Effects on neurite outgrowth and cell survival of a secreted fibroblast growth factor binding protein upregulated during spinal cord injury

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 293; no. 2; pp. R775 - R783
• Main Authors: Tassi, Elena, Walter, Sharon, Aigner, Achim, Cabal-Manzano, Rafael H, Ray, Ranjan, Reier, Paul J, Wellstein, Anton
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2007
• Subjects: Age Factors; Animals; Apoptosis - physiology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Cell Survival - drug effects; Cell Survival - physiology; Cells; Effects; Female; Fibroblast Growth Factor 2 - metabolism; Fibroblast Growth Factor 2 - pharmacology; Gene Expression - physiology; Nerve Regeneration - physiology; Neurites - drug effects; Neurites - physiology; PC12 Cells; Phosphorylation - drug effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Spinal cord injuries; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; Studies; Survival analysis; Tyrosine - metabolism; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00737.2006

1 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; 2 Department of Pharmacology, School of Medicine, Philipps University, Marburg, Germany; and 3 Department of Neuroscience, University of Florida, Gainesville, Florida Submitted 18 October 2006 ; accepted in final form 31 May 2007 The fibroblast growth factor binding protein (FGF-BP; GenBank accession no. NP_005121 ) is a secreted protein that mobilizes FGFs from the extracellular matrix, protects them from degradation, and enhances their biological activity. Several previous studies reported that FGF-BP is an early response gene upregulated during tissue repair processes including wound healing and atherogenesis. In this study we analyzed whether FGF-BP expression was impacted by spinal cord injury and could have an effect on neuronal cell viability. Immunohistochemical and in situ hybridization studies revealed a dramatic upregulation of FGF-BP protein and mRNA levels following unilateral hemisection and contusion injury of adult rat spinal cord. In spinal cord sections of laminectomized rats, increased FGF-BP expression was observed in the fibers and cell bodies ipsilateral to the lesion site but was absent in the uninjured spinal cord tissue contralateral to the lesion. Increased expression of FGF-BP was observed at all postinjury time points, examined with peak levels occurring at day 4 , a time when injury-induced increased levels of FGF2 have also been reported to be maximal. Moreover, using PC12 cells as a neuronal model, we observed that exogenous FGF-BP increased the capacity of FGF2 to stimulate neurite outgrowth and to increase cell survival. At the molecular level, FGF-BP enhanced FGF2-induced protein tyrosine phosphorylation and AKT/PKB activation. Collectively, these results suggest that FGF-BP is an early response gene after spinal cord injury and that its upregulation in regenerating spinal cord tissue may provide a molecular mechanism for enhancing the initial FGF2-mediated neurotrophic effects occurring after such tissue damage. PC12 cells; neurite outgrowth; apoptosis Address for reprint requests and other correspondence: A. Wellstein, Lombardi Comprehensive Cancer Center, Research Bldg. E311, Georgetown Univ., 3970 Reservoir Road, N.W., Washington, DC 20057 (e-mail: wellstea{at}georgetown.edu )