FGF SIGNALING IN SKELETAL DEVELOPMENT, HOMEOSTASIS AND AGING

Summary

Principal Investigator: David M Ornitz
Abstract: DESCRIPTION (provided by applicant): Osteoporosis and related bone diseases affect over 10 million Americans and result in 1.5 million fractures annually at a cost of $17-20 billion. The predominant treatment for osteoporosis is the use of drugs that block bone resorption (anti-resorptive or anti-catabolic agents). However, a primary feature of skeletal aging is a decline in the rate of bone formation, and there exists an unmet clinical need for anabolic agents to offset this decline. Tissue homeostasis, such as maintenance of bone mass, often relies on the tightly regulated activity of developmental signaling networks. Similarly, repair of injured bone or regeneration of osteopenic bone is likely to require reactivation of developmental signaling pathways. The primary objective of this proposal is to explore and elucidate the mechanisms by which Fibroblast Growth Factors (FGFs) regulate the osteoblast lineage during skeletal growth, homeostasis and aging. To manipulate regenerative response mechanisms in a beneficial way, and to restore homeostatic balance, it is essential to acquire knowledge about the normal developmental pathways and how they are reactivated and reused in adult tissues. To achieve these goals, we will investigate the mechanisms by which FGF signaling in osteoblasts regulates bone growth and homeostasis and determine if osteoblast FGF signaling can be manipulated to prevent or restore age-related bone loss. Our preliminary data supports a direct role for FGF receptor (FGFR) signaling in the osteoblast lineage in regulating bone growth and homeostasis. We show that inactivation of FGFRs in neonatal osteoprogenitor (OP) cells results in decreased skeletal growth, and inactivation of FGFRs in the adult osteoblast lineage results in loss of bone mass. We have constructed or acquired genetic tools that will allow us to control loss or gain of function of FGF signaling in adult long bone osteoblasts and in skeletal progenitor cells that give rise to chondrocytes and osteoblasts in vivo. Using these genetic tools, our goals are to: 1. Identify mechanisms for FGF regulation of osteoblast function during postnatal bone growth;2. Identify functional consequences of loss- and gain-of- FGFR-function in the activation/maintenance of osteoblast anabolic activity for skeletal homeostasis and age- related bone loss;3. Identify novel FGF-regulated genes and signaling pathways in the postnatal osteoblast lineage using comprehensive Next-Gen transcriptome analysis. Our multidisciplinary team brings together expertise in developmental and bone biology, bone structure and biomechanics, and genomics and bioinformatics that, combined with the genetic tools at our disposal, puts us in a unique position to address fundamental questions in the regulation of skeletal growth and homeostasis and develop new methods for effective FGF therapy to maintain or enhance bone mass during aging.
Funding Period: 2006-08-01 - 2017-03-31
more information: NIH RePORT

Top Publications

  1. pmc Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation
    Anne L Jacob
    Department of Molecular Biology and Pharmacology, Washington University Medical School, Campus Box 8103, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Dev Biol 296:315-28. 2006
  2. pmc Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles
    Sung Ho Huh
    Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Genes Dev 27:450-8. 2013
  3. pmc Delineating a conserved genetic cassette promoting outgrowth of body appendages
    Congxing Lin
    Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
    PLoS Genet 9:e1003231. 2013
  4. pmc Development of the endochondral skeleton
    Fanxin Long
    Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Cold Spring Harb Perspect Biol 5:a008334. 2013
  5. pmc FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium
    Mónica Vega-Hernández
    Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA
    Development 138:3331-40. 2011
  6. pmc Histomorphological study of palatal shelf elevation during murine secondary palate formation
    Kai Yu
    Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri, USA
    Dev Dyn 240:1737-44. 2011
  7. pmc FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice
    Friederike Böhm
    Department of Biology, Institute of Cell Biology, ETH Zurich, Switzerland
    Gastroenterology 139:1385-96. 2010
  8. pmc Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis
    Jingxuan Yang
    Department of Biology, Institute of Cell Biology, Eidgenossische Technische Hochschule Zurich, 8093 Zurich, Switzerland
    J Cell Biol 188:935-52. 2010
  9. pmc Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1
    Sung Ho Huh
    Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA
    Development 137:1137-47. 2010
  10. pmc Healing of non-displaced fractures produced by fatigue loading of the mouse ulna
    Mario D Martinez
    Department of Orthopaedic Surgery, Washington University, St Louis, Missouri, USA
    Bone 46:1604-12. 2010

Research Grants

Detail Information

Publications18

  1. pmc Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation
    Anne L Jacob
    Department of Molecular Biology and Pharmacology, Washington University Medical School, Campus Box 8103, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Dev Biol 296:315-28. 2006
    ..These data demonstrate that signaling through FGFR1 in osteoblasts is necessary to maintain the balance between bone formation and remodeling through a direct effect on osteoblast maturation...
  2. pmc Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles
    Sung Ho Huh
    Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Genes Dev 27:450-8. 2013
    ....
  3. pmc Delineating a conserved genetic cassette promoting outgrowth of body appendages
    Congxing Lin
    Division of Dermatology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA
    PLoS Genet 9:e1003231. 2013
    ..These observations indicate that a conserved WNT-SP8-FGF8 genetic cassette is employed by both appendages for promoting outgrowth, and suggest a deep homology shared by the limb and external genitalia...
  4. pmc Development of the endochondral skeleton
    Fanxin Long
    Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Cold Spring Harb Perspect Biol 5:a008334. 2013
    ..This review aims to integrate the known functions of extracellular signals and transcription factors that regulate development of the endochondral skeleton...
  5. pmc FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium
    Mónica Vega-Hernández
    Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA
    Development 138:3331-40. 2011
    ..Inactivation of this signaling pathway results in fewer epicardial derived cells within the compact myocardium, decreased myocardial proliferation and a resulting smaller thin-walled heart...
  6. pmc Histomorphological study of palatal shelf elevation during murine secondary palate formation
    Kai Yu
    Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri, USA
    Dev Dyn 240:1737-44. 2011
    ..Our study provides a framework that recognizes variation in timing of palatal morphogenesis along the AP axis that will aid in the investigation of the mechanisms regulating palatal shelf elevation...
  7. pmc FGF receptors 1 and 2 control chemically induced injury and compound detoxification in regenerating livers of mice
    Friederike Böhm
    Department of Biology, Institute of Cell Biology, ETH Zurich, Switzerland
    Gastroenterology 139:1385-96. 2010
    ..We investigated the functions and mechanisms of action of these receptors in liver homeostasis, regeneration, and fibrosis...
  8. pmc Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis
    Jingxuan Yang
    Department of Biology, Institute of Cell Biology, Eidgenossische Technische Hochschule Zurich, 8093 Zurich, Switzerland
    J Cell Biol 188:935-52. 2010
    ..Our results identify essential roles for FGFs in the regulation of the epidermal barrier and in the prevention of cutaneous inflammation, and highlight the importance of stromal-epithelial interactions in skin homeostasis and disease...
  9. pmc Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1
    Sung Ho Huh
    Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA
    Development 137:1137-47. 2010
    ..These findings identify Wnt-beta-catenin signaling as a crucial upstream regulator of a Tbx1-Fgf8 signaling pathway and suggest that factors that affect Wnt-beta-catenin signaling could modify the incidence and severity of DGS...
  10. pmc Healing of non-displaced fractures produced by fatigue loading of the mouse ulna
    Mario D Martinez
    Department of Orthopaedic Surgery, Washington University, St Louis, Missouri, USA
    Bone 46:1604-12. 2010
    ..In the future, the fatigue loading approach can be used create non-displaced bone fractures in transgenic and knockout mice to study the mechanisms by which the skeleton rapidly repairs damage...
  11. pmc Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate
    Alison K Snyder-Warwick
    Division of Plastic Surgery, Departments of Developmental Biology and Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 107:2515-20. 2010
    ..Knowledge of how mesenchymal FGF signaling regulates palatal shelf development may ultimately lead to pharmacological approaches to reduce cleft palate incidence in genetically predisposed humans...
  12. pmc Fibroblast growth factor expression during skeletal fracture healing in mice
    Gregory J Schmid
    Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Dev Dyn 238:766-74. 2009
    ..These studies identify distinct groups of FGFs that are differentially expressed and suggest active stage-specific roles for FGF signaling during the fracture repair process...
  13. pmc FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion
    Masayo Harada
    RIKEN Research Center for Allergy and Immunology, 1 7 22 Suehiro cho, Tsurumi ku, Yokohama, Kanagawa 230 0045, Japan
    Nat Genet 41:289-98. 2009
    ..We propose a mechanism in which the range of FGF9 signaling in developing tissues is limited by its ability to homodimerize and its affinity for extracellular matrix heparan sulfate proteoglycans...
  14. ncbi FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis
    Kai Yu
    Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110 USA
    Development 135:483-91. 2008
    ....
  15. ncbi Functional evolutionary history of the mouse Fgf gene family
    Nobuyuki Itoh
    Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, Japan
    Dev Dyn 237:18-27. 2008
    ..During the evolution of early vertebrates, the Fgf subfamilies further expanded to contain three or four members in each subfamily...
  16. pmc FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod
    Irene H Hung
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Campus Box 8103, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Dev Biol 307:300-13. 2007
    ..In developing stylopod elements, FGF9 promotes chondrocyte hypertrophy at early stages and regulates vascularization of the growth plate and osteogenesis at later stages of skeletal development...
  17. ncbi FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate
    Zhonghao Liu
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA
    Dev Biol 302:80-91. 2007
    ..FGF18 thus coordinates neovascularization of the growth plate with chondrocyte and osteoblast growth and differentiation...
  18. pmc Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice
    Jianquan Chen
    Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, Missouri, United States of America
    PLoS ONE 9:e85161. 2014
    ..Thus, potential contributions from the non-osteoblast-lineage cells should be considered when Osx-Cre is used to study gene functions in postnatal mice. ..

Research Grants30

  1. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  2. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  3. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  4. PTHrP/IHH Microenvironment Control for Growth Plate Tissue Engineering
    JUAN MANUEL TABOAS; Fiscal Year: 2013
    ..We will implant these constructs in dorsal subcutaneous pockets of immunodeficient mice and use histological and micro-CT assays to evaluate construct growth and GP-like structure maintenance. ..