Multiple sclerosis (MS) is a neurodegenerative disease of the CNS in which myelin sheaths generated by oligodendrocytes are destroyed through recurrent inflammation Citation[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 Citation[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 drug-based 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 Citation[3]. We have recently identified a positive regulator of remyelination called retinoid X receptor γ (Rxrg) by microarray profiling of differentially expressed genes from rodent CNS remyelination Citation[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 differentiation and remyelination. Notably, delivery of a pan-RXR agonist, 9-cis-retinoic acid (9cRA), to aged rats following demyelination resulted in the generation of more remyelinated axons, thus demonstrating that RXR is a promising target for remyelination therapy.
The mechanisms of RXR signaling and its regulation during CNS remyelination are currently unclear. Similar to other nuclear receptors, RXRs are ligand-induced transcription factors that function through heterodimeric association with other nuclear receptors. However, RXR is seated at the center of nuclear receptor activity because it can heterodimerize with a wide range of receptors, including members of retinoic acid receptor, thyroid hormone receptor, peroxisome proliferator activated receptor (PPAR), liver X receptor (LXR) and vitamin D receptor. Once activated, the RXR heterodimeric complex is able to induce the transcription of genes associated with cell differentiation. Moreover, RXRs are able to function as either permissive or nonpermissive heterodimers. In permissive dimerization, such as RXR–PPAR or RXR–LXR, the complex can be activated by RXR-selective ligands, such as 9cRA, whereas in nonpermissive dimerization, such as RXR–retinoic acid receptor, RXR–thyroid hormone receptor or RXR–vitamin D receptor, the complex can only be activated by ligands selective for the partners of RXR, and not by RXR-selective ligands alone, so that RXR activity is subordinated under nonpermissive dimerization. Since we found that RXR activation enhances CNS remyelination, the mechanism by which RXR signaling occurs in oligodendrocytes is probably through permissive heterodimerization, such as through binding to PPAR or LXR. Interestingly, PPARγ, which is also expressed by oligodendrocyte lineage cells, has been demonstrated to accelerate oligodendrocyte differentiation when it is activated Citation[5]. Moreover, deletion of LXRα and LXRβ in mice results in severe dysmyelination or myelin abnormalities Citation[6]. Identification of the RXR heterodimeric partner would, therefore, improve our understanding of RXR signaling in oligodendrocyte lineage cells, and help develop more finely tuned agonists that would target oligodendrocytes specifically in remyelination therapy.
Currently, RXR agonists are being tested for the treatment of certain cancers, and are also thought to be useful in the treatment of metabolic disorders Citation[7]. A licensed RXR agonist, Targretin® (bexarotene), is already in clinical use for treatment of cutaneous T-cell lymphoma Citation[8]. In experimental autoimmune encephalomyelitis, a well-established model of immune-mediated demyelination that mimics many aspects of MS, 9cRA has been demonstrated to suppress inflammation Citation[9]. Our work suggests that RXR agonists will be of value as a regenerative therapy, filling the unoccupied niche of a treatment for progressive MS. Thus, bexarotene and other RXR agonists could conceivably provide an important advance in MS therapy, contributing not only to damage suppression through immunomodulation but also axon preservation through enhancement of remyelination.
Acknowledgements
The authors gratefully acknowledge the UK Multiple Sclerosis Society and the National Multiple Sclerosis Society for their generous support of the authors’ work described in this article.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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