Oncomodulin, an ~12 kDa Ca(2+)-binding protein secreted from activated macrophages, has been shown to promote axonal regeneration from retinal ganglion cells (RGCs) following optic nerve injury. However, to date, the axonal growth-promoting capacity of oncomodulin in other models of 'regenerative failure' has not been evaluated. We assessed the capability of preconditioning treatment with oncomodulin to promote sensory axonal regeneration in an in vitro spot model of regenerative failure, and across the dorsal root zone (DREZ) after root crush injury. Neither the direct exposure of adult rat DRGs to oncomodulin, nor preconditioning of DRGs by intraganglionic injection of oncomodulin, stimulated axonal outgrowth in the in vitro proteoglycan spot gradient assay. However, direct exposure of unconditioned DRGs to both oncomodulin and db-cAMP in vitro, as well as preconditioning of DRGs with the combined treatment in vivo, resulted in significant, albeit modest, neurite extension across the inhibitory proteoglycan barrier. We next quantified axon regeneration through the C8 DREZ in adult rats after oncomodulin and/or db-cAMP preconditioning and chondroitinase (ChABC) injection into the DREZ immediately following a root crush injury. Axonal regeneration across the DREZ was not observed in control animals, or after injection of ChABC-alone. Treatment with oncomodulin- or db-cAMP-alone resulted in extremely sparse regeneration. However, significant, but meager, sensory axon regeneration across the DREZ was observed using the oncomodulin/ db-cAMP combination (p<0.001), supporting findings from previous studies suggesting that cAMP is necessary for the growth-promoting effects of oncomodulin. Although our results support a role for oncomodulin in macrophage-induced axonal regeneration, the effects of oncomodulin/db-cAMP on sensory regeneration were extremely limited in comparison to previous studies in the same injury model using zymosan.
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