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.

Public Health Relevance

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. An increased understanding of the mechanisms involved in the etiology and progression of osteoporosis is essential to improve prevention, diagnosis and treatment of bone loss and resulting skeletal fractures in an effort to reduce morbidity, mortality and the tremendous economic impact on our health care system. The Fibroblast Growth Factor signaling pathway provides an attractive therapeutic target to offset the decline in bone mass that occurs during the aging process.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Winer, Karen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Other Basic Sciences
Schools of Medicine
Saint Louis
United States
Zip Code
Chen, Jianquan; Shi, Yu; Regan, Jenna et al. (2014) Osx-Cre targets multiple cell types besides osteoblast lineage in postnatal mice. PLoS One 9:e85161
Huh, Sung-Ho; Narhi, Katja; Lindfors, Paivi H et al. (2013) Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles. Genes Dev 27:450-8
Long, Fanxin; Ornitz, David M (2013) Development of the endochondral skeleton. Cold Spring Harb Perspect Biol 5:a008334
Lin, Congxing; Yin, Yan; Bell, Sheila M et al. (2013) Delineating a conserved genetic cassette promoting outgrowth of body appendages. PLoS Genet 9:e1003231
Vega-Hernandez, Monica; Kovacs, Attila; De Langhe, Stijn et al. (2011) FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium. Development 138:3331-40
Yu, Kai; Ornitz, David M (2011) Histomorphological study of palatal shelf elevation during murine secondary palate formation. Dev Dyn 240:1737-44
Snyder-Warwick, Alison K; Perlyn, Chad A; Pan, Jing et al. (2010) Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate. Proc Natl Acad Sci U S A 107:2515-20
Yang, Jingxuan; Meyer, Michael; Muller, Anna-Katharina et al. (2010) Fibroblast growth factor receptors 1 and 2 in keratinocytes control the epidermal barrier and cutaneous homeostasis. J Cell Biol 188:935-52
Martinez, Mario D; Schmid, Gregory J; McKenzie, Jennifer A et al. (2010) Healing of non-displaced fractures produced by fatigue loading of the mouse ulna. Bone 46:1604-12
Huh, Sung-Ho; Ornitz, David M (2010) Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1. Development 137:1137-47

Showing the most recent 10 out of 18 publications