Inhibition of HYBID (KIAA1199)-mediated hyaluronan degradation and anti-wrinkle effect of Geranium thunbergii extract.

BACKGROUND: Hyaluronan (HA) is an essential constituent of extracellular matrix in the skin. HA reduction in the dermis and overexpression of HYBID (KIAA1199), a key molecule for HA degradation in skin fibroblasts, are implicated in facial skin wrinkling. AIMS: We aimed to obtain anti-wrinkle agent(s) by screening for inhibition of HYBID-mediated HA degradation. METHODS: Various plant extracts were screened for inhibition of HA degradation in HYBID-stable transfectants in HEK293 (HYBID/HEK293). Inhibition of HA-degrading activity and HYBID mRNA and protein expression by Geranium thunbergii extract was studied in skin fibroblasts and HYBID/HEK293 cells. Size distribution of newly produced HA was evaluated by preparing metabolically radiolabeled HA in skin fibroblasts. A double-blind, randomized, and placebo-controlled study was performed in healthy Japanese women (n = 21) by topically treating each side of the face with a lotion formulated with G. thunbergii extract or placebo for 8 weeks. RESULTS: Among the plant extracts tested, only G. thunbergii extract abolished HA depolymerization in skin fibroblasts and HYBID/HEK293 cells by down-regulating HYBID mRNA and protein expression and by inhibiting HYBID-mediated HA-degrading activity. Although untreated skin fibroblasts produced polydispersed HA, G. thunbergii extract-treated cells produced high-molecular-weight HA. Treatment with G. thunbergii extract-formulated lotion significantly improved skin elasticity and reduced skin wrinkling scores at the outer eye corner compared with the placebo formulation. CONCLUSIONS: Geranium thunbergii extract inhibited HYBID-mediated HA degradation in vitro and showed anti-wrinkle activity in vivo accompanying the improvement in skin elasticity. Our study provides a possible strategy for anti-wrinkle care through inhibition of HYBID-mediated HA degradation.

KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.

Hyaluronan (HA) has an extraordinarily high turnover in physiological tissues, and HA degradation is accelerated in inflammatory and neoplastic diseases. CD44 (a cell surface receptor) and two hyaluronidases (HYAL1 and HYAL2) are thought to be responsible for HA binding and degradation; however, the role of these molecules in HA catabolism remains controversial. Here we show that KIAA1199, a deafness gene of unknown function, plays a central role in HA binding and depolymerization that is independent of CD44 and HYAL enzymes. The specific binding of KIAA1199 to HA was demonstrated in glycosaminoglycan-binding assays. We found that knockdown of KIAA1199 abolished HA degradation by human skin fibroblasts and that transfection of KIAA1199 cDNA into cells conferred the ability to catabolize HA in an endo-ß-N-acetylglucosaminidase-dependent manner via the clathrin-coated pit pathway. Enhanced degradation of HA in synovial fibroblasts from patients with osteoarthritis or rheumatoid arthritis was correlated with increased levels of KIAA1199 expression and was abrogated by knockdown of KIAA1199. The level of KIAA1199 expression in uninflamed synovium was less than in osteoarthritic or rheumatoid synovium. These data suggest that KIAA1199 is a unique hyaladherin with a key role in HA catabolism in the dermis of the skin and arthritic synovium.