF [Ca2+] = 10-3M 1: 10,000 Ratio [Ca ] 2+ Intracellular Increase Rapidly for Cell Function Stored in Mitochondria and ER Universit y ofGalway. ie Parathyroid Hormone (PTH) Produced by Parathyroid gland (4) Located under thyroid Chief cells Primary function to regulate [Ca2+] in ECF Low Ca → inc secretion of PTH 2+ → PTH act on bone, kidney and intestine → Increases plasma [Ca2+] Universit y ofGalway. ie Parathyroid Hormone (PTH) Polypeptide 84 amino acid residues Peptide fragments can be active for hours Universit y Acts via cAMP second messenger ofGalway. ie Regulation of PTH secretion Ca2+ sensing receptors on chief cell Universit y ofGalway. ie Regulation of PTH Secretion Ca sensing receptors on chief cell 2+ Normal or Increased ECF [Ca2+] – Inhibition of PTH Ca2+ binding → activates PLC →  IP3/Ca2+ → Inhibits PTH Decreased ECF [Ca2+] – Rapid increase in PTH  Ca2+ bound →  PLC activation →  IP3/Ca2+ → No PTH Inhibition Long-term effects - alter gene transcription, synthesis, storage of PTH Universit y ofGalway. ie PTH on Bone PTH receptors on osteoblasts (not osteoclasts) Initially PTH cause increase bone formation (briefly) Basis for PTH in trt osteoporosis Long-lasting effect to increase bone resorption ↑osteoclast activity indirect via cytokines release from osteoblast ↑ no of osteoclasts; ↓ no of osteoblasts Increase Ca2+ and Phosphate to ECF Universit y ofGalway. ie Universit y ofGalway. ie Filtered at glomerulus - calcium enters the proximal tubule Proximal Convoluted and Proximal Straight Tubule 60%–70% of the filtered calcium is reabsorbed Cortical segments of the loop of Henle 20% of the filtered calcium is reabsorbed Distal convoluted tubule Approx. 10% of the filtered calcium is reabsorbed PTH sensitive  Distal Convoluted Tubule Calcium enters the cell via TRPV5 channels Binds calbindin D-28k intracellular Exits the cell by 2 pathways: Sodium/calcium exchanger (NCX1) Calcium (ATPase PMCA4) PTH stimulate calcium absorption via activation of TRPV5, NCX1 Universit y ofGalway. ie PTH on Kidney and Intestine Intestine Indirect action to stimulate Ca2+ absorption Via Activation of Vitamin D Stimulates 1α-hydroxylase and conversion of 25-hydroxycholecalciferol to 1,25- hydroxycholecalciferol Universit y ofGalway. ie