Jones Leonard L, Margolis Richard U, Tuszynski Mark H
Department of Neurosciences-0626, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Exp Neurol. 2003 Aug;182(2):399-411. doi: 10.1016/s0014-4886(03)00087-6.
Chondroitin sulfate proteoglycans (CSPGs) are extracellular matrix (ECM) molecules that are widely expressed throughout the developing and adult CNS. In vitro studies demonstrate their potential to restrict neurite outgrowth, and it is believed that CSPGs also inhibit axonal regeneration after CNS injury in vivo. Previous studies demonstrated that CSPGs are generally upregulated after spinal cord injury, and more recent reports have begun to identify individual proteoglycans that may play dominant roles in limiting axonal regeneration. The current study systematically examined the extended deposition patterns after CNS injury of four putatively inhibitory CSPGs that have not been extensively investigated previously in vivo: neurocan, brevican, phosphacan, and versican. After spinal cord injury, neurocan, brevican, and versican immunolabeling increased within days in injured spinal cord parenchyma surrounding the lesion site and peaked at 2 weeks. Neurocan and versican were persistently elevated for 4 weeks postinjury, and brevican expression persisted for at least 2 months. On the other hand, phosphacan immunolabeling decreased in the same region immediately following injury but later recovered and then peaked after 2 months. Combined glial fibrillary acidic protein (GFAP) immunohistochemistry and in situ hybridization demonstrated that GFAP astrocytes constituted a source of neurocan production after spinal cord injury. Thus, the production of several CSPG family members is differentially affected by spinal cord injury, overall establishing a CSPG-rich matrix that persists for up to 2 months following injury. Optimization of strategies to reduce CSPG expression to enhance regeneration may need to target several different family members over an extended period following injury.
硫酸软骨素蛋白聚糖（CSPGs）是细胞外基质（ECM）分子，在整个中枢神经系统（CNS）的发育和成年期均广泛表达。体外研究表明它们具有限制神经突生长的潜力，并且人们认为CSPGs在体内CNS损伤后也会抑制轴突再生。先前的研究表明，脊髓损伤后CSPGs通常会上调，最近的报道已开始鉴定可能在限制轴突再生中起主导作用的单个蛋白聚糖。本研究系统地检查了四种先前在体内未被广泛研究的假定具有抑制作用的CSPGs在CNS损伤后的扩展沉积模式：神经聚糖、短蛋白聚糖、磷蛋白聚糖和多功能蛋白聚糖。脊髓损伤后，神经聚糖、短蛋白聚糖和多功能蛋白聚糖的免疫标记在损伤部位周围的受损脊髓实质内数天内增加，并在2周时达到峰值。神经聚糖和多功能蛋白聚糖在损伤后4周持续升高，短蛋白聚糖的表达持续至少2个月。另一方面，磷蛋白聚糖的免疫标记在损伤后立即在同一区域减少，但随后恢复，然后在2个月后达到峰值。联合胶质纤维酸性蛋白（GFAP）免疫组织化学和原位杂交表明，GFAP星形胶质细胞是脊髓损伤后神经聚糖产生的来源。因此，几种CSPG家族成员的产生受到脊髓损伤的不同影响，总体上形成了一个富含CSPG的基质，该基质在损伤后可持续长达2个月。优化减少CSPG表达以促进再生的策略可能需要在损伤后的较长时间内针对几种不同的家族成员。
