Developmental biology is the study of how cells with specialized functions are derived from undifferentiated cells and how cells interact with each other and their environment to ultimately form tissues and organs. Therefore, it is important to understand the basic mechanisms of development in the skeleton if we are to make progress in engineering skeletal tissue. Members of the TGF-ss superfamily are secreted signaling proteins that regulate many aspects of development and tissue homeostasis including growth, patterning, and cellular differentiation. Polymorphisms and mutations in human Tgfb genes have been associated with pathology in the adult spine and previously, we showed using genetically engineered mouse models that Tgfbr2 is required for development and maintenance of the intervertebral disc (IVD). Our results suggested that 1) TGF-ss is required for boundary formation in the developing axial skeleton and 2) TGF-ss prevents formation of cartilage and promotes the formation of IVD cells in embryonic mesenchyme. In this revision (supplement) application, we will test the hypothesis that gradients of TGF-ss and BMP have threshold effects on mesenchymal progenitors resulting in differentiation along either cartilage or IVD lineages thereby generating a sharp boundary between the two cell types in the axial skeleton. We propose to model TGF-ss mediated boundary formation and the pattern of cellular differentiation in the axial skeleton using a biomimetic self- assembled nanomatrix that can mimic essential properties of natural extracellular matrix (ECM). The nanomatrix is made from a synthetic peptide-amphiphile (PA) and contains the following properties: 1) rapid three-dimensional network formation at physiological conditions 2) cell adhesive moieties to provide cell attachment, and 3) enzyme-mediated degradable sites for matrix remodeling. The nanomatrix can be engineered to contain growth factors throughout the matrix or in a zonal/gradient pattern. Therefore, the nanomatrix can provide an environment that mimics the extracellular matrix (ECM) and can be used as a template for studying tissue development. A clear understanding of how the skeletal system develops will have a direct impact on tissue engineering strategies. Partnerships like this, between developmental biology and bioengineering, will provide a basis for future strategies aimed at disc repair or regeneration. ? ? ? ?

Public Health Relevance

Relevence. Lower back pain, of which disc degeneration is a major cause, is the primary cause of disability in the United States. Costs related to low back pain are estimated to exceed $100 billion per year. Cell based tissue engineering therapies could provide major relief to those suffering severe disc disease. Developmental biology is the study of how cells with specialized functions are derived from undifferentiated cells and how cells interact with each other and their environment to ultimately form mature tissues and organs. Therefore, it is important to understand the basic mechanisms of development biology in the skeleton if we are to make progress in engineering skeletal tissue. This project represents a partnership between developmental biology and biomaterials engineering that will provide a basis for future strategies aimed at disc repair or regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR053860-02S1
Application #
7587216
Study Section
Special Emphasis Panel (ZAR1-MLB-G (M1))
Program Officer
Wang, Fei
Project Start
2007-04-18
Project End
2012-03-31
Budget Start
2008-09-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$145,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Alkhatib, Bashar; Ban, Ga I; Williams, Sade et al. (2018) IVD Development: Nucleus pulposus development and sclerotome specification. Curr Mol Biol Rep 4:132-141
Killion, Christy H; Mitchell, Elizabeth H; Duke, Corey G et al. (2017) Mechanical loading regulates organization of the actin cytoskeleton and column formation in postnatal growth plate. Mol Biol Cell 28:1862-1870
Peters, Sarah B; Wang, Ying; Serra, Rosa (2017) Tgfbr2 is required in osterix expressing cells for postnatal skeletal development. Bone 97:54-64
Cox, Megan K; Appelboom, Brittany L; Ban, Ga I et al. (2014) Erg cooperates with TGF-? to control mesenchymal differentiation. Exp Cell Res 328:410-8
Wang, Ying; Cox, Megan K; Coricor, George et al. (2013) Inactivation of Tgfbr2 in Osterix-Cre expressing dental mesenchyme disrupts molar root formation. Dev Biol 382:27-37
Chang, Ching-Fang; Serra, Rosa (2013) Ift88 regulates Hedgehog signaling, Sfrp5 expression, and ?-catenin activity in post-natal growth plate. J Orthop Res 31:350-6
Wang, Ying; Serra, Rosa (2012) PDGF mediates TGFýý-induced migration during development of the spinous process. Dev Biol 365:110-7
Ramaswamy, Girish; Sohn, Philip; Eberhardt, Alan et al. (2012) Altered responsiveness to TGF-ýý results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage. Arthritis Res Ther 14:R49
Chang, C-F; Ramaswamy, G; Serra, R (2012) Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis. Osteoarthritis Cartilage 20:152-61
Sohn, Philip; Cox, Megan; Chen, Dongquan et al. (2010) Molecular profiling of the developing mouse axial skeleton: a role for Tgfbr2 in the development of the intervertebral disc. BMC Dev Biol 10:29

Showing the most recent 10 out of 13 publications