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.