patricia ducy hhsc1616 x5-9299 pd2193@columbia · 3 embryonic origin of the skeleton chondrocytes...
TRANSCRIPT
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• ≥ 200 elements
• Two tissues: cartilage, bone
• Three cell types: chondrocytes, osteoblasts, osteoclasts
• Three “environments”: marrow, blood, SNS
Skeleton
Growth Formation Resorption
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Embryonic origin of the skeleton
Chondrocytes & Osteoblasts Osteoclasts
Cranial neural crest cells
Somitic mesoderm
Lateral plate mesoderm
Craniofacial skeleton
Axial skeleton
Appendicular Skeleton
Monocyte lineage
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Skeleton Biology
Patterning
Skeletogenesis
Homeostasis
Dev
elop
men
t Li
fe
Location and shape of skeletal elements
Differentiated cells Bone structure Growth/Modeling
Remodeling Balance between Formation/Resorption
Fracture repair
Birth
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Skeleton Pathologies
Patterning
Skeletogenesis
Homeostasis
Dev
elop
men
t Li
fe
Dysostoses
Dysplasia
Mineralization defects Degenerative diseases
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Genetic defects associated with skeleton development
(RUNX2)
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Skeleton patterning • Condensation of mesenchymal cells to form the scaffold
of each future skeletal element – Migration – Adhesion – Proliferation
• Early steps use signaling molecules and pathways generally involved in patterning other tissues (FGFs, Wnts, BMPs)
• Orchestrated by specific set of genes acting as territories organizers
• When not embryonic lethal disorders often localized
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Hox transcription factors
• First described in Drosophila where they control body plan organization
• Arranged in 4 genomic clusters in mammals
• Expression patterns follow the cluster arrangement
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Homeotic transformations in absence of Hox transcription factors
Wellik, Dev. Dynamics 236 (2007)
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Hox transcription factors control vertebrate limb patterning
BHoxA/HoxD
clusters
* only in HoxD cluster
9 10 11 12* 13 Genomic organization
Site of expression
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Mutations in HOXD13 cause synpolydactyly*�in humans
Muragaki et al., Science 272 (1996)
*OMIM 18600, 186300
Patient with increased number of Ala repeat in
HOXD13
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Skeletogenesis
• Cell differentiation – Chondrocytes, osteoblasts, osteoclasts
• Bone morphogenesis – Formation of growth plate cartilage, bone shaft and
marrow cavity – Vascular invasion and innervation
• Defects generalized
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Two skeletogenetic mechanisms
• Endochondral ossification – Differentiation of a cartilaginous scaffold (chondrocytes)
later replaced by bone (osteoblasts) – Most of the skeletal elements
• Intramembranous ossification – Direct differentiation of the condensed mesenchymal cells
into osteoblasts – Many bones of the skull, clavicles
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Hypertrophy
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Sox9
• Transcription factor of the HMG family
• Regulates the expression of chondrocyte-specific genes
• Sox9 haploinsufficiency causes Campomelic dysplasia (OMIM 114290)
• Earliest known regulator of chondrocyte differentiation
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Sox9-deficient cells cannot differentiate into chondrocytes
Bi et al., Nat. Genet 22 (1999)
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Hypertrophy
Sox9 Sox5, 6
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Accelerated chondrocyte hypertrophy in PTHrP-deficient mice
Karp et al., Development 127 (2000)
+/+ PTHrP -/-
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PTHrP
• Ubiquitously expressed growth factor
• Shares the same receptor with PTH • Mice “knockout” only phenotype is a generalized
growth plate cartilage defect
• PTHrP protein signals to its receptor in the prehypertrophic chondrocytes and blocks their hypertrophic differentiation
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Dwarfism in Ihh-deficient mice
Ihh -/-
St-Jacques et al. , Genes Dev. 13 (1999)
+/+
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Indian hedgehog (Ihh)
• One of 3 members of the Hedgehog family of growth factors
• Widely expressed during development
• Expression positively regulated by the transcription factor Runx2
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Reduced chondrocyte proliferation and delayed chondrocyte hypertrophy in Ihh-deficient mice
Ihh -/-
St-Jacques et al. , Genes Dev. 13 (1999)
+/+ Ihh -/- +/+
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Chondrocyte maturation is regulated by a PTHrP/Ihh feedback loop
Perichondrium
Resting
Proliferating
Pre-hypertrophic PTHrP receptor
Hypertrophic
PTHrP
Ihh
No PTHrP No Ihh
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Mutations in the PTH/PTHrP receptor cause Jansen and Bloomstrand chondrodysplasia
Jansen metaphyseal chondrodysplasia
OMIM 156400
Blomstrand's lethal chondrodysplasia
OMIM 215045
Activating mutations
Loss-of-function mutations
Schipani & Provost. Brith Defects Res. 69 (2003)
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Hypertrophy
Sox9 Sox5, 6
Ihh/PTHrP Runx2
VEGF
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Endochondral ossification
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Arrest of osteoblast differentiation in Runx2-deficient mice
+/+ Runx2 -/-
Otto et al., Cell 89 (1997)
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Runx2
• One of three members of the runt family of transcription factors
• Identified as a regulator of the Osteocalcin promoter
• Necessary and sufficient for osteoblast differentiation
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Cleidocranial dysplasia (CCD, OMIM 119600)�is caused by Runx2 haploinsufficiency
+/+
+/-
Mundlos et al., Cell 89 (1997) Lee et al. , Nat Genetics 16 (1997)
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Intramembranous ossification
Growth
Closure
Suture formation
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Disorders of suture fusion
Delay
Acceleration = craniosynostosis
Msx2, Runx2 haploinsufficiency
FGFR1, 2, 3 activating mutations Msx2 activating mutations Twist haploinsufficiency
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Osteoblast differentiation
Osteoprogenitor Osteoblast
Osx, ATF4
Pre-osteoblast
Runx2
Twist (Saethre-Chotzen Syndrome OMIM 101400)
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Atf4-/- WT
E14
Delayed osteogenesis�in absence of Atf4
Yang et al., Cell 117 (2004)
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Delayed osteogenesis in Atf4-deficient mice
WT
Atf4 -/-
P0 E16 E15
Yang et al., Cell 117 (2004)
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ATF4
• Divergent member of the ATF/CREB family of leucine-zipper transcription factors
• Required for amino-acid import
• Identified as a regulator of the Osteocalcin promoter
• Activated by the Rsk2 kinase
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ATF4
• Lack of ATF4 phosphorylation by inactivating mutations in Rsk2 causes the skeletal defects associated with Coffin-Lowry syndrome (OMIM 303600)
• Increased ATF4 phosphorylation by Rsk2 causes the skeletal defects associated with Neurofibromatosis Type I (OMIM 162200)
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ATF4
• Divergent member of the ATF/CREB family of leucine-zipper transcription factors
• Required for amino-acid import
• Identified as a regulator of the Osteocalcin promoter
• Activated by the Rsk2 kinase
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A high protein diet normalizes bone formation in Atf4-/- and Rsk2-/- mice
BV/TV BFR Ob.S/BS
High protein diet
Elefteriou et al., Cell Metab. 4 (2006)
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BV/TV
BFR
ObS/BS
Nf1ob-/- wt
15.3±1 153.3±11
19.6±0.4* 313.9±7.0*
Nf1ob-/- wt
14.8±0.7 157.0±11
15.3±0.6 186.2±22
Normal diet
19.1±0.8 31.8±1.6* 19.0±0.5 19.7±1.0
A low protein diet normalizes bone formation in a mouse model of Neurofibromatosis type I
Low protein diet
Elefteriou et al., Cell Metab. 4 (2006)
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articular cartilage (chondrocytes)
secondary ossification centre (osteoblasts/osteoclasts)
reserve cartilage proliferating cells
hypertrophic cells
trabecular bone (osteoblasts/osteoclasts)
cortical bone (osteoblasts)
calcified cartilage
Structure of a growing long bone
Growth plate Cartilage
(chondrocytes)
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Control of osteoclast differentiation and function
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Osteopenia in OPG-deficient mice
Bucay et al., Genes Dev. 12 (1998)
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Osteopetrosis in RANK-L deficient mice
Lacey et al., Cell 93 (1998)
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Osteoblast progenitor
Osteoclast progenitor
RANK-L OPG
RANK
Inactive complex
A ctive complex
TRAF 6 TRAF 2/5
NF k B JNK
Osteoclast Maturation AP1 activation
NF k B JNK c-src
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Research directions
Patterning
Skeletogenesis
Homeostasis
Dev
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men
t Li
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Diseases Knowledge