Exciting discoveries in many diverse fields of hyaluronan (HA) biology over the last 40 years have centered around the ability of HA to bind cell surface HA receptors (e.g., CD44, Layilin, LYVE-1, HARE/Stab2 and RHAMM) and sometimes also to activate intracellular signal transduction pathways, frequently involving ERK1/2. Although perplexing, a major characteristic of HA-mediated signal pathway activation for some receptors has been a dependence on the size of the bound HA. Receptors that directly interact with HA, which may not include TLR2/4, bind very well to any HA molecule >8–20 sugars, depending on the receptor. Despite their ability to bind virtually any size HA, only HA chains of a particular mass range can activate receptor-mediated cell signaling. Many studies have demonstrated parts of this emerging story by utilizing different: HA receptors, cell types, animal models, HA sources, HA sizes, assays to assess HA mass and varying controls to verify HA specificity or HA size-dependence. Recent reports have highlighted issues with potential endotoxin contamination of HA fragments, especially those generated by hyaluronidase digestion. Also, researchers unfamiliar with HA polydispersity must adjust to working with, and interpreting data for, preparations without a unique molecular mass (molecular weight). The confusion, uncertainty and skepticism generated by these and other factors has hindered the development of a general consensus about HA-specific and HA-size dependent receptor activation. An overview of issues, suggested strategies and validating controls is presented to aid those planning an HA-mediated receptor signaling study or those trying to evaluate the literature.

中文翻译：

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计划，评估和审查受体信号转导研究，以评估透明质酸的大小依赖性和特异性

在过去的40年中，透明质酸（HA）生物学的许多不同领域中令人兴奋的发现都围绕着HA结合细胞表面HA受体（例如CD44，Layilin，LYVE-1，HARE / Stab2和RHAMM）的能力。激活细胞内信号转导途径，经常涉及ERK1 / 2。尽管令人困惑，但对于某些受体而言，HA介导的信号通路激活的主要特征是对结合的HA大小的依赖。与HA直接相互作用的受体（可能不包括TLR2 / 4）可以与任何大于8-20糖的HA分子很好地结合，具体取决于受体。尽管它们具有结合几乎任何大小的HA的能力，但只有特定质量范围的HA链才能激活受体介导的细胞信号传导。许多研究通过利用以下方面证明了这个新兴故事的各个部分：HA受体，细胞类型，动物模型，HA来源，HA大小，评估HA质量的测定法和各种对照以验证HA特异性或HA大小依赖性。最近的报告强调了HA片段潜在的内毒素污染问题，尤其是透明质酸酶消化产生的那些问题。另外，不熟悉HA多分散性的研究人员必须适应于处理没有独特分子量（分子量）的制剂并解释其数据。这些因素和其他因素引起的混乱，不确定性和怀疑态度阻碍了有关HA特异性和HA大小依赖性受体激活的普遍共识的发展。介绍了问题，建议的策略和验证控制的概述，以帮助计划HA介导的受体信号传导研究的人员或试图评估文献的人员。