bone physiology & regulation of calcium metabolism

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BONE PHYSIOLOGY & REGULATION OF CALCIUM METABOLISM -MOHAN PHANEENDRA AKANA 9 TH SEMESTER 2012 BATCH ROLL NO:2

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Page 1: Bone physiology & regulation of calcium metabolism

BONE PHYSIOLOGY & REGULATION OF CALCIUM METABOLISM

-MOHAN PHANEENDRA AKANA 9TH SEMESTER 2012 BATCH ROLL NO:2 NOV 5TH 2016

Page 2: Bone physiology & regulation of calcium metabolism

ORGANIC & INORGANIC CONSTITUENTS OF BONE

MATRIX• ORGANIC MATRIX: 35% GROUND SUBSTANCE GAGs , Proteoglycans , water GLYCOPROTEINS OSTEONECTIN , OSTEOCALCIN TYPE II COLLAGEN

• INORGANIC IONS : 65 % CALCIUM + PHOSPHATE + HYDROXYL IONS = Ca10(PO4)6(OH)2 {CALCIUM HYROXYAPATITE}

Page 3: Bone physiology & regulation of calcium metabolism

REQUIREMENTS FOR BONE GROWTH

• CALCIUM• PHOSPHORUS• VITAMIN D & CALCITRIOL• PTH• CALCITONIN• VITAMIN A (FOR GROUND SUBSTANCE)• VITAMIN C• SEX STEROIDS• AMINOACIDS

Page 4: Bone physiology & regulation of calcium metabolism

MARKERS OF BONE DISEASE• GENERAL MARKERS: SERUM CALCIUM SERUM INORGANIC PHOSPHORUS SERUM MAGNESIUM URINARY EXCETION OF Ca & P TOTAL ALKALINE PHOSPHATASE TOTAL ACID PHOSPHATASE

Page 5: Bone physiology & regulation of calcium metabolism

• MARKERS OF BONE RESORPTION: TARTARATE RESISTANT ACID PHOSPHATASE(TRAP) TELOPEPTIDES & PYRIDINIUM CROSS LINKS DERIVED FROM

COLLAGEN URINARY HYDROXYPROLINE EXCRETION SERUM CARBOXY TERMINAL TELOPEPTIDE OF TYPE-1 COLLAGEN (s-

CTx) N-TELOPEPTIDE OF TYPE-1 COLLAGEN

Page 6: Bone physiology & regulation of calcium metabolism

• MARKERS OF BONE FORMATION: SERUM BONE SPECIFIC ISOENZYME OF ALKALINE PHOSPHATASE SERUM OSTEOCALCIN PROCOLLAGEN TYPE-1 PEPTIDASE

Page 7: Bone physiology & regulation of calcium metabolism

CELLS INVOLVED IN BONE PHYSIOLOGY

• OSTEOPROGENITOR CELLS

• OSTEOBLASTS & LINING CELLS

• OSTEOCYTES

• OSTEOCLASTS

Page 8: Bone physiology & regulation of calcium metabolism

OSTEOPROGENITOR CELLS• Pleuripotent mesenchymal cells

• Vicinity of all bone surfaces

• Stimulated by growth factors

• Differentiated into osteoblasts

• By the process,RUNX2/CBFA1 transcription factor network & WNT/B-catenin signaling pathway

Page 9: Bone physiology & regulation of calcium metabolism

OSTEOBLASTS & LINING CELLS• Locate on the surface of the cells

• Synthesize , transport & arrange many proteins of matrix

• Initiate the process of mineralization

• Posses receptors that bind regulatory harmones ,cytokines , growth factors ,extracellular matrix proteins

Page 10: Bone physiology & regulation of calcium metabolism

• Several factors that regulate the differentiation & function of osteoclasts

• If these are surrounded by newly deposited organic matrix , they transform into osteocytes

• DEPOSIT BONE: RANDOM WEAVE WOVEN BONE ORDERLY LAYERED MANNER LAMELLAR BONE

Page 11: Bone physiology & regulation of calcium metabolism

OSTEOCYTES• Communicate with each other on the bone surface by means of

CANALICULI

• Control of calcium & phosphate levels

• mechanotransduction

Page 12: Bone physiology & regulation of calcium metabolism

OSTEOCLASTS• Responsible for bone resorption

• M-CSF,IL-1,TNF(CYTOKINES & GF)HUMAN OSTEOCLAST DIFFERENTIATION & MATURATION

• Binds to bone surface by INTEGRINS

• Forms resorption pit(RESORPTION BAYS or LACUNAE OF HOWSHIP)

• Removes mineral by generating an acidic environment utilizing proton pump system & digests the organic component by releasing PROTEASES

Page 13: Bone physiology & regulation of calcium metabolism

PARACRINE MOLECULAR MECHANISM

1)The transmembrane receptor RANK (RECEPTOR ACTIVATOR FOR NF-KB)

2)RANK LIGAND(expressed on osteoblasts & marrow stromal cells)

3)OSTEOPROTEGRIN

• NF-KBGENERATION & SURVIVAL OF OSTEOCLASTS• TYROSINE KINASE ACTIVITYGENERATION OF OSTEOCLASTS• BONE RESORPTION & BONE PRODUCTION DEPENDS ON RANKL:OPG RATIO

Page 14: Bone physiology & regulation of calcium metabolism
Page 15: Bone physiology & regulation of calcium metabolism

MARROW STROMAL CELLS

WNT PROTEINS

BINDS TO LRP-5 & LRP-6 RECEPTORS ON OSTEOBLASTS

ACTIVATION OF B-CATENIN PRODUCTION

OSTEOPROTEGRIN

Page 16: Bone physiology & regulation of calcium metabolism

PROTEINS OF BONE MATRIX• OSTEOBLAST DERIVED PROTEINS: TYPE-1 COLLAGEN CELL ADHESION PROTEINSOSTEOPONTIN FIBRONECTIN THROMBOSPONDIN CALCIUM BINDING PROTEINSOSTEONECTIN BONE SIALOPROTEIN PROTEINS INVOLVED IN MINERALIZATIONOSTEOCALCIN ENZYMES COLLAGENASE,ALKALINE PHOSPHATASE

GROWTH FACTORS IGF-1,TGF-B,PDGF CYTOKINES IL-1,IL-6,RANKL

Page 17: Bone physiology & regulation of calcium metabolism

• PROTEINS CONCENTRATED FROM SERUM: B2-MICROGLOBULIN ALBUMIN

Page 18: Bone physiology & regulation of calcium metabolism

BONE MODELING,REMODELING &PEAK BONE MASS

• Local collection of osteocytes , osteoblasts & osteoclasts work together to control bone formation and resorption creating a functional unit

BASIC MULTICELLULAR UNIT(BMU)

Page 19: Bone physiology & regulation of calcium metabolism

EARLY IN LIFE

BONE FORMATION PREDOMINATES

SKELETON GROWS & ENLARGES

MODELING

LATER IN LIFE

SKELETAL MATURITY

BREAKDOWN & RENEWALOF BONE

SKELETAL MAINTAINANCE

REMODELING

Page 20: Bone physiology & regulation of calcium metabolism

BONE GROWTH & DEVELOPMENT INTIAL BONES ARE CARTILAGENOUS

OSTEOCLAST-TYPE CELLS REMOVAL OF CARTILAGE

ENCHONDRAL OSSIFICATION

Page 21: Bone physiology & regulation of calcium metabolism

• PRIMARY CENTRE OF OSSIFICATION: periosteum in the mid-shaft generates osteoblasts that deposit the beginning of cortex

• SECONDARY CENTRE OF OSSIFICATION:• sequence of events occurs in the EPIPHYSIS,resulting in the removal

of cartilage & deposition of bone in centrifugal fashion

• GROWTH PLATE: A plate of cartilage entrapped between centres of ossification

Page 22: Bone physiology & regulation of calcium metabolism

FACTORS REGULATING CALCIUM LEVEL

• 3 HARMONES: VITAMIN-D PARATHARMONE CALCITONIN

• 3 PRINCIPAL TISSUES: INTESTINES KIDNEYS BONE

Page 23: Bone physiology & regulation of calcium metabolism

STEPS IN VITAMIN-D3(CALCITRIOL) METABOLISM

• Photochemical synthesis of VIT-D from 7-dehydrocholestrol in the skin & absorption of VIT-D from foods & supplements in the gut

• Binding of VIT-D from both sources to PLASMA ALPHA 1 GLOBULIN (D-Binding protein or DBP) & transport to liver

• Conversion of VIT-D into 25-HYDROXY CHOLECALCIFEROL(25-OH-D) in the liver,through the effect of 25-Ohases

• Conversion of 25-OH-D into 1,25-DIHYDROXYVITAMIN D

Page 24: Bone physiology & regulation of calcium metabolism
Page 25: Bone physiology & regulation of calcium metabolism

• VITAMIN-D is acting independently on bone• VIT-D increases & activity of OSTEOBLASTS , the bone forming cells• CALCITRIOL stimulates

osteoblast

secrete ALKALINE PHOSPHATASE

the local concentration of phosphate is increased

Ionic product : calcium + phosphorus mineralization

Page 26: Bone physiology & regulation of calcium metabolism

PARATHARMONE(PTH) PTH activates adenyl cyclase to form cAMP

cAMP increases synthesis of lysosomal enzymes

Enzymes break the bony organic matrix and releases calcium

Net effect of PTH is increase serum Ca & decrease serum phosphate

Page 27: Bone physiology & regulation of calcium metabolism

CaSR

Page 28: Bone physiology & regulation of calcium metabolism

PARATHARMONE

• BONE OSTEOCLASTS

DEMINERALIZATION &DECALCIFICATION

NUMBER INCREASED RELEASE OF LACTATE SECRETION OF COLLAGENASE

SOLUBILIZES COLLAGEN LOSS OF BONE MATRIX & RESORPTION

Page 29: Bone physiology & regulation of calcium metabolism
Page 30: Bone physiology & regulation of calcium metabolism

CALCITONIN• Calcitonin decreases serum calcium level

• It inhibits resorption of bone

• It decreases the activity of osteoclasts and increases that of osteoblasts

• PTH & CALCITONIN are directly antagonistic

Page 31: Bone physiology & regulation of calcium metabolism
Page 32: Bone physiology & regulation of calcium metabolism

VITAMIN-DSTIMULATIONelevated PTH Decreased serum calciumdecreased serum phosphate

INHIBITIONDecreased PTH Increased serum calcium increased serum phosphate

PARATHORMONE(PTH)STIMULATIONdecreased serum ca levels

INHIBITIONelevated serum ca levels and 1,25(OH)2D

CALCITONINSTIMULATIONIncreased Calcium levels

INHIBITIONDecreased serum calcium levels

Page 33: Bone physiology & regulation of calcium metabolism

CLINICAL PEARLS• OSTEOPOROSIS

• PAGET’S DISEASE

• OSTEOPETROSIS

• OSTEOMALACIA

• RENAL RICKETS

Page 34: Bone physiology & regulation of calcium metabolism

OSTEOPOROSIS• Most common metabolic bone disease.

• Rate of resorption > rate of bone formation.

• SERUM CALCIUM• SERUM PHOSPHATE NORMAL LIMITS• ALKALINE PHOSPHATASE{if there is hypercalcemia primary hyperparathyroidism should be ruled out}

Page 35: Bone physiology & regulation of calcium metabolism

PAGET’S DISEASE• Osteoclasts become abnormally activated

• Irregular pattern of resorption

• Intense osteoblastic response with irregular new bone formation is seen.

• ELEVATED ALKALINE PHOSPHATASE LEVELS

• SERUM Ca & PHOSPHATE LEVELS ARE USUALLY NORMAL

Page 36: Bone physiology & regulation of calcium metabolism

OSTEOPETROSIS

• Rare hereditary disorder .

• Defective osteoclastic function and overgrowth of bone.

• SERUM ALKALINE PHOSPHATASE & PTH ARE INCREASED

• SERUM CALCIUM IS USUALLY NORMAL

Page 37: Bone physiology & regulation of calcium metabolism

OSTEOMALACIA• Bone softening of bone in adult due to deficiency of vitamin D.

• when vitamin d is lowdecreased resorption and decreased absorption from intestine.

• LOW SERUM Ca LEVEL & PHOSPHATE

• ALKALINE PHOSPHATASE IS HIGH

Page 38: Bone physiology & regulation of calcium metabolism

RENAL RICKETS [RENAL OSTEODYSTROPHY]

Patients with chronic renal failure

Liable to bone change that affect bone formation and mineralization Signs of secondary hyperparathyroidism is severe

Biochemical features like low serum calcium &high serum phosphate

Page 39: Bone physiology & regulation of calcium metabolism

• ELEVATED ALKALINE PHOSPHATASE LEVELS.

• URINARY EXCRETION OF CALCIUM AND PHOSPHATE IS DIMINISHED

• PLASMA PTH IS RAISED.

Page 40: Bone physiology & regulation of calcium metabolism

REFERENCES:• PATHOLOGIC BASIS OF DISEASE– ROBBINS & COTRAN (8TH EDITION)

• TEXT BOOK OF BIOCHEMISTRY FOR MEDICAL STUDENTS-DM VASUDEVAN(6TH EDITION)

• HARRISON’S PRINCIPLES OF GENERAL MEDICINE (19TH EDITION)

• TEXT BOOK OF HUMAN HISTOLOGY--INDERBIR SINGH (6TH EDITION)

• HUMAN EMBRYOLOGY– INDERBIR SINGH (9TH EDITION)

Page 41: Bone physiology & regulation of calcium metabolism

THAN’Q’ 1 & ALL

NO SUPER COMPUTER IS SUPERIOR THAN HUMAN BRAIN,ONLY THING IS WE HAVE TO SORT OUT OUR OWN PASSWORD!!!