Retinoid X receptors as a potential avenue for regenerative medicine in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease of the CNS in which myelin sheaths generated by oligodendrocytes are destroyed through recurrent inflammation [1]. The continuous destruction of myelin sheaths is associated with progressive degeneration of central axons, resulting in clinical decline. MS is the most common neurological disorder among young adults, and is thought to affect more than 2 million individuals worldwide. Current treatment strategies mainly aim to suppress inflammation by using immunomodulatory drugs. This is effective for the treatment of MS during the acute stages of the disease (i.e., relapse–remitting), but is largely ineffective in the chronic stages (i.e., secondary progressive), where inflammation has mostly subsided but clinical decline continues. Several lines of evidence suggest that restoring myelin to demyelinated axons will provide an effective means of preventing their loss, and so a major goal in MS research is to identify strategies to repair CNS demyelination through regenerative therapy [2]. This could involve either transplantation of stem or myelinating cells into the CNS of patients with MS, or pharmacological stimulation of myelin regeneration (remyelination) by endogenous stem and precursor cells. Regenerative therapy in MS would restore conduction and function and prevent further deterioration of axons, thus possibly bring disease progression to a halt. Although cell transplantation has been shown to be effective in animal models of myelin diseases, it is not well suited to being a treatment for MS. The multifocal nature of the disease presents obvious difficulties for direct, ‘plaque-guided’ delivery of myelinating cells, while systemic delivery of myelinating cells makes little direct contribution to repair (although it does provide potent disease-suppressing immunomodulation). In many ways, a more attractive strategy is to take a drugbased approach aimed at enhancing remyelination by promoting oligodendrocyte differentiation of endogenous CNS stem cells. Several potential drug targets for remyelination therapy have emerged in recent years and include LINGO-1, Notch1 and Wnt – all of which are negative regulators of CNS remyelination [3]. We have recently identified a positive regulator of remyelination called retinoid X receptor g (Rxrg) by microarray profiling of differentially expressed genes from rodent CNS remyelination [4]. Rxrg is a member of the RXR family of nuclear receptors that also includes Rxra and Rxrb. All three RXR members are differentially expressed in remyelination, with Rxrg displaying the greatest differential expression. We found that Rxrg is highly expressed in oligodendrocyte lineage cells during remyelination, and that inhibition of RXR activity impaired oligodendrocyte