Like other areas of the mammalian central nervous system, retinal ganglion cell (RGC) axons of the optic nerve are resistant to regeneration following injury. However, some treatments have been shown to enhance their regrowth and/or survival. Elevating cAMP or suppressing the known growth-inhibiting activities of myelin-associated proteins has been shown to promote modest regrowth of damaged axons.1-3 Under some circumstances, certain factors associated with inflammation may also be potent inducers of axonal regeneration.4,5 For instance, promoting intraocular inflammation, either through lens injury or pharmacological treatment, enhances RGC axon outgrowth following optic nerve damage.6 Remarkably, inflammation-induced RGC regeneration may occur over long distances, supporting axon regrowth through the optic chiasm and to the superior colliculus where new synaptic connections have been demonstrated.7 Recently, it has been shown that factors secreted by eye-infiltrating macrophages play a significant role in this effect, but until now, the identity of the macrophage-derived growth factor has remained elusive.8
|Figure 1. Inflammation can promote retinal ganglion cell regeneration following optic nerve injury. A recent study provides evidence that the calcium-binding protein oncomodulin, combined with elevated cAMP and the presence of mannose, are important for the effect. Infiltrating macrophages appear to be the main source of oncomodulin in the eye. Oncomodulin is also upregulated at the site of nerve injury by an unknown mechanism.
Oncomodulin is a small, ~12 kDa calcium-binding protein in the parvalbumin family.9 It exhibits an EF hand domain found in several related proteins including a-parvalbumin, calmodulin, calbindin, and S100b. Not previously known for its growth-promoting effects, a recent study provides several lines of evidence suggesting that oncomodulin is the macrophage-derived factor capable of inducing RGC axon regeneration.10 Oncomodulin is constitutively secreted by activated macrophages in the vitreous and retina in response to inflammatory conditions that promote optic nerve regeneration, and it is upregulated by an unclear mechanism at the site of experimental optic nerve injury (Figure 1).10 In addition, active macrophage-conditioned medium significantly stimulates retinal ganglion cell axon outgrowth in vitro, an activity blocked by depleting oncomodulin and mimicked by treatment with the recombinant protein.8,10 These proregeneration effects appear to significantly exceed those of more traditional neurotrophic factors including BDNF, CNTF, and GDNF.10 Importantly, oncomodulin does not appear to have growth-promoting activity by itself. Also required are elevated levels of cAMP and the presence of the small sugar mannose. The reason is not definitively known, but cAMP may be required for translocation of the oncomodulin receptor to the membrane. Indeed, oncomodulin binds RGCs with high affinity in vitro, but only when cAMP is pharmacologically elevated or if the membrane is permeabilized allowing oncomodulin access to the cytosolic compartment.10 Oncomodulin exhibits a similar dependence on cAMP in vivo. When a combination of the recombinant protein and cAMP analogs are injected into the vitreous, the regrowth of damaged optic nerve axons increases several fold above that stimulated by either compound alone. The other required component, mannose, is found endogenously in the vitreous.
Given the relatively limited treatments available for patients with CNS injury or neurodegenerative disease, the mechanisms underlying the novel role of oncomodulin in promoting nerve regeneration warrant further study. For instance, what is the identity of the receptor? Evidence seems to exclude certain receptor subtypes known to promote similar activities. Signaling cascades often associated with growth/neurotrophic factors including PI 3-Kinase, MAP Kinase, and JAK/STAT play little role, while CaM Kinase II activity may be important.10 In addition, the pro-growth activity of oncomodulin is not accompanied by an increase in cell survival.10 Does oncomodulin affect regeneration elsewhere in the nervous system? Inflammatory factors have been shown to enhance dorsal root ganglion (DRG) neurite outgrowth in vivo, and macrophage injections into regions of transected spinal cord can support partial return of motor function.4,11 Pre-treatment with oncomodulin does support DRG neurite outgrowth in vitro, even on a growth-inhibitory chondroitin sulfate proteoglycan substrate.10 Whether it has pro-outgrowth potential in other areas of the nervous system remains to be determined.
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