Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions.

OBJECTIVE: To determine the role of bone morphogenetic proteins (BMPs) in stimulating glial scar formation in demyelinating lesions of the adult spinal cord. METHODS: The dorsal columns of adult rats were injected with lysolecithin to induce a local demyelinating lesion. Levels of BMP4 and BMP7 proteins were assayed and compared with glial fibrillary acidic protein expression in the injury area. BMP-responsive cells were identified by expression of phosphorylated Smad1/5/8. Cultures of mature spinal cord astrocytes were treated with BMP4, and levels of chondroitin sulphate proteoglycans (CSPGs) were measured. The effect of BMP4 on CSPG gene regulation was determined by real-time polymerase chain reaction for CSPG core proteins. RESULTS: BMP4 and BMP7 increase rapidly at the site of demyelination, and astrocytes surrounding the lesion increase expression of phosphorylated Smad1/5/8. Cultured mature astrocytes respond directly to BMPs with Smad1 translocation to the nucleus, increased phosphorylated Smad1/5/8, and increases in glial fibrillary acidic protein and CSPG expression. BMP treatment also increased CSPG messenger RNA for CSPG core proteins, including aggrecan and neurocan. Increases in CSPG expression in astrocytes by BMPs were blocked by the inhibitor noggin. Injections of BMP4 or BMP7 into the dorsal columns in the absence of demyelination led to increases in CSPG expression. INTERPRETATION: Local increases in BMPs at the site of a demyelinating lesion causes upregulation of gliosis, glial scar formation, and heightened expression of CSPGs such as neurocan and aggrecan that may inhibit remyelination.

Patterning of spinal cord oligodendrocyte development by dorsally derived BMP4.

Oligodendrocyte precursors (OPCs) initially arise in the motor neuron domain of the ventral ventricular zone of the developing spinal cord. After dispersal throughout gray and white matter, OPCs differentiate in a characteristic ventral to dorsal sequence. The spatial localization of OPC induction is in part a result of both positive local sonic hedgehog signaling and dorsally derived inhibitory cues. One component of dorsal inhibitory signals seems to be members of the transforming growth factor beta (TGFbeta) superfamily such as the bone morphogenetic proteins (BMPs). We show that during the initial appearance and subsequent maturation of OPCs, BMP4 was expressed specifically in the dorsal midline and its expression was correlated spatially and temporally with phospho-Smad 1+, BMP4-responsive cells. Implantation of sonic hedgehog (Shh)-coated beads adjacent to dorsal spinal cord in Xenopus embryos induced ectopic dorsal OPCs whereas BMP4-coated beads inhibited OPC appearance. More importantly, blocking endogenous dorsal BMP4 with anti-BMP4-coated beads locally induced ectopic OPCs. Similar results were obtained using soluble ligands on slice preparations of rodent spinal cord in vitro. In dissociated cell cultures of embryonic rat spinal cord, Shh and BMP4 had antagonistic effects on OPC development and the sensitivity of oligodendrocyte lineage cells to BMP4 increased with maturation. These data suggest that BMP4 contributes to the pattern of spinal cord oligodendrogenesis by regulating both induction and maturation of spinal cord OPCs.