Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions
Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions
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DOI：
10.1002/ana.21179
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发表时间：
2007-09-01
影响因子：
11.2
通讯作者：
Miller, Robert H.
中科院分区：
文献类型：
--
作者：
Fuller, Molly L.;DeChant, Anne K.;Miller, Robert H.
目的：目的：探讨骨形态发生蛋白（BMPs）在成年大鼠脊髓脱髓鞘病变中刺激胶质瘢痕形成的作用。检测骨形成蛋白4和骨形成蛋白7的表达水平，并与损伤区胶质细胞酸性蛋白的表达进行比较。BMP-反应性细胞通过磷酸化Smad 1/5/8的表达来鉴定。用BMP 4处理成熟脊髓星形胶质细胞的培养物，并测量硫酸软骨素蛋白聚糖（CSPG）的水平。BMP 4对CSPG基因调控的影响通过实时聚合酶链反应（real-time polymerase chain reaction for CSPG core proteins.Results）测定：BMP 4和BMP 7在脱髓鞘部位迅速增加，病变周围星形胶质细胞增加磷酸化Smad 1/5/8的表达。培养的成熟星形胶质细胞直接响应BMP与Smad 1易位到细胞核，增加磷酸化Smad 1/5/8，并增加胶质细胞酸性蛋白和CSPG的表达。BMP处理还增加了CSPG核心蛋白的CSPG信使RNA，包括聚集蛋白聚糖和神经聚糖。抑制剂noggin可阻断BMP引起的星形胶质细胞CSPG表达的增加。注射BMP 4或BMP 7到背柱在脱髓鞘的情况下导致CSPG expression.Interpretation增加：在脱髓鞘病变的部位的BMP的局部增加导致上调的神经胶质增生，神经胶质瘢痕形成，和CSPG的表达升高，如神经聚糖和聚集蛋白聚糖，可能抑制髓鞘再生。
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.