FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions

Abstract

Multiple sclerosis is a demyelinating disease that affects ϳ2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in response to the FGF-2 produced by microglial cells in the periplaque. Also in human tissue, FGF-2 is upregulated in perivascular astrocytes in regions of the normal-appearing gray matter, where the integrity of the blood-brain barrier is compromised. In culture, FGF-2 and Anosmin-1 influence adult mouse oligodendrocyte precursor cell migration in the same manner as at embryonic stages, providing an explanation for the histopathological observations: FGF-2 attracts/ enhances its migration, which is hindered by Anosmin-1. We propose that FGF-2 and Anosmin-1 are markers for the histopathological type and the level of inflammation of multiple sclerosis lesions, and that they may serve as novel pharmacogenetic targets to design future therapies that favor effective remyelination and protect the blood-brain barrier.

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

“…This ligand/receptor interaction is critically involved in OPC differentiation and remyelination in a model of toxic demyelination [103]. The ECM of vascular endothelial cells can trap FGF-2 (bFGF), which facilitates neurogenesis [104] and promotes OPC migration to demyelinated lesions [105]. Epidermal growth factor (EGF), pigment epithelium-derived factor (PEDF) and TGF-α have been implicated in adult neurogenesis and oligodendrogenesis [95,106].…”

The Adhesion Molecule Anosmin-1 in Neurology: Kallmann Syndrome and Beyond

“…The arrival to the OB of newly generated neuroblasts from the SVZ is crucial for the maintenance of the olfactory function in rodents (Lois and AlvarezBuylla 1994 ;Lois et al 1996 ). Related to this, anosmin-1 has been shown to play a different role in glial cells: in oligodendrocyte precursors cells (OPC), the relative concentration of anosmin-1 and FGF-2 modulates OPC migration through their interaction with FGFR1 in the optic nerve during development and in the adult brain in mice (Bribián et al 2006 ;Clemente et al 2011 ). More specifi cally, anosmin-1 inhibits the motogenic effect of FGF-2 via FGFR1 (Bribián et al 2006 ;Clemente et al 2011 ).…”

“…Related to this, anosmin-1 has been shown to play a different role in glial cells: in oligodendrocyte precursors cells (OPC), the relative concentration of anosmin-1 and FGF-2 modulates OPC migration through their interaction with FGFR1 in the optic nerve during development and in the adult brain in mice (Bribián et al 2006 ;Clemente et al 2011 ). More specifi cally, anosmin-1 inhibits the motogenic effect of FGF-2 via FGFR1 (Bribián et al 2006 ;Clemente et al 2011 ). But this effect on migration is tightly related to cell adhesiveness and, in this cell type, anosmin-1 has a stronger adhesive effect than laminin and fi bronectin, reducing cell motility in consequence (Bribián et al 2006(Bribián et al , 2008.…”

“…Associated to demyelinated plaques, alterations have been described in the expression pattern of several molecules involved in OPC biology during development such as CXCL1/GRO-α (Omari et al 2005 ), semaphorin 3A and 3 F (Williams et al 2007 ) and sonic hedgehog (Wang et al 2008 ). Regarding the FGF2/anosmin-1 system, the distribution of FGF2 and anosmin-1 varies between the different kinds of demyelinated plaques in MS patients, showing a complementary spatial pattern (Clemente et al 2011 ). In areas with active remyelinating activity, i.e.…”

“…In areas with active remyelinating activity, i.e. active lesions and the periplaque of chronic-active plaques (Frohman et al 2006 ), FGF2 is up-regulated in infi ltrating as well as microgliaderived macrophages, whereas anosmin-1 is absent (Clemente et al 2011 ). In contrast, where the remyelination process is completely compromised i.e.…”