Bourguignon Lilly Y W
Department of Medicine, University of California at San Francisco, and the Endocrine Unit, VA Medical Center, San Francisco, California.
Am J Pathol. 2014 Jul;184(7):1912-9. doi: 10.1016/j.ajpath.2014.03.010. Epub 2014 May 9.
Hyaluronan (HA), a major component of the extracellular matrix, is enriched in skin tissues, particularly the epidermis. HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, CD44. This article reviews the current evidence for HA/CD44-mediated activation of RhoGTPase signaling and calcium mobilization, leading to the regulation of keratinocyte activities and various epidermal functions. It further discusses the role of HA-mediated CD44 interactions with unique downstream effectors, such as RhoGTPases (RhoA and Rac1), Rho-kinase, protein kinase-Nγ, and phosphoinositide-specific phospholipases (phospholipases Cε and Cγ1) in coordinating certain intracellular signaling pathways, such as calcium mobilization, phosphatidylinositol 3-kinase-AKT activation, cortactin-actin binding, and actin-associated cytoskeleton reorganization; generating the onset of important keratinocyte activities, such as cell adhesion, proliferation, migration, and differentiation; and performing epidermal functions. Topical application of selective HA fragments (large versus small HA) to the skin of wild-type mice (but not CD44 knockout mice) improves keratinocyte-associated epidermal functions and accelerates permeability barrier recovery and skin wound healing. Consequently, specific HA fragment (large versus small HA)-mediated signaling events (through the CD44 receptor) are required for keratinocyte activities, which offer new HA-based therapeutic options for patients experiencing epidermal dysfunction and skin damage as well as aging-related skin diseases, such as epidermal thinning (atrophy), permeability barrier dysfunction, and chronic nonhealing wounds.
透明质酸（HA）是细胞外基质的主要成分，在皮肤组织尤其是表皮中含量丰富。HA与细胞表面受体CD44这一普遍存在、数量众多且功能重要的家族相结合。本文综述了当前关于HA/CD44介导的RhoGTPase信号激活和钙动员的证据，这些过程导致角质形成细胞活性和各种表皮功能的调节。文章还进一步讨论了HA介导的CD44与独特下游效应分子（如RhoGTPases（RhoA和Rac1）、Rho激酶、蛋白激酶-Nγ以及磷脂酰肌醇特异性磷脂酶（磷脂酶Cε和Cγ1））相互作用在协调某些细胞内信号通路（如钙动员、磷脂酰肌醇3激酶-AKT激活、皮质肌动蛋白结合以及肌动蛋白相关细胞骨架重组）中的作用；引发重要的角质形成细胞活性（如细胞黏附、增殖、迁移和分化）；以及执行表皮功能。将选择性HA片段（大分子HA与小分子HA）局部应用于野生型小鼠（而非CD44基因敲除小鼠）的皮肤，可改善与角质形成细胞相关的表皮功能，并加速渗透屏障恢复和皮肤伤口愈合。因此，角质形成细胞活性需要特定HA片段（大分子HA与小分子HA）介导的（通过CD44受体的）信号事件，这为患有表皮功能障碍、皮肤损伤以及衰老相关皮肤病（如表皮变薄（萎缩）、渗透屏障功能障碍和慢性不愈合伤口）的患者提供了基于HA的新治疗选择。
