Matrix hyaluronan-activated CD44 signaling promotes keratinocyte activities and improves abnormal epidermal functions

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Calcium Signaling
  • Cytoskeleton / metabolism
  • Epidermal Cells
  • Epidermis / physiopathology*
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hyaluronic Acid / metabolism*
  • Keratinocytes / cytology*
  • Mice, Knockout
  • Signal Transduction
  • Skin Aging
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein / metabolism


  • Hyaluronan Receptors
  • Hyaluronic Acid
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein