Slide 1

Biochemistry Department1

Chemical Composition of BoneChemical Composition of BoneCopyright 2003 Pearson Education, Inc. publishing as Benjamin CummingsChemical Composition of BoneChemical Composition of Bone: InorganicCopyright 2003 Pearson Education, Inc. publishing as Benjamin CummingsOsteoclastsResorbe bone matrix from sites where it is deteriorating or not neededDigest bone matrix componentsFocal decalcification and extracellular digestion by acid hydrolases and uptake of digested materialDisappear after resorptionAssist with mineral homeostasis

Chemistry of the boneMatrixMineral

Matrix - osteoidCollagen type I and VLayers of various orientations (add to the strength of the matrix)Other proteins 10% of the bone protein Direct formation of fibers Enhance mineralization Provide signals for remodeling

MineralA calcium phosphate/carbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2 Hydroxyapatite crystals Imperfect Contain Mg, Na, K

Mineralization of the boneCalcification occurs by extracellular deposition of hydroxyapatite crystalsTrapping of calcium and phosphate ions in concentrations that would initiate deposition of calcium phosphate in the solid phase, followed by its conversion to crystalline hydroxyapatiteMechanisms exist to both initiate and inhibit calcification

Bone remodeling processProceeds in cycles first resorption than bone formationThe calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Bone remodeling cycle (1)Endosteal sinusMonocytePre-osteoclastOsteocyteOsteoclastMacrophagePre-osteoblastOsteoblastBone-lining cellOsteoidNew boneOld boneNon Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Bone remodeling cycle (2)Endosteal sinusMonocytePre-osteoclastOsteocyteOsteoclastMacrophagePre-osteoblastOsteoblastBone-lining cellOsteoidNewboneOldboneNon Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Bone remodeling cycle (3)OsteoclastsMonocytesPre-osteoblastsOsteoblastsOsteocytesNon Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Bone Deposition and ResorptionCa2+ and phosphate concentrations are affected by:Bone formation and resorption.Intestinal absorption of Ca2+ and P043-.Urinary excretion.Osteoblasts:Secrete an organic matrix of collagen proteins.Deposit hydroxyapatite crystals.Osteoclasts:Secrete enzymes to dissolve hydroxyapatite.Formation and resorption of bone occur constantly at rates determined by osteoblasts and osteoclasts.

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Bone Deposition and Resorption (continued)Bone resorption occurs when an osteoclast attaches to the bone matrix and forms ruffled membrane.Osteoclast secretes products that dissolve both Ca2+ and P043- ; and digest the matrix.Transport of H+ by H+ ATPase pump in ruffled border.Cl- channel allows Cl- to flow to H+ to maintain electrical neutrality.Protein matrix digested by cathepsin K.Cytoplasm prevented from becoming to basic by a Cl-/HC03- pump. Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Bone Deposition and Resorption (continued)

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Bone Resorption

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.25Figure 4812. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology: Text & Atlas, 10th ed. McGraw-Hill, 2003.)Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Coordination of Resorption and FormationPhase ISignal from osteoblastsStimulation of osteoblastic precursor cells to become osteoclastsProcess takes 10 days

Coordination of Resorption and FormationPhase IIOsteoclast resorb bone creating cavity Macrophages clean upPhase III New bone laid down by osteoblasts Takes 3 months

Pathways of differentiation ofosteoclasts and osteoblasts

Hormonal InfluenceVitamin DParathyroid HormoneCalcitoninEstrogenAndrogen

Vitamin DOsteoblast have receptors for (1,25-(OH)2-D)Increases activity of both osteoblasts and osteoclastsIncreases osteocytic osteolysis (remodeling)Increases mineralization through increased intestinal calcium absorptionFeedback action of (1,25-(OH)2-D) represses gene for PTH synthesis

Parathyroid HormoneAccelerates removal of calcium from bone to increase Ca levels in bloodPTH receptors present on both osteoblasts and osteoclastsOsteoblasts respond to PTH byChange of shape and cytoskeletal arrangementInhibition of collagen synthesisStimulation of IL-6, macrophage colony-stimulating factor secretionChronic stimulation of the PTH causes hypercalcemia and leads to resorptive effects of PTH on bone

Parathyroid Hormone (PTH)Single most important hormone in the control of blood [Ca2+].Stimulated by decreased blood [Ca2+].Stimulates osteoclasts to reabsorb bone.Stimulates kidneys to reabsorb Ca2+ from glomerular filtrate, and inhibit reabsorption of P043-.Promotes formation of 1,25 vitamin D3.Many cancers secrete PTH-related protein that interacts with PTH receptors.Produce hypercalcemia.CalcitoninC cells of thyroid gland secrete calcitoninStraight chain peptide - 32 aaSynthesized from a large preprohormoneRise in plasma calcium is major stimulus of calcitonin secretionPlasma concentration is 10-20 pg/ml and half life is 5 min

Actions of CalcitoninOsteoclasts are target cells for calcitoninMajor effect of calcitonin is rapid fall of plasma calcium concentration caused by inhibition of bone resorptionMagnitude of decrease is proportional to the baseline rate of bone turnover

CalcitoninWorks with PTH and 1,25 vitamin D3 to regulate blood [Ca2+].Stimulated by increased plasma [Ca2+].Inhibits the activity of osteoclasts. Stimulates urinary excretion of Ca2+ and P043- by inhibiting reabsorption.Physiological significance in adults is questionable. Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.1,25 Vitamin D3Pre-vitamin D3 is synthesized in the skin when exposed to mid-ultraviolet waves.Pre-vitamin D3 isomerized to vitamin D3 (cholecalciferol).Cholecalciferol is hydroxylated in liver to form 25 hydroxycholecalciferol. In proximal convoluted tubule is hydroxylated to 1,25 dihydroxycholecalciferol (active vitamin D3).Stimulated by PTH.Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Production of 1,25 dihydroxyvitamin D3Insert fig. 19.20

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.1,25 dihydroxyvitamin D3 (continued)Directly stimulates intestinal absorption of Ca2+ and P043-.When Ca2+ intake is inadequate, directly stimulates bone reabsorption.Stimulates reabsorption of Ca2+ and P043- by the kidney.Simultaneously raising Ca2+ and P043- results in increased tendency of these 2 ions to precipitate as hydroxyapatite crystals.Stimulated by PTH.Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Negative Feedback ControlInsert fig. 19.23

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Other systemic hormonesEstrogensIncrease bone remodelingAndrogensIncrease bone formation

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.Other systemic hormonesGrowth hormoneIncreases bone remodelingGlucocorticoidsInhibit bone formationThyroid hormonesIncrease bone resorptionIncrease bone formation

Non Commercial Use OnlyInformation and material on slide kit may be reproduced and distributed for educational use only For commercial usage, please contactthe webmaster for permission.Copyright 2006, Les Laboratoires Servier - all rights reserved.

Figure 6.12Hormonal Control of Blood CaFigure 6.11

Rising bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlImbalanceImbalanceFigure 6.11

ThyroidglandRising bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlImbalanceImbalanceFigure 6.11

PTH;calcitoninsecretedThyroidglandRising bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlImbalanceImbalanceHormonal Control of Blood CaFigure 6.11

Calcitoninstimulatescalcium saltdepositin boneThyroidglandRising bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlImbalanceImbalancePTH;calcitoninsecretedHormonal Control of Blood CaFigure 6.11

Calcitoninstimulatescalcium saltdepositin boneThyroidglandRising bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlPTH;calcitoninsecretedHormonal Control of Blood Ca

Falling bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlImbalanceImbalanceFigure 6.11Hormonal Control of Blood Ca

Parathyroidglands releaseparathyroidhormone (PTH)ThyroidglandParathyroidglandsFalling bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlImbalanceImbalanceFigure 6.11Hormonal Control of Blood Ca

Parathyroidglands releaseparathyroidhormone (PTH)ThyroidglandParathyroidglandsFalling bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlPTHImbalanceImbalanceFigure 6.11Hormonal Control of Blood Ca

Parathyroidglands releaseparathyroidhormone (PTH)ThyroidglandParathyroidglandsOsteoclastsdegrade bonematrix and releaseCa2+ into bloodFalling bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlPTHImbalanceImbalanceFigure 6.11Hormonal Control of Blood Ca

Parathyroidglands releaseparathyroidhormone (PTH)ThyroidglandParathyroidglandsOsteoclastsdegrade bonematrix and releaseCa2+ into bloodFalling bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlPTHFigure 6.11Hormonal Control of Blood CaFigure 6.11

Calcitoninstimulatescalcium saltdepositin boneParathyroidglands releaseparathyroidhormone (PTH)ThyroidglandThyroidglandParathyroidglandsOsteoclastsdegrade bonematrix and releaseCa2+ into bloodFalling bloodCa2+ levelsRising bloodCa2+ levelsCalcium homeostasis of blood: 911 mg/100 mlPTHImbalanceImbalancePTH;calcitoninsecretedHormonal Control of Blood CaEpiphyseal plate new bone growth siteChondrocytes, osteoblasts & calcification build boneBone Growth and Calcium MetabolismCopyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings6-56Calcium HomeostasisBone is major storage site for calciumThe level of calcium in the blood depends upon movement of calcium into or out of bone.Calcium enters bone when osteoblasts create new bone; calcium leaves bone when osteoclasts break down boneTwo hormones control blood calcium levels- parathyroid hormone and calcitonin.566-57Calcium Homeostasis

57Bone Growth and Calcium MetabolismFigure 23-19: Bone growth at the epiphyseal plate

Copyright 2004 Pearson Education, Inc., publishing as Benjamin CummingsMaintain [plasma]: from diet, from bone "storage", recycledKey roles: muscle contraction, bone support, cell signalingCalcium Metabolism:PLAYAnimation: Fluids & Electrolytes: Electrolyte HomeostasisCopyright 2004 Pearson Education, Inc., publishing as Benjamin CummingsCalcium Metabolism:Figure 23-20: Calcium balance in the body

Copyright 2004 Pearson Education, Inc., publishing as Benjamin CummingsControl of Calcium Balance & MetabolismFigure 23-23: Endocrine control of calcium balanceParathyroid HCalcitrolVitamin DSun/dietCalcitoninThyroidC-cells(Phosphate balance)Copyright 2004 Pearson Education, Inc., publishing as Benjamin CummingsOsteoporosis: Disease of Bone Growth & Calcium MetabolismFigure 23-21: Osteoclasts are responsible for bone resorption

Bone reabsorption exceeds depositionOsteoclasts mobilize Ca++ to plasmaFactors: inadequate Ca++ intake, genes, hormones, smokingCopyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings

PTH, Calcium & PhosphateWhat is cartilage?Skeletal tissue--maintains certain shape and formVery resilient (bouncy or rubbery), mostly waterGrows fast--forms embryonic skeletonCopyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings64Kinds of cartilageHyaline cartilage--most common, found in jointsElastic cartilage--epiglottis, earFibrocartilage--annular fibrosis of intervertebral disk, menisci of kneeCopyright 2004 Pearson Education, Inc., publishing as Benjamin Cummings65

cartilage

Cells of Bone Tissue