Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions

• Published in: Annals of neurology 2007-09, Vol.62 (3), p.288-300
• Main Authors: Fuller, Molly L., DeChant, Anne K., Rothstein, Brian, Caprariello, Andrew, Wang, Rae, Hall, Alison K., Miller, Robert H.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Biological and medical sciences; Blotting, Western; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins - metabolism; Bone Morphogenetic Proteins - physiology; Cell Proliferation; Cells, Cultured; Chondroitin Sulfates - metabolism; Demyelinating Diseases - chemically induced; Demyelinating Diseases - pathology; DNA - biosynthesis; DNA - genetics; Female; Glial Fibrillary Acidic Protein - biosynthesis; Gliosis - pathology; Immunohistochemistry; Injuries of the nervous system and the skull. Diseases due to physical agents; Lysophosphatidylcholines; Medical sciences; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neuroglia - pathology; Neurology; Phosphorylation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Smad Proteins - biosynthesis; Spinal Cord Diseases - chemically induced; Spinal Cord Diseases - pathology; Traumas. Diseases due to physical agents; Up-Regulation - genetics; Up-Regulation - physiology
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21179

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. Ann Neurol 2007