in transgenic mice expressing an antisense CD44 construct.27 Furthermore, a significant decrease in the expression of several keratinocyte differential markers (ie, involucrin and filaggrin) is linked to the CD44 knock-out mice model, suggesting
that both HA and CD44 play a key role in maintaining normal epidermal physiology and keratinocyte differentiation. In addition, epidermal hyperplasia induced by topical retinoids is accompanied by an enhanced expression of CD44 and HAS, which results in a net increase in the skin HA levels in both the dermis and epidermis.28 The effects of retinoids on CD44 levels also explain their capacity to revert ultraviolet (UV)-induced lowering expression of this receptor.29 In addition to CD44, HA can also bind to a less characterized receptor called RHAMM receptor and to hyaladherins (ie, versican, aggrecan, neurocan, brevican, fibrinogen, trypsin inhibitor), a family of molecules that promotes the stabilization of HA by preventing the degradation HA.
BIOLOGICAL FUNCTIONS: IT IS ALL ABOUT LOCATION AND SIZE
Although the HA primary structure is simple, its biological functions
are complexly regulated by cellular localization and the structure and the size of HA-polymer. HA localization is divided into 3 categories: free extracellular HA, extracellular and cell-associated (pericellular) HA, and intracellular HA. Endogenous extracellular HA requires cross-linking to proteoglycans such as versican or aggrecan in an attempt to stabilize this molecule.30,31 Further interactions with other matrix proteins such as collagen networks result in the formation of complex super-molecular structures that are key for the mechanical support and integrity of the tissues, as well as to confer resistance from shear forces.32 Pericellular HA is connected to cell surface receptors such as CD44 and membrane-associated HA synthesizing enzymes (ie, HAS2 and HAS3).33,34 The interaction of pericellular HA and its receptors
is believed to play a role in the anti-adhesive properties
