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

a. Mesenchymalcondensa)onsb. Chondrogenesisand

chondrocyteprolifera)onc. Onsetofhypertrophyd. Terminalchondrocyte

differen)a)one.  Primaryossifica)oncenter

forma)onf-g. Establishmentofepiphyseal

growthplatesandsecondaryossifica)oncenters

Kronenberg,H.(2003)Nature.423:332-336.

E14.5

E15.5 E18.5 Postnatal

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Mouse E18.5 Proximal Tibia

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Runx2 mutant mice (null) Osterix mutant mice (null)

Nakashima K et al., (2002) Cell (108)1:17-29. Otto F et al., (1997) Cell (89)5:765-771.

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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MolecularRegulaFonofJointDevelopment

Koyama,etal.(2008)DevelopmentalBiology.1:62-73.