Skeleton Development Patricia Ducy HHSC 1616 x 5
- Slides: 45
Skeleton Development Patricia Ducy HHSC 1616 x 5 -9299 pd 2193@columbia. edu 1
Skeleton • ≥ 200 elements • Two tissues: cartilage, bone • Three cell types: chondrocytes, osteoblasts, osteoclasts Growth Formation Resorption • Three “environments”: marrow, blood, SNS 2
Embryonic origin of the skeleton Cranial neural crest cells Somitic mesoderm Lateral plate mesoderm Craniofacial skeleton Axial skeleton Appendicular Skeleton Chondrocytes & Osteoblasts Monocyte lineage Osteoclasts 3
Development Skeleton Biology Patterning Location and shape of skeletal elements Skeletogenesis Differentiated cells Bone structure Growth/Modeling Life Birth Homeostasis Remodeling Balance between Formation/Resorption Fracture repair 4
Life Development Skeleton Pathologies Patterning Dysostoses Skeletogenesis Dysplasia Homeostasis Mineralization defects Degenerative diseases 5
Genetic defects associated with skeleton development (RUNX 2) 6
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 7
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 8
Homeotic transformations in absence of Hox transcription factors Wellik, Dev. Dynamics 236 (2007) 9
Hox transcription factors control vertebrate limb patterning Genomic organization Site of expression 10
Mutations in HOXD 13 cause synpolydactyly* in humans *OMIM 18600, 186300 Patient with increased number of Ala repeat in HOXD 13 Muragaki et al. , Science 272 (1996) 11
Skeletogenesis • Cell differentiation – Chondrocytes, osteoblasts, osteoclasts • Bone morphogenesis – Formation of growth plate cartilage, bone shaft and marrow cavity – Vascular invasion and innervation • Defects generalized 12
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 13
Hypertrophy 14
Sox 9 • Transcription factor of the HMG family • Regulates the expression of chondrocyte-specific genes • Sox 9 haploinsufficiency causes Campomelic dysplasia (OMIM 114290) • Earliest known regulator of chondrocyte differentiation 15
Sox 9 -deficient cells cannot differentiate into chondrocytes Bi et al. , Nat. Genet 22 (1999) 16
Sox 9 Sox 5, 6 Hypertrophy 17
Accelerated chondrocyte hypertrophy in PTHr. P-deficient mice +/+ PTHr. P -/- Karp et al. , Development 127 (2000) 18
PTHr. P • Ubiquitously expressed growth factor • Shares the same receptor with PTH • Mice “knockout” only phenotype is a generalized growth plate cartilage defect • PTHr. P protein signals to its receptor in the prehypertrophic chondrocytes and blocks their hypertrophic differentiation 19
Dwarfism in Ihh-deficient mice +/+ Ihh -/- St-Jacques et al. , Genes Dev. 13 (1999) 20
Indian hedgehog (Ihh) • One of 3 members of the Hedgehog family of growth factors • Widely expressed during development • Expression positively regulated transcription factor Runx 2 by the 21
Reduced chondrocyte proliferation and delayed chondrocyte hypertrophy in Ihh-deficient mice +/+ Ihh -/- St-Jacques et al. , Genes Dev. 13 (1999) 22
Chondrocyte maturation is regulated by a PTHr. P/Ihh feedback loop Perichondrium PTHr. P No Ihh Resting Proliferating Pre-hypertrophic PTHr. P receptor Ihh Hypertrophic 23
Mutations in the PTH/PTHr. P receptor cause Jansen and Bloomstrand chondrodysplasia Activating mutations Loss-of-function mutations Jansen metaphyseal chondrodysplasia OMIM 156400 Blomstrand's lethal chondrodysplasia OMIM 215045 Schipani & Provost. Brith Defects Res. 69 (2003) 24
Sox 9 Sox 5, 6 Ihh/PTHr. P Runx 2 Hypertrophy VEGF 25
Endochondral ossification 26
Arrest of osteoblast differentiation in Runx 2 -deficient mice +/+ Runx 2 -/- Otto et al. , Cell 89 (1997) 27
Runx 2 • One of three members of the runt family of transcription factors • Identified as a regulator of the Osteocalcin promoter • Necessary and differentiation sufficient for osteoblast 28
Cleidocranial dysplasia (CCD, OMIM 119600) is caused by Runx 2 haploinsufficiency +/+ +/Mundlos et al. , Cell 89 (1997) Lee et al. , Nat Genetics 16 (1997) 29
Intramembranous ossification Suture formation Growth Closure 30
Disorders of suture fusion Delay Msx 2, Runx 2 haploinsufficiency Acceleration = craniosynostosis FGFR 1, 2, 3 activating mutations Msx 2 activating mutations Twist haploinsufficiency 31
Osteoblast differentiation Twist (Saethre-Chotzen Syndrome OMIM 101400) Runx 2 Osteoprogenitor Osx, ATF 4 Pre-osteoblast Osteoblast 32
Delayed osteogenesis in absence of Atf 4 WT Atf 4 -/- E 14 Yang et al. , Cell 117 (2004) 33
Delayed osteogenesis in Atf 4 -deficient mice E 15 E 16 P 0 WT Atf 4 -/- Yang et al. , Cell 117 (2004) 34
ATF 4 • 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 Rsk 2 kinase 35
ATF 4 • Lack of ATF 4 phosphorylation by inactivating mutations in Rsk 2 causes the skeletal defects associated with Coffin-Lowry syndrome (OMIM 303600) • Increased ATF 4 phosphorylation by Rsk 2 causes the skeletal defects associated with Neurofibromatosis Type I (OMIM 162200) 36
ATF 4 • 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 Rsk 2 kinase 37
A high protein diet normalizes bone formation in Atf 4 -/- and Rsk 2 -/- mice High protein diet BV/TV BFR Ob. S/BS Elefteriou et al. , Cell Metab. 4 (2006) 38
A low protein diet normalizes bone formation in a mouse model of Neurofibromatosis type I Normal diet wt Nf 1 ob-/- Low protein diet wt Nf 1 ob-/- BFR 15. 3± 1 153. 3± 11 19. 6± 0. 4* 313. 9± 7. 0* 14. 8± 0. 7 157. 0± 11 15. 3± 0. 6 186. 2± 22 Ob. S/BS 19. 1± 0. 8 31. 8± 1. 6* 19. 0± 0. 5 19. 7± 1. 0 BV/TV Elefteriou et al. , Cell Metab. 4 (2006) 39
Structure of a growing long bone articular cartilage (chondrocytes) secondary ossification centre (osteoblasts/osteoclasts) reserve cartilage proliferating cells hypertrophic cells calcified cartilage Growth plate Cartilage (chondrocytes) trabecular bone (osteoblasts/osteoclasts) cortical bone (osteoblasts) 40
Control of osteoclast differentiation and function 41
Osteopenia in OPG-deficient mice Bucay et al. , Genes Dev. 12 (1998) 42
Osteopetrosis in RANK-L deficient mice Lacey et al. , Cell 93 (1998) 43
Osteoblast progenitor OPG RANK-L Inactive complex Active complex RANK TRAF 6 TRAF 2/5 Osteoclast progenitor c-src Osteoclast Maturation NFk. B JNK AP 1 activation 44
Research directions Life Development Knowledge Diseases Patterning Skeletogenesis Homeostasis 45
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