Formation and degradation of bone, markers of bone turnover 2022.pdf

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1. Formation and degradation of
bone, markers of bone turnover
(C) Natalia Dachanidze

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3. Bone forming cells
•Osteoblastsarederivedfrom
stromal stem cells
(fibroblastcolonyforming
units, F-CFU) that
differentiate into
osteoprogenitorcells.
•Thesamestemcellscanalso
give rise to
fibroblasts,endothelialcells
oradipocytes.
•Inmore mature bone,
osteoprogenitor cellsare
presentattheperiosteumand
stemcellsarepresentinbone
marrow.
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4. •The osteoprogenitorcells may differentiate into
chondrocytesor osteoblasts.
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5. Bone resorbingcells
•Osteoclastsarenotderivedfromstromalstemcells,
butinsteadareofhematopoieticorigin.
•Theyarederivedfromapluripotenthematopoietic
stemcell(granulocyte/macrophagecolonyforming
unit,GM-CFU),whichcandifferentiateintoa
monocyte progenitor cell or into
erythrocytes,granulocytes,lymphocytes and
megakaryocytes.
•Theosteoclastisresponsibleforboneresorption
associatedwithbonemodeling,remodelingand
pathology.
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8. Resorption
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13. Alkaline phosphataseaction
•Normally,bone-formingcellscalledosteoblasts
secretepacketsoftheenzymealkaline
phosphatase.
•Thesepacketsreleasephosphategroupsfrom
thesurfaceofcells,whichthencombinewith
calciumandtogetherdepositinthematrixas
"bonecrystals,".
•Inhypophosphatasiathesepacketsofalkaline
phosphatasearemissing.Thusthematrix
cannotcalcifyandtheboneremainssoft
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14. 1.Thealkalinephosphatase’smainfunctionistoremovethe
phosphategroupfromtheproteinsandothermolecules.
1.ALPisassociatedwithlipidtransportintheintestine.
2.ALPisalsoassociatedwiththecalcificationprocessofthe
bone.
3.AlkalinephosphataseiscalledAlkalinebecauseitsfunctionis
seenbetweenapHof9to10andbestatapHof9.0
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16. Effect of ALP on bone:
1.Thestimuluswhichincreasesboneactivitycauses
anincreaseintheALPlevel.Soelevatedlevels
indicateliverorbonediseases.
2.Bonealkalinephosphataseisproducedbythe
osteoblastoftheboneandnotfromtheosteoclasts.
3.ALPlevelrisesduringactiveboneformationlikein
infants,children,andadolescents.Sotheyhave
raisedthelevelto3timesofthenormthanthe
adults.
4.Bonealkalinephosphataseindicatesbone-forming
activity.
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17. Modeling
•Thealterationinthesizeandshapeofbones
duringgrowthbytheprocessesofbone
formationandresorptionistermedmodeling.
•Ineachcaseitisduetotheprocessesofbone
formation and resorptionoccuring
independentlyatdifferentsites.
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21. Remodeling
•Boneremodelingoccursthroughoutlife.
Innewboneitgivesrisetotheconversionof
wovenboneintomaturelamellarbone,andin
matureboneitaccountsforthecontinuous
turnoverofbonethatisnecessaryfor
maintenanceofitsstructureandcalcium
homeostasis.
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25. ➢Coupling
Theprocessesofbonesynthesisandbonebreakdowngoon
simultaneouslyandthestatusofthebonerepresentsthenetresultof
abalancebetweenthetwoprocesses.Thisphenomenoniscalled
coupling.
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26. Functions of remodelling
▪To prevent accumulation of damaged bone by regenerating
new bone.
▪Allowing to respond to the changes in mechanical forces.
▪Mineral homeostasis.
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27. MEDIATORSOFBONEREMODELLING :
▪Parathyroidhormone
▪Calcitonin
▪VitaminDmetabolitesi.e.,1,25-dihydroxycholecalciferol
▪Cytokines
▪Prostaglandins
▪Growthfactors
▪Mechanicalfactors
▪Bacterialproducts.
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29. MARKERSOFBONETURNOVER:
Themarkersofboneformationare:(serummarkers)
•Alkalinephosphatase(total)
•Alkalinephosphatase(skeletalisoenzymes)
•Osteocalcin
•ProcollagenIextensionpeptide
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30. Themarkersofboneresorptionare:(urinarymarkers)
•Urinecalcium
•Urinehydroxyproline
•Collagencrosslinkingfragments
•UrineN–telopeptide
•UrineC-telopeptide
•Urinetotalpyridinoline
•Urinefreedeoxypyridinoline
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32. Markers of bone formation
1.Bone-specificalkalinephosphatase
(BAP,boneALP)-Specificproductof
osteoblasts.Someassaysshowupto20%
cross-reactivitywiththeliverisoenzyme(LAP)
2.Osteocalcin(OC)-Specificproductof
osteoblasts;manyimmunoreactiveformsin
blood;somemaybederivedfrombone
resorption.
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33. Markers of bone formation
•3)C-terminalpropeptideoftypeI
procollagen(PICP)-Specificproductof
proliferatingosteoblastsandfibroblasts.
•4)N-terminalpropeptideoftypeI
procollagen(PINP)-Specificproductof
proliferatingosteoblastandfibroblasts;partly
incorporatedintoboneextracellularmatrix.
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34. Collagen-related markers
1.Hydroxyproline,totalanddialysable(Hyp)-
Presentinallfibrillarcollagensandpartly
collagenousproteins,includingC1qandelastin.
Presentinnewlysynthesisedandmaturecollagen,
i.e.bothcollagensynthesisandtissuebreakdown
contributetourinaryhydroxyproline.
2.Hydroxylysine-glycosides-Hydroxylysinein
collagenisglycosylatedtovaryingdegrees,
dependingontissuetype.Glycosylgalactosyl-
OHLysinhighproportionincollagensofsoft
tissues,andC1q;Galyctosyl-OHLysinhigh
proportioninskeletalcollagens.
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35. •4)Pyridinoline(PYD)-Collagens,withhighest
concentrationsincartilageandbone;absent
fromskin;presentinmaturecollagenonly.
•5)Deoxypyridinoline(DPD)-Collagens,with
highestconcentrationinbone;absentfrom
cartilageorskin;presentinmaturecollagen
only.
•6) Carboxyterminal cross-linked
telopeptideoftypeIcollagen(ICTP,CTX-
MMP)-CollagentypeI,withhighest
contributionprobablyfrombone;maybe
derivedfromnewlysynthesisedcollagen.
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36. Non-CollagenousProteins
1.Bone Sialoprotein (BSP)- Acidic,
phosphorylatedglycoprotein,synthesisedby
osteoblastsandosteoclastic-likecells,laiddown
inboneextracellularmatrix.Appearstobe
associatedwithosteoclastfunction.
2.Osteocalcinfragments(ufOC,U-Mid-OC,U-
LongOC)-Certainage-modifiedOCfragmentsare
releasedduringosteoclasticboneresorptionand
maybeconsideredanindexofboneresorption.
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37. OsteoclastEnzymes
1.Cathepsins(e.g.K,L)-CathepsinK,a
cysteineprotease,playsanessentialrolein
osteoclast-mediatedbonematrixdegradation
bycleavinghelicalandtelopeptideregionsof
collagentypeI.CathepsinKandLcleavethe
loopdomainofTRAPandactivatethelatent
enzyme.CathepsinLhasasimilarfunctionin
macrophages.
(C) Natalia Dachanidze