Endochondral bone formation is complex and requires the coordination of several signals. Defects in the regulation of chondrocyte differentiation can result in chondrodysplasias and osteoarthritis. Factors that coordinate the formation of endochondral bones are just beginning to be defined. The long-term objective of this study is to understand, at the molecular level, the signals involved in the regulation of endochondral bone formation and how alterations in these signals contribute to diseases of the skeletal system with emphasis on the mechanism of action of members of the Transforming Growth Factor-beta (TGF-beta) superfamily. Members of the TGF-beta superfamily are secreted growth factors that regulate many aspects of growth and differentiation. Expression of a dominant-negative form of the TGF-beta type II receptor in mouse skeletal tissue results in increased terminal chondrocyte differentiation and osteoarthritis, suggesting TGF-betas act to regulate chondrocyte differentiation in vivo. During the previous granting period we used an embryonic metatarsal organ culture model, which can be easily manipulated, to dissect out interactions between specific signaling cascades. Our studies suggested that the perichondrium mediates the effects of TGF-beta on both the exit of chondrocytes from the cell cycle through an unknown factor, and their subsequent differentiation through the Indian Hedgehog-Parathyroid Hormone related Peptide feedback loop. Based on these observations and potential clinical significance to chondrodysplasias and osteoarthritis, studies to determine the mechanistic basis of how TGF-beta regulates cartilage differentiation will continue through the following Specific Aims: (1) to test the hypothesis that TGF-beta2 acts in a negative feed back loop with Ihh and PTHrP to regulate hypertrophic differentiation; (2) to determine if differentially modified forms of Hedgehog proteins regulate specific aspects of endochondral bone formation; (3) to test the hypothesis that TGF-beta acts on the perichondrium through the Insulin-like Growth Factor (IGF) and/or Fibroblast Growth Factor (FGF) signaling systems to regulate chondrocyte proliferation; and (4) to determine the role of TGF-beta signaling directly in chondrocytes using conditional deletion of the TGF-beta receptor in transgenic mice. The results of these studies will enhance our understanding of molecular events involved in development and maintenance of the skeletal system. ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Orthopedics and Musculoskeletal Study Section (ORTH)
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Tyree, Bernadette
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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Seo, Hwa-Seon; Serra, Rosa (2009) Tgfbr2 is required for development of the skull vault. Dev Biol 334:481-90
Haycraft, Courtney J; Serra, Rosa (2008) Cilia involvement in patterning and maintenance of the skeleton. Curr Top Dev Biol 85:303-32
Serra, Rosa (2008) Role of intraflagellar transport and primary cilia in skeletal development. Anat Rec (Hoboken) 291:1049-61
Seo, Hwa-Seon; Serra, Rosa (2007) Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol 310:304-16
Song, Buer; Haycraft, Courtney J; Seo, Hwa-seon et al. (2007) Development of the post-natal growth plate requires intraflagellar transport proteins. Dev Biol 305:202-16
Haycraft, Courtney J; Zhang, Qihong; Song, Buer et al. (2007) Intraflagellar transport is essential for endochondral bone formation. Development 134:307-16
Baffi, Michael O; Moran, Molly A; Serra, Rosa (2006) Tgfbr2 regulates the maintenance of boundaries in the axial skeleton. Dev Biol 296:363-74
Mukherjee, Aditi; Dong, Sai Sai; Clemens, Thomas et al. (2005) Co-ordination of TGF-beta and FGF signaling pathways in bone organ cultures. Mech Dev 122:557-71
Baffi, Michael O; Slattery, Erin; Sohn, Philip et al. (2004) Conditional deletion of the TGF-beta type II receptor in Col2a expressing cells results in defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Dev Biol 276:124-42
Alvarez, Jesus; Serra, Rosa (2004) Unique and redundant roles of Smad3 in TGF-beta-mediated regulation of long bone development in organ culture. Dev Dyn 230:685-99

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