FGFs that regulate growth plate development.
Abstract 2005 MHE Conference
David M. Ornitz, Irene Hung, Zhonghao Liu, Kory Lavine,
Kai Yu, Hidemi Kanazawa, Ann Jacob.
Department of Molecular Biology and Pharmacology,
Washington University School of Medicine.
Fibroblast growth factors (FGFs) are essential molecules for mammalian development. A growing
number of human genetic diseases that affect skeletal development are caused by point mutations
in the genes encoding FGF receptors 1, 2 and 3. These disorders result in craniosynostosis and
chondrodysplasia syndromes and thus demonstrate that FGF signaling pathways are essential
regulators of chondrogenesis and osteogenesis. Loss of function and skeletal-specific conditional
loss of function mutations in mouse FGF receptors 1-3 also show specific defects in skeletal
development and in the structure and integrity of adult bone.
In contrast to the increasing amount of data demonstrating a role for FGFRs in skeletogenesis,
there is very little information on the FGF ligands that signal to these receptors to regulate skeletal
development, growth, remodeling and repair. Mice lacking FGF2 (bFGF) have a mild decrease in bone
mass and trabecular bone formation, but no morphological defects in their skeleton.
Examination of skeletal development in mice lacking FGF18 revealed moderate skeletal
dysmorphology and a significant delay in ossification of distal bones that is not seen in mice lacking
FGF receptors 1, 2 or 3 in osteoblast or chondrocyte lineages. In contrast, analysis of mice lacking
Fgf9 revealed a delay in ossification primarily affecting proximal bones. The dysmorphology and
delayed ossification phenotype of these knockout mice suggest that FGF9 and FGF18 signal to
skeletal cells (chondrocytes and osteoblasts) to regulate early skeletal development and to
non-skeletal mesenchymal cells to regulate peri-skeletal vasculogenesis and vascular invasion of the
primitive growth plate.
We have also observed that mice lacking both FGF9 and FGF18 have very severe skeletal
dysmorphology with delayed ossification and agenesis of the intramembranous bones of the
cranium. These data further suggest that FGF9 and FGF18 form overlapping and inverted gradients
in the appendicular skeleton that regulate both development and vascularization.
Abstract 2005 MHE Conference
David M. Ornitz, Irene Hung, Zhonghao Liu, Kory Lavine,
Kai Yu, Hidemi Kanazawa, Ann Jacob.
Department of Molecular Biology and Pharmacology,
Washington University School of Medicine.
Fibroblast growth factors (FGFs) are essential molecules for mammalian development. A growing
number of human genetic diseases that affect skeletal development are caused by point mutations
in the genes encoding FGF receptors 1, 2 and 3. These disorders result in craniosynostosis and
chondrodysplasia syndromes and thus demonstrate that FGF signaling pathways are essential
regulators of chondrogenesis and osteogenesis. Loss of function and skeletal-specific conditional
loss of function mutations in mouse FGF receptors 1-3 also show specific defects in skeletal
development and in the structure and integrity of adult bone.
In contrast to the increasing amount of data demonstrating a role for FGFRs in skeletogenesis,
there is very little information on the FGF ligands that signal to these receptors to regulate skeletal
development, growth, remodeling and repair. Mice lacking FGF2 (bFGF) have a mild decrease in bone
mass and trabecular bone formation, but no morphological defects in their skeleton.
Examination of skeletal development in mice lacking FGF18 revealed moderate skeletal
dysmorphology and a significant delay in ossification of distal bones that is not seen in mice lacking
FGF receptors 1, 2 or 3 in osteoblast or chondrocyte lineages. In contrast, analysis of mice lacking
Fgf9 revealed a delay in ossification primarily affecting proximal bones. The dysmorphology and
delayed ossification phenotype of these knockout mice suggest that FGF9 and FGF18 signal to
skeletal cells (chondrocytes and osteoblasts) to regulate early skeletal development and to
non-skeletal mesenchymal cells to regulate peri-skeletal vasculogenesis and vascular invasion of the
primitive growth plate.
We have also observed that mice lacking both FGF9 and FGF18 have very severe skeletal
dysmorphology with delayed ossification and agenesis of the intramembranous bones of the
cranium. These data further suggest that FGF9 and FGF18 form overlapping and inverted gradients
in the appendicular skeleton that regulate both development and vascularization.
Research authored by Dr. Ornitz
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
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National Library of Medicine, Directory of Health Organizations (SIS) website, as well as the link for Patient
Information on The Diseases Database a cross-referenced index of human disease, and the Intute: health & life
sciences a free online service providing access to the very best Web resources for education and research
located in the UK
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