Phys4530B*–*Skeletal*Health*and*Diseases*

Frank*Beier*–*DSB0035A,*;eier@uwo.ca*Cheryle*Séguin*–*cheryle.seguin@schulich.uwo.ca**Stephen*Sims*–*stephen.sims@schulich.uwo.ca*

***

Course'Schedule'

Car.lage'and'Osteoarthri.s'(5'sec.ons;'Beier)'*1.*IntroducIon*to*the*Skeleton*and*Skeletal*Development**–*Jan*7**2.*CarIlage*Biology*and*Pathology*of*OsteoarthriIs*–*Jan*14**3.*Student*Discussions*–*Jan*21***4.*Diseases*of*Ectopic*OssificaIon,*Metabolic*Roles*of*the*Skeleton*–** *Jan*28**5.*Student*Discussions*–*Feb*4**6.*Midterm*Exam*–*Feb*11*

*Spine'and'Skeletal'Regenera.on'(3'sec.ons;'Séguin)'

*7.*Spine*Biology*and*DegeneraIve*Disc*Disease*–*Feb.*25**8.*Skeletal*regeneraIon*–*March*4**9.*Mechanobiology*of*the*skeleton*(Séguin)*–*March*11*

*Bone'and'Osteoporosis'(3'sec.ons;'Dixon)'

*10.*Endocrinology*of*the*skeleton*–*March*18**11.*Bone*remodeling*–*March*25***12.*Osteoporosis*and*related*metabolic*bone*diseases*–*Apr*1*

Marks'and'Exams'

•  10*%*parIcipaIon,*15*%*paper*summary,*25*%*midterm*and*50*%*final*exam*

•  Exams*will*be*largely*short*and*long*answer*quesIons*

•  Emphasis*will*be*on*understanding*concepts*and*connecIng*content*from*different*lectures*

Musculoskeletal'Diseases'in'Canada'

•  More*than*11*million*Canadians*suffer*from*MSK*diseases*(4*million*arthriIs,*the*majority*osteoarthriIs;*2*million*osteoporosis)*

•  In*2000,*MSK*diseases*caused*more*than*22*billion*CAN*$*in*direct*and*indirect*costs*–*the*highest*amount*of*all*disease*groups*

•  Number*of*affected*individuals*and*associated*costs*are*expected*to*raise*dramaIcally*over*the*next*decades*

Public*Health*Agency*of*Canada,*Economic*Burden*of*Illness*in*Canada*2000.*

Costs'of'Major'Diseases'in'Canada'

Musculoskeletal'Diseases'in'Canada'

•  Impact*of*MSK*diseases*is*further*elevated*by*comorbidiIes*and*novel*roles*of*the*skeleton*–  Comorbidity*of*osteoarthriIs*and*other*diseases*–  Bone*controls*stem*cell*niche*in*marrow*(e.g.*hematopoieIc*cells)*

–  The*skeleton*acts*as*regulator*of*whole*body*metabolism**•  Beder*ways*to*prevent,*diagnose*and*treat*MSK*diseases*are*clearly*required*(in*parIcular*for*osteoarthriIs)*

•  But*funding*for*research*on*MSK*diseases*is*disproporIonate*

Musculoskeletal'Diseases'WorldFWide'

•  Lancet*December*2015*–*Global*Burden*of*Disease*Study*–  *examined*global*impact*of*all*major*diseases*

•  MSK*diseases*affect*>*1.7*billion*people*directly*•  4th*greatest*impact*on*death*and*disability*combined*•  Increase*in*burden*from*MSK*disease:*45*%*over*the*last*20*years*

•  Lower*back*pain*leading*cause*of*disability*worldwide,*while*osteoarthriIs*shows*the*most*rapid*increase*

The'Skeleton'

hdp://www.teachpe.com/images/anatomy/skeleton.jpg*

•  Human*adult:*206*bones*•  Formed*through*two*different*processes:*

– Endochondral*ossificaIon*–  Intramembraneous*ossificaIon*

•  Divided*into**– Craniofacial*skeleton*(skull)*– Axial*skeleton*(ribs,*vertebrae)*– Appendicular*skeleton*(limbs)*****

The'Skeleton'

A'typical'long'bone'

hdp://www.bbc.co.uk/schools/gcsebitesize/pe/appliedanatomy/2_anatomy_skeleton_rev4.shtml*

•  LocomoIon*(together*with*muscles,*tendons*etc)*

•  Support*of*body*funcIon,*form*(e.g.*lungs)*•  ProtecIon*of*internal*organs*(brain,*heart*etc)*•  Calcium,*phosphate*homeostasis*•  Bone*marrow:*haematopoiesis*•  Metabolic*control*•  Specialized*funcIons*(e.g.*middle*ear*bones)*

Func.on'of'the'skeleton'

•  Chondrocytes*–*carIlage*cells*•  Osteoblasts*–*bonelforming*cells*(can*differenIate*further*into*osteocytes)*

•  Osteoclasts*–*bonelresorbing*cells*

•  Important:*communicaIon*between*different*cell*types*is*criIcal*for*skeletal*development,*growth*and*funcIon*

Skeletal'cell'types'

hdp://www.scielo.org.ar/scielo.php?pid=S0327l95452005000200002&script=sci_ardext*

Chondrocytes'

Osteoblasts'and'osteoclasts'

Komarova*et*al.,*Bone*2003*

•  Developmental*diseases*– GeneIc*diseases*(chondrodysplasias,*osteogenesis*imperfecta..)*

– Environmental*condiIons*(malnutriIon,*medicaIons,*injuries..)*

•  Diseases*in*the*adult*– OsteoarthriIs*– Osteoporosis*– DegeneraIve*Disc*Disease/Back*Pain*

Diseases'of'the'Skeleton'

•  The*skeleton*is*a*very*complex*organ*with*mulIple*cell*types*that*interact*in*many*ways*

•  In*addiIon,*mechanical*factors*play*a*prominent*role*in*controlling*skeletal*physiology*

•  These*factors*cannot*be*recapitulated*faithfully*in*vitro*

•  Thus,*animal*models*are*required*

How'do'we'study'func.on'and'the'diseases'of'the'skeleton'?'

•  Economic*model*because*of*size,*lifespan*•  Possibility*for*geneIc*manipulaIon*

– Transgenic,*knockout,*knockin,*condiIonal*knockout*

•  GeneIc*modificaIons*can*be*combined*with*other*manipulaIons*– Surgery,*diet,*drugs,*exercise*

The'mouse'as'model'organism'for'studies'on'skeletal'physiology'and'disease'

Skeletal'Development'

Con*******************KO*Con************* ko*************

Two'types'of'bone'forma.on'

Intramembraneous'ossifica.on:'directly*from*precursor*cells;*mostly*bones*of*the*skull**

Endochondral'ossifica.on:'through*a*carIlage*intermediate;*ribs,*vertebrae,*appendicular*skeleton*

Bradley**et*al.,*Crit.*Rev.*Eukaryote*Gene*Expr.*2011*

Intramembraneous'ossifica.on'

Flenniken*et*al.,*Development*2005*

Bones'of'the'skull:'calvariae'

Endochondral'ossifica.on'

Solomon*et*al.,*2008*

Secondary*OssificaIon*Center*

Primary*OssificaIon*Center*

Growth*Plate*resIng*

proliferaIng*

hypertrophic*

epiphysis*

epiphysis*

SOC*

Chondrocyte'Differen.a.on'

Mesenchymal! precursor!

chondroblast! proliferating !chondrocyte!

hypertrophic !chondrocyte!

Sox9!

Collagen X!BSP!MMP13!Cyclin D1!

The'growth'plate'

Nilsson,*Hormone*Res.*2005*

The'growth'plate'

van*der*Eerden,*Endocr*Rev*2003*

•  Endocrine*factors*(Growth*hormone,*IGF,*thyroid*hormone,*glucocorIcoids*etc.)*

•  Local*growth*factors*(Hedgehog,*Wnt,*FGFs,*BMPs,*CNP*etc.)*

•  NutriIon*•  Biomechanical*factors*

Regula.on'of'the'growth'plate'

Agoston*et*al.,*BMC*Dev*Biol*2007*

Regula.on'of'bone'growth'by'CFtype'natriure.c'pep.de'

control' Jasplakinolide'Cytochalasin'D'

1'mm'A.'Woods'

Regula.on'of'bone'growth'by'ac.nFmodifying'drugs'

•  Longitudinal*growth*and*therefore*final*height*is*controlled*by*the*growth*plate*

•  Each*form*of*growth*retardaIon*therefore*involves*the*growth*plate,*directly*or*indirectly*

•  GeneIc*defects*directly*affecIng*the*growth*plates:*chondrodysplasias*

•  Examples*of*chondrodysplasias:*mutaIons*in*FGFR3*(achondroplasia),*Sox9,*collagen*II**

Growth'disorders'

Growth*failure*can*also*be*caused*by:**•  Endocrine*disorders*•  MedicaIon*•  Mal/undernutriIon*

Growth'disorders'II'

Control

10-6 M

10-7 M

10-8 M

1 mm

Dexamethasone'suppresses'bone'growth'

Baybayan,'unpublished'

DMSO*Control*

10l6*M**DEX*

10l7*M**DEX*

10l8*M**DEX*

0.00*

0.25*

0.50*

0.75*

** ** **Average'cha

nge'in'length'

(mm)'

**Significantly*different*with*a*plvalue*less*than*0.05*Treatments'

•  Growth*plate*controls*longitudinal*growth*of*endochondral*bones*

•  However,*ordered*transiIon*from*hypertrophic*carIlage*to*bone*is*equally*important*for*bone*health*

•  This*involves*interacIons*of*chondrocytes,*osteoblasts,*osteoclasts*and*endothelial*cells;*e.g.:*apoptosis*of*chondrocytes,*blood*vessel*invasion,*degradaIon*of*chondrocyte*matrix,*differenIaIon*of*osteoblasts,*modeling*of*bone*

Growth'and'Ossifica.on'

Example:'Car.lage'controls'bone'forma.on'

Car.lage'Development'and'Osteoarthri.s'

chondrogenesis'

car.lage''growth''

car.lage''degrada.on''

permanent''car.lage''

Endochondral''ossifica.on'

Ar.cular''car.lage'

Osteoarthri.s'

Repair?''