Upload
mohan-phaneendra-akana
View
110
Download
1
Embed Size (px)
Citation preview
BONE PHYSIOLOGY & REGULATION OF CALCIUM METABOLISM
-MOHAN PHANEENDRA AKANA 9TH SEMESTER 2012 BATCH ROLL NO:2 NOV 5TH 2016
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}
REQUIREMENTS FOR BONE GROWTH
• CALCIUM• PHOSPHORUS• VITAMIN D & CALCITRIOL• PTH• CALCITONIN• VITAMIN A (FOR GROUND SUBSTANCE)• VITAMIN C• SEX STEROIDS• AMINOACIDS
MARKERS OF BONE DISEASE• GENERAL MARKERS: SERUM CALCIUM SERUM INORGANIC PHOSPHORUS SERUM MAGNESIUM URINARY EXCETION OF Ca & P TOTAL ALKALINE PHOSPHATASE TOTAL ACID PHOSPHATASE
• 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
• MARKERS OF BONE FORMATION: SERUM BONE SPECIFIC ISOENZYME OF ALKALINE PHOSPHATASE SERUM OSTEOCALCIN PROCOLLAGEN TYPE-1 PEPTIDASE
CELLS INVOLVED IN BONE PHYSIOLOGY
• OSTEOPROGENITOR CELLS
• OSTEOBLASTS & LINING CELLS
• OSTEOCYTES
• OSTEOCLASTS
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
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
• 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
OSTEOCYTES• Communicate with each other on the bone surface by means of
CANALICULI
• Control of calcium & phosphate levels
• mechanotransduction
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
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
MARROW STROMAL CELLS
WNT PROTEINS
BINDS TO LRP-5 & LRP-6 RECEPTORS ON OSTEOBLASTS
ACTIVATION OF B-CATENIN PRODUCTION
OSTEOPROTEGRIN
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
• PROTEINS CONCENTRATED FROM SERUM: B2-MICROGLOBULIN ALBUMIN
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)
EARLY IN LIFE
BONE FORMATION PREDOMINATES
SKELETON GROWS & ENLARGES
MODELING
LATER IN LIFE
SKELETAL MATURITY
BREAKDOWN & RENEWALOF BONE
SKELETAL MAINTAINANCE
REMODELING
BONE GROWTH & DEVELOPMENT INTIAL BONES ARE CARTILAGENOUS
OSTEOCLAST-TYPE CELLS REMOVAL OF CARTILAGE
ENCHONDRAL OSSIFICATION
• 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
FACTORS REGULATING CALCIUM LEVEL
• 3 HARMONES: VITAMIN-D PARATHARMONE CALCITONIN
• 3 PRINCIPAL TISSUES: INTESTINES KIDNEYS BONE
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
• 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
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
CaSR
PARATHARMONE
• BONE OSTEOCLASTS
DEMINERALIZATION &DECALCIFICATION
NUMBER INCREASED RELEASE OF LACTATE SECRETION OF COLLAGENASE
SOLUBILIZES COLLAGEN LOSS OF BONE MATRIX & RESORPTION
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
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
CLINICAL PEARLS• OSTEOPOROSIS
• PAGET’S DISEASE
• OSTEOPETROSIS
• OSTEOMALACIA
• RENAL RICKETS
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}
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
OSTEOPETROSIS
• Rare hereditary disorder .
• Defective osteoclastic function and overgrowth of bone.
• SERUM ALKALINE PHOSPHATASE & PTH ARE INCREASED
• SERUM CALCIUM IS USUALLY NORMAL
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
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
• ELEVATED ALKALINE PHOSPHATASE LEVELS.
• URINARY EXCRETION OF CALCIUM AND PHOSPHATE IS DIMINISHED
• PLASMA PTH IS RAISED.
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)
THAN’Q’ 1 & ALL
NO SUPER COMPUTER IS SUPERIOR THAN HUMAN BRAIN,ONLY THING IS WE HAVE TO SORT OUT OUR OWN PASSWORD!!!