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Transcriptional Analysis of Fracture Healing and the Induction of Embryonic Stem Cell–Related Genes

By Manish Bais, Jody McLean, Paola Sebastiani, Megan Young, Nathan Wigner, Temple Smith, Darrell N. Kotton, Thomas A. Einhorn and Louis C. Gerstenfeld


Fractures are among the most common human traumas. Fracture healing represents a unique temporarily definable post-natal process in which to study the complex interactions of multiple molecular events that regulate endochondral skeletal tissue formation. Because of the regenerative nature of fracture healing, it is hypothesized that large numbers of post-natal stem cells are recruited and contribute to formation of the multiple cell lineages that contribute to this process. Bayesian modeling was used to generate the temporal profiles of the transcriptome during fracture healing. The temporal relationships between ontologies that are associated with various biologic, metabolic, and regulatory pathways were identified and related to developmental processes associated with skeletogenesis, vasculogenesis, and neurogenesis. The complement of all the expressed BMPs, Wnts, FGFs, and their receptors were related to the subsets of transcription factors that were concurrently expressed during fracture healing. We further defined during fracture healing the temporal patterns of expression for 174 of the 193 genes known to be associated with human genetic skeletal disorders. In order to identify the common regulatory features that might be present in stem cells that are recruited during fracture healing to other types of stem cells, we queried the transcriptome of fracture healing against that seen in embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs). Approximately 300 known genes that are preferentially expressed in ESCs and ∼350 of the known genes that are preferentially expressed in MSCs showed induction during fracture healing. Nanog, one of the central epigenetic regulators associated with ESC stem cell maintenance, was shown to be associated in multiple forms or bone repair as well as MSC differentiation. In summary, these data present the first temporal analysis of the transcriptome of an endochondral bone formation process that takes place during fracture healing. They show that neurogenesis as well as vasculogenesis are predominant components of skeletal tissue formation and suggest common pathways are shared between post-natal stem cells and those seen in ESCs

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  1. (2003). A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair.
  2. (2007). Activities of N-Myc in the developing limb link control of skeletal size with digit separation.
  3. (2006). Analysis of fracture healing by large-scale transcriptional profile identified temporal relationships between metalloproteinase and ADAMTS mRNA expression.
  4. (2007). Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells.
  5. (2006). Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation.
  6. (2006). BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype.
  7. (2005). BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways.
  8. (2003). BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop.
  9. (2006). BMP-4 is required for hepatic specification of mouse embryonic stem cellderived definitive endoderm.
  10. (2006). BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing.
  11. (2006). BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways.
  12. (2001). Bone and Joint Healing. In: Bucholz RW, Heckman JD, eds. Rockwood and Green’s Fractures in Adults.
  13. (2005). Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus.
  14. (2008). Central Control of Bone Remodeling.
  15. (2006). Chapter 47: Fractures of the shaft of the femur.
  16. (2002). Cluster analysis of gene expression dynamics.
  17. (2006). Clustering short gene expression profiles
  18. (2008). Conditional Clustering of Temporal Expression Profiles.
  19. (2006). Conservation of Pitx1 expression during amphibian limb morphogenesis.
  20. (2007). DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res.35 (Web Server issue):
  21. (2008). Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/{beta}-catenin, Activin/Nodal and BMP signaling.
  22. (2000). Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury.
  23. (2005). Derivation of multipotent mesenchymal precursors from human embryonic stem cells.
  24. (2002). Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing.
  25. (2008). Dissecting direct reprogramming through integrative genomic analysis.
  26. (2004). Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene.
  27. (2007). Effects of a single percutaneous injection of basic fibroblast growth factor on the healing of a closed femoral shaft fracture in the rat.
  28. (2007). Enhanced Chondrogenesis and Wnt-signaling in Parathyroid Hormone Treated Fractures.
  29. (2001). Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing.
  30. (2008). Focal adhesion kinase/Src suppresses early chondrogenesis: central role of CCN2.
  31. (2003). Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation.
  32. (2007). Genes with greater up-regulation in the fracture callus of older rats with delayed healing.
  33. (2008). Genetic Variation in the Patterns of Skeletal Progenitor Cell Differentiation and Progression During Endochondral Bone Formation Affects the Rate of Fracture Healing.
  34. (2005). Germ layer induction from embryonic stem cells. Exp Hematol.
  35. (2002). Hypothalamic Y2 receptors regulate bone formation.
  36. (2003). Identifying biological themes within lists of genes with EASE.
  37. (2003). Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption.
  38. (2001). Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-alpha signaling. Cells Tissues Organs.
  39. (2007). Metaanalysis of human embryonic stem cells transcriptome integrated into a webbased expression atlas. Stem Cells.
  40. (2006). Microarray analysis of gene expression during the inflammation and endochondral bone formation stages of rat femur fracture repair.
  41. (2007). Molecular and proteomic characterization of human mesenchymal stem cells derived from amniotic fluid: comparison to bone marrow mesenchymal stem cells. Stem Cells Dev.
  42. (2008). Molecular bases of the sympathetic regulation of bone mass.
  43. (2007). Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate.
  44. (2008). Mouse Genome Database Group. The Mouse Genome Database (MGD): mouse biology and model systems. Nucleic Acids Res.36 (Database issue):
  45. (2006). Nanog binds to Smad1 and blocks bone morphogenetic protein-induced differentiation of embryonic stem cells.
  46. (2008). Nanog inhibits the switch of myogenic cells towards the osteogenic lineage.
  47. (2008). NANOG is a direct target of TGFbeta/activin-mediated SMAD signaling in human ESCs.
  48. (2000). Neurohormones and catecholamines as functional components of the bone marrow microenvironment.
  49. (1996). Noradrenergic and peptidergic innervation of the mouse femur bone marrow.
  50. (2007). Nosology and classification of genetic skeletal disorders:
  51. of Health and Human Services (2004) Bone Health and Osteoporosis: A Report of the Surgeon General.
  52. (1969). On the development of bone marrow innervation in new-born rats as studied with silver impregnation and electron microscopy.
  53. (2002). Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur.
  54. (2005). Overview of the fracture healing cascade.
  55. (2005). Pathophysiology of polytrauma.
  56. (1993). Pattern of gene expression following rat tibial marrow ablation.
  57. (1984). Production of a standard closed fracture in laboratory animal bone.
  58. (1998). Recapitulation of signals regulating embryonic bone formation during postnatal growth and in fracture repair.
  59. (2008). Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate.
  60. (2005). Regulation of osteoblastogenesis and bone mass by
  61. (2000). Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12.
  62. (2001). Spatial and temporal gene expression for fibroblast growth factor type I receptor (FGFR1) during fracture healing in the rat.
  63. (2008). Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming.
  64. (2003). The effect of age on gene expression in adult and juvenile rats following femoral fracture.
  65. (2000). The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.
  66. (2003). Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation.
  67. (2002). Transcriptional profiling of bone regeneration: Insight into the molecular complexity of wound repair.
  68. (2005). Tumor necrosis factor alpha (TNF-a) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing.
  69. (1990). Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the ‘‘neuro-reticular complex’’.
  70. (2009). Wnt pathway, an essential role in bone regeneration.
  71. (2006). Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis.

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