OBS 2017 Jonason - Welcome to URMC - Rochester, NYHuman Disorders of Skeletal Paerning,...
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Skeletal Development Jennifer H. Jonason, Ph.D. Assistant Professor of Orthopaedics and Rehabilita5on Center for Musculoskeletal Research Orthopaedic Basic Science Course Spring 2017
Transcript of OBS 2017 Jonason - Welcome to URMC - Rochester, NYHuman Disorders of Skeletal Paerning,...
SkeletalDevelopment
JenniferH.Jonason,Ph.D.AssistantProfessorofOrthopaedicsandRehabilita5on
CenterforMusculoskeletalResearch
OrthopaedicBasicScienceCourseSpring2017
LectureObjecFves
• Introduc)ontolimbpa1erningandthesignalingcenters/pathwaysresponsibleforproximal-to-distalandanterior-to-posteriorpa1erning
• Introduc)on/reviewofintramembranousandendochondralboneforma)onandmesenchymalprogenitorcelldifferen)a)on
• Introduc)ontojointforma)onandgeneexpressionpa1ernscharacteris)cofadevelopingjoint
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Patterning: the process in which the positions and identities of cells with different fates are laid down. Specification: the process preceding determination during which a cell acquires its fate. The exposure of specified cells to different signals might alter their fates; the fate of specified cells is not fixed. Determination: When cell fate is fixed so that the cell will initiate differentiation into the specified cell type even if the cell is isolated or transplanted into a different environment or tissue; occurs before the appearance of sell-type-specific morphological characteristics, but is often followed by differentiation.
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•! Polydactyly (extra digits) •! Oligodactyly (missing digits) •! Amelia (absence of limbs) •! Meroamelia (partial absence of a limb)
•! Brachydactyly (shortened digits) •! Campomelic Dysplasia (SOX9 haploinsufficiency) •! Ellis-van Creveld Syndrome (EVC mutations) •! Cleidocranial Dysplasia (RUNX2 haploinsufficiency)
•! Dwarfing Chondrodysplasias •! Hypochondroplasia •! Achondroplasia •! Thanatophoric Dysplasia
•! Craniosynostosis syndromes
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•! Polydactyly (extra digits) •! Oligodactyly (missing digits) •! Amelia (absence of limbs) •! Meroamelia (partial absence of a limb)
•! Brachydactyly (shortened digits) •! Campomelic Dysplasia (SOX9 haploinsufficiency) •! Ellis-van Creveld Syndrome (EVC mutations) •! Cleidocranial Dysplasia (RUNX2 haploinsufficiency)
•! Dwarfing Chondrodysplasias •! Hypochondroplasia •! Achondroplasia •! Thanatophoric Dysplasia
•! Craniosynostosis syndromes
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•! Polydactyly (extra digits) •! Oligodactyly (missing digits) •! Amelia (absence of limbs) •! Meroamelia (partial absence of a limb)
•! Brachydactyly (shortened digits) •! Campomelic Dysplasia (SOX9 haploinsufficiency) •! Ellis-van Creveld Syndrome (EVC mutations) •! Cleidocranial Dysplasia (RUNX2 haploinsufficiency)
•! Dwarfing Chondrodysplasias •! Hypochondroplasia •! Achondroplasia •! Thanatophoric Dysplasia
•! Craniosynostosis syndromes
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Tetra-amelia (mutations in WNT3)
HumanDisordersofSkeletalPaGerning,DifferenFaFon,andGrowth
• Polydactyly (extra digits) • Oligodactyly (missing digits) • Amelia (absence of limbs) • Meroamelia (partial absence of a limb)
• Brachydactyly (shortened digits) • Campomelic Dysplasia (SOX9 haploinsufficiency) • Ellis-van Creveld Syndrome (EVC mutations) • Cleidocranial Dysplasia (RUNX2 haploinsufficiency)
• Dwarfing Chondrodysplasias • Hypochondroplasia • Achondroplasia • Thanatophoric Dysplasia
• Craniosynostosis syndromes
Forreview,KornakandMundlos(2003)Am.J.Hum.Genet.73:447-474.
IntramembranousversusEndochondralOssificaFon
• Intramembranous: bone formation directly from mesenchymal condensations; flat bones (skull, mandible, clavicles)
• Endochondral: bone formation following the formation of a hyaline cartilage
template; all other bones (long bones, etc.)
AdaptedfromOrnitzandMarie(2002)GenesandDevelopment.16:1446-65.
EndochondralBoneFormaFon
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chondrocyteprolifera)onc. Onsetofhypertrophyd. Terminalchondrocyte
differen)a)one. Primaryossifica)oncenter
forma)onf-g. Establishmentofepiphyseal
growthplatesandsecondaryossifica)oncenters
Kronenberg,H.(2003)Nature.423:332-336.
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CleidocranialDysplasia(CCD)• AutosomaldominantdisorderduetohaploinsufficiencyofRUNX2• Clinicalfeaturesinclude;hypoplas)cclavicles,delayedossifica)onofthe
cranialsuturesandfontanelles,dentalanomalies,andshortstature• Atriskfordevelopmentofosteoporosisandfracture
OGo,et. al. (1997)Cell.89:765-771.
WT Runx2+/-
hGp://denFstryandmedicine.blogspot.com/2011/05/cleidocranial-dysostosis-cleidocranial.html
hGp://drgstoothpix.com/2014/05/09/case-of-the-week-cleidocranial-dysplasia/
Supernumeraryteeth
HumanDisordersofSkeletalPaGerning,DifferenFaFon,andGrowth
• Polydactyly (extra digits) • Oligodactyly (missing digits) • Amelia (absence of limbs) • Meroamelia (partial absence of a limb)
• Brachydactyly (shortened digits) • Campomelic Dysplasia (SOX9 haploinsufficiency) • Ellis-van Creveld Syndrome (EVC mutations) • Cleidocranial Dysplasia (RUNX2 haploinsufficiency)
• Dwarfing Chondrodysplasias • Hypochondroplasia • Achondroplasia • Thanatophoric Dysplasia
• Craniosynostosis syndromes
Forreview,KornakandMundlos(2003)Am.J.Hum.Genet.73:447-474.
HumanDisordersofSkeletalPaGerning,DifferenFaFon,andGrowth
• Polydactyly (extra digits) • Oligodactyly (missing digits) • Amelia (absence of limbs) • Meroamelia (partial absence of a limb)
• Brachydactyly (shortened digits) • Campomelic Dysplasia (SOX9 haploinsufficiency) • Ellis-van Creveld Syndrome (EVC mutations) • Cleidocranial Dysplasia (RUNX2 haploinsufficiency)
• Dwarfing Chondrodysplasias (caused by activating FGFR3 mutations) • Hypochondroplasia (least severe; short stature) • Achondroplasia (most common; short stature, frontal bossing) • Thanatophoric Dysplasia (most severe; most patients die of respiratory
distress following birth)
• Craniosynostosis syndromes (premature closure of sutures)
Forreview,KornakandMundlos(2003)Am.J.Hum.Genet.73:447-474.
FGFR3MouseModels
FGFR3AcFvaFon(FGFR3G374Rneo−/+)Achondroplasiamodel
Wang,et. al. (1999)PNAS.96:4455-4460.
Chondrocyte-specificlossofFgfr3leadstoenhancedproliferaFonandmaturaFon
Zhou,et. al. (2015)PlosGenet.11:ePub.
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Yoon,etal.(2006)Development.133:4667-4678.
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