The Role of Osteopontin in the Peripheral and Central Nervous Systems

The glycoprotein osteopontin (OPN) is a secreted and heavily phosphorylated peptide that plays a role in a variety of cellular processes from cell adhesion to apoptosis. These actions are principally thought to be mediated via interactions with CD44.and integrins. OPN is expressed in a wide variety of tissues including the peripheral and central nervous systems (PNS and CNS respectively), although its exact function in these tissues remains unclear. We identified OPN as a putative axotomy response gene from a previously generated dorsal root ganglia (DRG) subtractive cDNA library. Immunohistochemical ,staining demonstrated that OPN protein colocalises with neurofilament but not other nociceptive markers. Mechanosensory thresholds in osteopontin knockout (OPN KO) animals are significantly increased compared to wild-type (WT) controls, although there are no differences in allodynia between genotypes after a spared nerve injury (SNI) model of neuropathic pain. Moreover, exogenous recombinant OPN has no effect on neurite outgrowth from adult WT sensory neurons, and no differences in neurite outgrowth were observed in OPN KO animals compared to WT controls. Within the CNS, previous studies have demonstrated that OPN expression increases in a number of cell types after injury, although its precise function is equivocal. Here, I demonstrate that organotypic hippocampal OPN KO cultures display increased apoptosis following glutamate induced cell death compared to WT controls. Moreover, exogenous recombinant OPN is neuroprotective to OPN KO and WT cultures. This neuroprotective effect is integrin mediated and involves activation ofthe Akt and ERK pathways. In summary, these studies further extend our understanding of the neuroprotective and possible cell survival roles played by OPN in the nervous system. Further studies are now warranted to extend those presented here and define the mechanisms that underlie the observed effects thus far delineated.EThOS - Electronic Theses Online ServiceGBUnited Kingdo