is not clear but it may enhance HYAL1 degradation activity. Activities
of HYAL1 and HYAL2 depend on HA-CD44 association, which strongly suggests that HA-degradation is a receptor mediated
process.19 The role of extracellular HYALs in HA degradation is still controversial as HA-degradation products are rarely detected
outside the cells in vivo.20-22 The final destination of HA catabolic processes is different in the epidermis and dermis. In the epidermis, HA is mainly degraded intracellularly after endocytic
internalization, while in the dermis HA-fragments are predominantly drained by afferent lymphatic vessels or uptaken via a receptor-mediated process by the endothelium.23 Non-enzymatic
depolymerization of extracellular HA is accomplished by reactive oxygen species (ROS) in the presence of reducing agents such as ascorbic acid, thiols, ferrous, or cuprous ions, and by Maillard products (that are also involved in the formation of advanced glycation endproducts).24
CD44: THE MAIN HYALURONIC ACID RECEPTOR
Hyaluronic acid binds to an ubiquitous, abundant, and functionally
important family of cell surface receptors called CD44. CD44
is encoded by a single gene in which alternative splicing determines variations within different cell types. Binding of HA to CD44 requires the activation of the latter by removal of the sialic acid,25 which suggests a very tight regulation in the activation of HA-CD44 signaling. HA-CD44 interactions activate unique signal transduction pathways that initiate a concomitant onset of multiple cellular functions. Two major intracellular signaling pathways (RhoA-ROK vs Rac-PKN) are partially responsible for the selective control of a variety of HA-linked functions such as proliferation, survival, migration, cell-cell adhesion, and barrier formation. Recent evidence suggests
that the size of HA that binds to CD44 is a key factor in triggering a specific intracellular signal transduction pathway under physiological or pathological conditions such as skin atrophy, psoriasis, atopic dermatitis, actinic keratosis, and chronic non-healing wounds.26
In addition, a close relationship exists between CD44 expression
and HA levels in the skin. For example, it has been reported that a significant reduction of HA levels is observed