Lavorgna Tessa R, Gressett Timothy E, Chastain Wesley H, Bix Gregory J
Tulane University School of Medicine, New Orleans, LA, United States.
Clinical Neuroscience Research Center, Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA, United States.
Front Physiol. 2023 May 30;14:1189731. doi: 10.3389/fphys.2023.1189731. eCollection 2023.
Perlecan is a 500 kDa proteoglycan residing in the extracellular matrix of endothelial basement membranes with five distinct protein domains and three heparan sulfate chains. The complex structure of perlecan and the interaction it has with its local environment accounts for its various cellular and tissue-related effects, to include cartilage, bone, neural and cardiac development, angiogenesis, and blood brain barrier stability. As perlecan is a key contributor to extracellular matrix health involved in many tissues and processes throughout the body, dysregulation of perlecan has the potential to contribute to various neurological and musculoskeletal diseases. Here we review key findings associated with perlecan dysregulation in the context of disease. This is a narrative review article examining perlecan’s role in diseases of neural and musucloskeletal pathology and its potential as a therapeutic index. Literature searches were conducted on the PubMed database, and were focused on perlecan's impact in neurological disease, to include ischemic stroke, Alzheimer's Disease (AD) and brain arteriovenous malformation (BAVM), as well as musculoskeletal pathology, including Dyssegmental Dysplasia Silverman-Handmaker type (DDSH), Schwartz-Jampel syndrome (SJS), sarcopenia, and osteoarthritis (OA). PRISMA guidelines were utilized in the search and final selection of articles.Increased perlecan levels were associated with sarcopenia, OA, and BAVM, while decreased perlecan was associated with DDSH, and SJS. We also examined the therapeutic potential of perlecan signaling in ischemic stroke, AD, and osteoarthritic animal models. Perlecan experimentally improved outcomes in such models of ischemic stroke and AD, and we found that it may be a promising component of future therapeutics for such pathology. In treating the pathophysiology of sarcopenia, OA, and BAVM, inhibiting the effect of perlecan may be beneficial. As perlecan binds to both α-5 integrin and VEGFR2 receptors, tissue specific inhibitors of these proteins warrant further study. In addition, analysis of experimental data revealed promising insight into the potential uses of perlecan domain V as a broad treatment for ischemic stroke and AD. As these diseases have limited therapeutic options, further study into perlecan or its derivatives and its potential to be used as novel therapeutic for these and other diseases should be seriously considered.
基底膜聚糖是一种500 kDa的蛋白聚糖，存在于内皮基底膜的细胞外基质中，具有五个不同的蛋白质结构域和三条硫酸乙酰肝素链。基底膜聚糖的复杂结构及其与局部环境的相互作用，解释了其各种与细胞和组织相关的作用，包括软骨、骨骼、神经和心脏发育、血管生成以及血脑屏障稳定性。由于基底膜聚糖是参与全身许多组织和过程的细胞外基质健康的关键贡献者，基底膜聚糖的失调有可能导致各种神经和肌肉骨骼疾病。在此，我们综述了与疾病背景下基底膜聚糖失调相关的关键发现。这是一篇叙述性综述文章，探讨基底膜聚糖在神经和肌肉骨骼病理学疾病中的作用及其作为治疗指标的潜力。在PubMed数据库上进行了文献检索，重点关注基底膜聚糖在神经疾病中的影响，包括缺血性中风、阿尔茨海默病（AD）和脑动静脉畸形（BAVM），以及肌肉骨骼病理学，包括银曼 - 汉德马克型节段发育异常（DDSH）、施瓦茨 - 詹佩尔综合征（SJS）、肌肉减少症和骨关节炎（OA）。在文章的检索和最终选择中采用了PRISMA指南。基底膜聚糖水平升高与肌肉减少症、OA和BAVM相关，而基底膜聚糖水平降低与DDSH和SJS相关。我们还研究了基底膜聚糖信号在缺血性中风、AD和骨关节炎动物模型中的治疗潜力。基底膜聚糖在缺血性中风和AD的此类模型中实验性地改善了结果，并且我们发现它可能是未来针对此类病理学治疗的一个有前景的组成部分。在治疗肌肉减少症、OA和BAVM的病理生理学方面，抑制基底膜聚糖的作用可能是有益的。由于基底膜聚糖与α - 5整合素和VEGFR2受体都结合，这些蛋白质的组织特异性抑制剂值得进一步研究。此外，对实验数据的分析揭示了关于基底膜聚糖结构域V作为缺血性中风和AD广泛治疗方法的潜在用途的有前景的见解。由于这些疾病的治疗选择有限，应认真考虑对基底膜聚糖或其衍生物及其作为这些疾病和其他疾病新型治疗方法的潜力进行进一步研究。
