TY - JOUR
T1 - Oncomodulin affords limited regeneration to injured sensory axons in vitro and in vivo
AU - Harel, Ran
AU - Iannotti, Christopher A.
AU - Hoh, Daniel
AU - Clark, Megan
AU - Silver, Jerry
AU - Steinmetz, Michael P.
N1 - Funding Information:
This work was supported by a grant from the Cleveland Clinic Foundation (M.P.S.) and the Advanced Leadership Program for Innovative & Original Thinking (TALPIOT) in Medicine, Sheba Medical Center, Tel Hashomer, Israel (R.H.). The authors have no conflicting interests.
PY - 2012/2
Y1 - 2012/2
N2 - Oncomodulin, an ~12kDa 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.
AB - Oncomodulin, an ~12kDa 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.
KW - Axon regeneration
KW - Chondroitin sulfate proteoglycan
KW - Conditioning lesion
KW - Glial scar
KW - Inflammation
KW - Oncomodulin
UR - http://www.scopus.com/inward/record.url?scp=84856555483&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2011.04.017
DO - 10.1016/j.expneurol.2011.04.017
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C2 - 22078758
AN - SCOPUS:84856555483
SN - 0014-4886
VL - 233
SP - 708
EP - 716
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -