Synergistic effects of osteonectin and NGF in promoting survival and neurite outgrowth of superior cervical ganglion neurons

Schwann cells (SCs) play a major role in the successful regeneration of peripheral nerves regeneration. Here we examined the effects of osteonectin (ON), a major factor secreted by SCs, on survival and neuritogenesis of mouse superior cervical ganglion (SCG) neurons. SC conditioned medium (SCCM) not only promoted the survival and neuritogenesis of SCG neurons at a level comparable to nerve growth factor (NGF) but also doubled the neurite length of NGF-treated SCG neurons. SCCM neuritogenic effects were not blocked by the tyrosine kinase receptor (Trk) inhibitor K252a demonstrating that these are not due solely to classical neurotrophic factors. Anti-ON neutralizing antibody diminished the SCCM-induced survival and neuritogenesis significantly. In the presence of K252a, the SCCM neuritogenic effects were blocked completely by anti-ON which suggests synergistic effects of ON with Trk-mediated growth factors. ON alone increased the survival and neurite outgrowth of SCG neurons significantly at high density cultures. ON at low concentration acts synergistically with NGF which induced maximum survival and neurite outgrowth (> 50% increase). However, ON at high concentration was detrimental to survival (64% decrease) and neurite outgrowth (87% decrease) even in the presence of NGF. The well documented counter-adhesive effect of ON may account for this observation. Nevertheless, the growth promoting effects of ON became more pronounced as the cell density increased which suggests a possible interaction of ON with growth factors secreted by SCG neurons (autocrine or paracrine effects). Taken together, our study indicates that ON plays important roles in nervous system repair through its synergistic effects with growth factors.