Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction.
BACKGROUND
Mouse epidermal chronologic aging is closely associated with aberrant matrix (hyaluronan, HA)-size distribution/production and impaired keratinocyte proliferation/differentiation, leading to a marked thinning of the epidermis with functional consequence that causes a slower recovery of permeability barrier function.


OBJECTIVE
The goal of this study is to demonstrate mechanism-based, corrective therapeutic strategies using topical applications of small HA (HAS) and/or large HA (HAL) [or a sequential small HA (HAS) and large HA(HAL) (HAs→HAL) treatment] as well as RhoGTPase signaling perturbation agents to regulate HA/CD44-mediated signaling, thereby restoring normal epidermal function, and permeability barrier homeostasis in aged mouse skin.


METHODS
A number of biochemical, cell biological/molecular, pharmacological and physiological approaches were used to investigate matrix HA-CD44-mediated RhoGTPase signaling in regulating epidermal functions and skin aging.


RESULTS
In this study we demonstrated that topical application of small HA (HAS) promotes keratinocyte proliferation and increases skin thickness, while it fails to upregulate keratinocyte differentiation or permeability barrier repair in aged mouse skin. In contrast, large HA (HAL) induces only minimal changes in keratinocyte proliferation and skin thickness, but restores keratinocyte differentiation and improves permeability barrier function in aged epidermis. Since neither HAS nor HAL corrects these epidermal defects in aged CD44 knock-out mice, CD44 likely mediates HA-associated epidermal functions in aged mouse skin. Finally, blockade of Rho-kinase activity with Y27632 or protein kinase-Nγ activity with Ro31-8220 significantly decreased the HA (HAS or HAL)-mediated changes in epidermal function in aged mouse skin.


CONCLUSION
The results of our study show first that HA application of different sizes regulates epidermal proliferation, differentiation and barrier function in aged mouse skin. Second, manipulation of matrix (HA) interaction with CD44 and RhoGTPase signaling could provide further novel therapeutic approaches that could be targeted for the treatment of various aging-related skin disorders.
['Bourguignon|Lilly Y W|LY|', 'Wong|Gabriel|G|', 'Xia|Weiliang|W|', 'Man|Mao-Qiang|MQ|', 'Holleran|Walter M|WM|', 'Elias|Peter M|PM|']
D000818:Animals D002454:Cell Differentiation D049109:Cell Proliferation D002478:Cells, Cultured D004791:Enzyme Inhibitors D004817:Epidermis D005109:Extracellular Matrix D000091344:Filaggrin Proteins D006801:Humans D018960:Hyaluronan Receptors D006820:Hyaluronic Acid D007381:Intermediate Filament Proteins D015603:Keratinocytes D008297:Male D051379:Mice D018345:Mice, Knockout D008970:Molecular Weight D011493:Protein Kinase C D011498:Protein Precursors D015398:Signal Transduction D015595:Skin Aging D020741:rho GTP-Binding Proteins D054460:rho-Associated Kinases
CD44 RhoGTPase signaling Keratinocyte functions Skin aging Matrix hyaluronan