Basement Membrane Helps Maintain Epidermal Hyaluronan Content

Abstract

Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix of most mammalian tissues, including the epidermis. It is synthesized in epidermis, and mainly metabolized after transfer to the liver via lymphatic vessels in the dermis following its passage through the basement membrane (BM) at the dermal-epidermal junction. The aim of the present study was to investigate the influence of BM integrity on the level of HA in the epidermis. Epidermal HA content was decreased in sun-exposed skin of older subjects, whose BM structure was impaired, compared with sun-exposed young skin and sun-protected skin, in which BM integrity was well maintained. In an organotypic culture model of sun-exposed facial skin, epidermal HA was increased in the presence of inhibitors of BM-degrading matrix metalloproteinases and heparanase. In a skin equivalent model treated with these inhibitors, HA content was increased in the epidermis, but decreased in conditioned medium. These findings suggest that the BM at the dermal-epidermal junction plays an important role in maintaining epidermal HA levels. Hyaluronan (HA) is the major glycosaminoglycan in the extracellular matrix of most mammalian tissues, including the epidermis. It is synthesized in epidermis, and mainly metabolized after transfer to the liver via lymphatic vessels in the dermis following its passage through the basement membrane (BM) at the dermal-epidermal junction. The aim of the present study was to investigate the influence of BM integrity on the level of HA in the epidermis. Epidermal HA content was decreased in sun-exposed skin of older subjects, whose BM structure was impaired, compared with sun-exposed young skin and sun-protected skin, in which BM integrity was well maintained. In an organotypic culture model of sun-exposed facial skin, epidermal HA was increased in the presence of inhibitors of BM-degrading matrix metalloproteinases and heparanase. In a skin equivalent model treated with these inhibitors, HA content was increased in the epidermis, but decreased in conditioned medium. These findings suggest that the BM at the dermal-epidermal junction plays an important role in maintaining epidermal HA levels. Hyaluronan (HA) contains numerous negatively charged carboxyl groups, which contribute to the maintenance of skin tissue water content and permeability barrier homeostasis.1Taylor K.R. Gallo R.L. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation.FASEB J. 2006; 20: 9-22Crossref PubMed Scopus (472) Google Scholar HA and its receptor CD44 also play roles in many other physiological functions, including cell proliferation, adhesion, migration, differentiation, inflammatory response, and wound healing.2Bourguignon L.Y. Ramez M. Gilad E. Singleton P.A. Man M.Q. Crumrine D.A. Elias P.M. Feingold K.R. Hyaluronan-CD44 interaction stimulates keratinocyte differentiation, lamellar body formation/secretion, and permeability barrier homeostasis.J Invest Dermatol. 2006; 126: 1356-1365Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar,3Stern R. Maibach H.I. Hyaluronan in skin: aspects of aging and its pharmacologic modulation.Clin Dermatol. 2008; 26: 106-122Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar The aging of human skin can be explained in terms of the combination of intrinsic aging (ie, the natural aging process) and photoaging, which is premature skin aging resulting from chronic sunlight exposure. There have been several studies on intrinsic aging- and photoaging-dependent changes of HA in human skin in vivo,4Oh J.H. Kim Y.K. Jung J.Y. Shin J.E. Kim K.H. Cho K.H. Eun H.C. Chung J.H. Intrinsic aging- and photoaging-dependent level changes of glycosaminoglycans and their correlation with water content in human skin.J Dermatol Sci. 2011; 62: 192-201Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 5Oh J.H. Kim Y.K. Jung J.Y. Shin J.E. Chung J.H. Changes in glycosaminoglycans and related proteoglycans in intrinsically aged human skin in vivo.Exp Dermatol. 2011; 20: 454-456Crossref PubMed Scopus (71) Google Scholar, 6Meyer L.J. Stern R. Age-dependent changes of hyaluronan in human skin.J Invest Dermatol. 1994; 102: 385-389Crossref PubMed Scopus (161) Google Scholar but the mechanism of age-dependent changes of epidermal HA content remains unclear. HA is mainly localized around the cells of the basal and spinous layers,7Tuhkanen A.L. Tammi M. Pelttari A. Agren U.M. Tammi R. Ultrastructural analysis of human epidermal CD44 reveals preferential distribution on plasma membrane domains facing the hyaluronan-rich matrix pouches.J Histochem Cytochem. 1998; 46: 241-248Crossref PubMed Scopus (26) Google Scholar,8Tammi R. Agren U.M. Tuhkanen A.L. Tammi M. Hyaluronan metabolism in skin.Prog Histochem Cytochem. 1994; 29: 1-81Crossref PubMed Scopus (136) Google Scholar and is synthesized directly in the extracellular matrix by three hyaluronan synthases (HAS1, HAS2, and HAS3).9Rilla K. Siiskonen H. Spicer A.P. Hyttinen J.M. Tammi M.I. Tammi R.H. Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity.J Biol Chem. 2005; 280: 31890-31897Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar These HASs differ in their temporal expression pattern during development, their specific activity, and the size of the HA polymers they produce.10Itano N. Sawai T. Yoshida M. Lenas P. Yamada Y. Imagawa M. Shinomura T. Hamaguchi M. Yoshida Y. Ohnuki Y. Miyauchi S. Spicer A.P. McDonald J.A. Kimata K. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties.J Biol Chem. 1999; 274: 25085-25092Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar The expression levels of HAS1-3 in sun-exposed skin are lower than those in sun-protected skin.11Tzellos T.G. Klagas I. Vahtsevanos K. Triaridis S. Printza A. Kyrgidis A. Karakiulakis G. Zouboulis C.C. Papakonstantinou E. Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes.Exp Dermatol. 2009; 18: 1028-1035Crossref PubMed Scopus (76) Google Scholar Other studies have found that expression of HAS1-3 in cultured human keratinocytes increases after UVB irradiation.12Rauhala L. Hamalainen L. Salonen P. Bart G. Tammi M. Pasonen-Seppanen S. Tammi R. Low dose ultraviolet B irradiation increases hyaluronan synthesis in epidermal keratinocytes via sequential induction of hyaluronan synthases Has1-3 mediated by p38 and Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling.J Biol Chem. 2013; 288: 17999-18012Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,13Kakizaki I. Itano N. Kimata K. Hanada K. Kon A. Yamaguchi M. Takahashi T. Takagaki K. Up-regulation of hyaluronan synthase genes in cultured human epidermal keratinocytes by UVB irradiation.Arch Biochem Biophys. 2008; 471: 85-93Crossref PubMed Scopus (29) Google Scholar The current model of HA turnover in the whole body is as follows. Large negatively charged molecules (1000 to 10,000 kDa) of HA are partially degraded by hyaluronidase-1 (HYAL1) in the epidermis,14Kurdykowski S. Mine S. Bardey V. Danoux L. Jeanmaire C. Pauly G. Brabencova E. Wegrowski Y. Maquart F.X. Ultraviolet-B irradiation induces differential regulations of hyaluronidase expression and activity in normal human keratinocytes.Photochem Photobiol. 2011; 87: 1105-1112Crossref PubMed Scopus (24) Google Scholar and by HYAL1, HYAL2, and hyaluronan binding protein involved in hyaluronan depolymerization (HYBID) in the dermis,15Yoshida H. Nagaoka A. Kusaka-Kikushima A. Tobiishi M. Kawabata K. Sayo T. Sakai S. Sugiyama Y. Enomoto H. Okada Y. Inoue S. KIAA1199, a of is a hyaluronan binding protein involved in hyaluronan A. 2013; PubMed Scopus Google Scholar size to The HA in the dermis are the lymphatic vessels via interaction with lymphatic hyaluronan receptor R. S. S. is an receptor for hyaluronan in lymphatic Biol Chem. Full Text Full Text PDF PubMed Scopus Google Scholar and are degraded in the J.A. L. of the hyaluronan receptor for Biol Chem. Full Text Full Text PDF PubMed Scopus Google S. H. cells are a of and of hyaluronic acid in the PubMed Scopus Google Scholar HA that in the the at the and is in the J.A. C. A. to the hyaluronan receptor for hyaluronan by Biol Chem. Full Text Full Text PDF PubMed Scopus Google J.A. The of the hyaluronan receptor for contains Biol Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar HA synthesized in the is mainly in the and the liver after through the basement membrane a of is degraded in the and by S. R. Sayo T. Inoue S. Hyaluronan in the normal Invest Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Maibach H.I. Tammi M. of synthesized molecular hyaluronan in the epidermal and of human skin in Invest Dermatol. PubMed Scopus Google Scholar, J. C. V. S. M. Y. is mainly in the to the epidermal Invest Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar HA that turnover of HA is in skin, the for HA J.A. The of the hyaluronan receptor for contains Biol Chem. 2008; Full Text Full Text PDF PubMed Scopus Google of in Google of hyaluronan in skin in and PubMed Scopus Google Scholar is to of the and genes is in sun-exposed skin compared with sun-protected skin.11Tzellos T.G. Klagas I. Vahtsevanos K. Triaridis S. Printza A. Kyrgidis A. Karakiulakis G. Zouboulis C.C. Papakonstantinou E. Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes.Exp Dermatol. 2009; 18: 1028-1035Crossref PubMed Scopus (76) Google H. Nagaoka A. A. M. S. T. R. Sayo T. Okada Y. Takahashi Y. of hyaluronan and increased expression of and with in Dermatol. PubMed Scopus Google Scholar the lymphatic is also by UVB K. S. M. ultraviolet of lymphatic 2006; Full Text Full Text PDF PubMed Scopus (76) Google Scholar HA content in the is increased from to after UVB and during to M. Sayo T. Yoshida H. A. Kawabata K. Sugiyama Y. Inoue S. Changes in epidermal hyaluronan metabolism following UVB Dermatol Sci. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar The BM at the dermal-epidermal junction to the E. U.M. J.H. The of from in PubMed Scopus (112) Google Scholar and cell for epidermal and T. E. cell and of mammalian 2005; PubMed Scopus Google Scholar In sun-exposed skin, the BM is at the and a alterations in and aged skin.J Invest Dermatol. Full Text PDF PubMed Scopus Google S. of basement membrane in skin Dermatol 2009; Full Text Full Text PDF PubMed Scopus Google Scholar and in the are by irradiation in skin equivalent and organotypic human skin S. of basement membrane in skin Dermatol 2009; Full Text Full Text PDF PubMed Scopus Google S. Y. Takahashi K. K. N. S. of by ultraviolet B irradiation to of basement membrane at the dermal-epidermal junction in human Dermatol 2011; PubMed Scopus Google Scholar and BM structure is in the presence of and S. Y. M. of epidermal basement membrane integrity on permeability barrier Dermatol Sci. Full Text Full Text PDF PubMed Scopus Google S. H. N. T. S. a and matrix epidermal basement membrane structure and epidermal barrier Dermatol. PubMed Scopus Google Scholar It is that the of BM integrity in sun-exposed skin by and inhibitors to increased of hyaluronan in the epidermis. In the present and organotypic human skin are to from The of the of and to for skin from the of and The of the are in in and and in for specific and synthesized in to the S. H. N. T. S. a and matrix epidermal basement membrane structure and epidermal barrier Dermatol. PubMed Scopus Google Scholar, E. A. P. H. as 2006; PubMed Scopus Google Scholar, L.J. R. L. S. L. R.L. S. V. V. of a and that in Chem. PubMed Scopus Google Scholar The model and from The model was cultured in the presence of The culture was and for of after the of in and in for the and and was for human skin aged to the of the are in was which cultured in the presence of and after UVB irradiation after the of in and in for human skin aged to the of the are in was and cultured in the presence of and after the of in and in for was at with CD44 HA binding protein was with a with an and with a was in and with with acid for with for S. Maibach H.I. Stern R. of hyaluronan are by Histochem Cytochem. PubMed Scopus Google Scholar and with an with a The and dermis from human skin and the tissue was and with The protein of these tissue was on the of the of acid protein The of HA and in the tissue and culture with a HA and an normal epidermal keratinocytes from several aged cultured with at in a with of keratinocytes a and for with was from for and the culture was for HA The epidermal from the cultured keratinocytes was a and was synthesized a of HAS2, HYAL1, and genes in the was by as S. T. M. S. of in at the dermal-epidermal junction on epidermal Dermatol. 2011; 20: PubMed Scopus Google Scholar The as and HAS2, and and HYAL1, and and HYAL2, and The are as the was by analysis of with the of changes of HA content in skin have been for was to hyaluronic acid in and skin from the The HA was lower in skin than in skin skin to the age-dependent of HA content in sun-exposed facial skin, for was to hyaluronic acid in of aged skin from sun-protected and sun-exposed HA was with aging in sun-exposed skin than in sun-protected skin the of HA content with aging in sun-exposed skin was in the and HA to CD44 in the epidermis, for CD44 was The CD44 level in the was in skin from older compared with that from CD44 expression also decreased with aging The CD44 level in the was in skin than in skin skin CD44 is to to in for was The that in the and at the BM with in with findings The content of whole skin was in older compared with these findings that HA and are decreased in sun-exposed skin compared with sun-protected of CD44 in from of of CD44 in sun-protected skin sun-protected skin sun-exposed skin and sun-exposed skin CD44 in cultured keratinocytes from sun-protected skin of in their to and in their to was by are the of from Large HA is synthesized by and degraded by in the epidermis, expression levels in cultured keratinocytes from of was and increased with in with findings and The HA content of the culture increased with aging HA content was in sun-exposed the of irradiation on the expression of genes related to HA synthesis and was and was after UVB compared with keratinocytes and and The HA content of the culture after UVB irradiation these that the induction of HA synthesis in keratinocytes after UVB irradiation was associated with the of HA content in the of sun-exposed facial skin of older Epidermal HA content was in skin of older compared with that in HA from cultured keratinocytes increased with but with UVB the basement membrane at the is by UVB was that the basement membrane as a barrier to HA in the epidermis. The of the BM at the of organotypic human skin and skin after UVB is by with the and the the HA content in the and the of the basement membrane of organotypic human skin after UVB following with and of the culture are in of the and human skin after of culture are in The was increased after with the inhibitors, compared with the The of was in cultured skin after UVB irradiation and and was increased in the presence of inhibitors that epidermal content was also increased by the inhibitors of the in the presence of inhibitors, compared with the The was also increased in the presence of inhibitors, in with findings These findings in cultured and skin are with the that the basement membrane as a barrier to HA in the epidermis. BM integrity in the model is by with and inhibitors investigate the of BM integrity at the on the distribution of HA in the epidermis, for and and was increased in the after the investigate the distribution of HA in the HA in the epidermis, and cultured of the model in the presence of and HA was increased in the and in the dermis following with the and inhibitors and The inhibitors the HA level in the culture In that the epidermal content was increased in the presence of the inhibitors was increased in the presence of as by and for in with findings In that the of was in the presence of inhibitors, compared with the in with findings In the of the expression of including HAS2, HYAL1, and HYAL2, was in the presence of these inhibitors These suggest that the of HA in the was to of HA from the epidermis, than induction of expression in the epidermis. in that the BM at the transfer of HA from the the dermis and culture medium. and are in the of sun-exposed S. of basement membrane in skin Dermatol 2009; Full Text Full Text PDF PubMed Scopus Google S. Y. Takahashi K. K. N. S. of by ultraviolet B irradiation to of basement membrane at the dermal-epidermal junction in human Dermatol 2011; PubMed Scopus Google S. and of changes in skin: of basement membrane and Dermatol. PubMed Scopus Google Scholar to of the BM with the of alterations in and aged skin.J Invest Dermatol. Full Text PDF PubMed Scopus Google Scholar In is in study of the specific of expression of matrix metalloproteinases in the skin, the of and basal cell PubMed Scopus Google Scholar The present findings that inhibitors of and BM and the of in the organotypic human skin model S. Y. M. of epidermal basement membrane integrity on permeability barrier Dermatol Sci. Full Text Full Text PDF PubMed Scopus Google S. H. N. T. S. a and matrix epidermal basement membrane structure and epidermal barrier Dermatol. PubMed Scopus Google Scholar as well as in the model S. M. S. E. role of in of at the dermal-epidermal Dermatol. 2011; 20: PubMed Scopus Google Scholar The HA content in the was increased by of the BM in the model and the organotypic human skin model the HA content in the was in sun-exposed skin from older in the BM is be S. of basement membrane in skin Dermatol 2009; Full Text Full Text PDF PubMed Scopus Google Scholar Yoshida H. Nagaoka A. A. M. S. T. R. Sayo T. Okada Y. Takahashi Y. of hyaluronan and increased expression of and with in Dermatol. PubMed Scopus Google Scholar that the HA content of whole skin was in sun-exposed skin compared with that in sun-protected and L.J. Stern R. Age-dependent changes of hyaluronan in human skin.J Invest Dermatol. 1994; 102: 385-389Crossref PubMed Scopus (161) Google Scholar found that the HA in the decreased with and HA was in the of skin from an J.H. Kim Y.K. Jung J.Y. Shin J.E. Kim K.H. Cho K.H. Eun H.C. Chung J.H. Intrinsic aging- and photoaging-dependent level changes of glycosaminoglycans and their correlation with water content in human skin.J Dermatol Sci. 2011; 62: 192-201Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar that the HA content in the was by aging in sun-exposed skin, as in sun-protected of the been in skin from to alterations in and aged skin.J Invest Dermatol. Full Text PDF PubMed Scopus Google Scholar the other and of the have been in the skin of S. of basement membrane in skin Dermatol 2009; Full Text Full Text PDF PubMed Scopus Google Scholar Tammi R.H. Tammi M.I. M. S. basal the metabolism and distribution of hyaluronan in epidermal keratinocyte on PubMed Scopus Google Scholar that the BM at the as a barrier that of HA in the epidermis. the level of HA in the be to the of the BM at the In is to the of HA in the R. J.A. Maibach H.I. Tammi M. in human treated with acid in skin Invest Dermatol. Full Text PDF PubMed Scopus Google Scholar induces HA in keratinocytes by the of Hyttinen J.M. Tammi M.I. Tammi R.H. hyaluronan and are mediated by in epidermal Invest Dermatol. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar but also the of the at the of skin with increases a PubMed Scopus Google Scholar of the been found to the of BM structure at the and increased the water content in the S. H. N. T. S. a and matrix epidermal basement membrane structure and epidermal barrier Dermatol. PubMed Scopus Google Scholar these findings are with the that the BM at the as a barrier to the of synthesized HA from the epidermis, of HA in the epidermis. In the of epidermal HA content was by three skin In an model by keratinocytes on E. T. tissue in and as tissue of PubMed Scopus Google Scholar basement membrane after the S. Y. N. Y. K. E. T. of matrix inhibitors epidermal basement membrane skin partially Dermatol. 2005; PubMed Scopus Google Scholar and its was by with and S. M. S. E. role of in of at the dermal-epidermal Dermatol. 2011; 20: PubMed Scopus Google Scholar In human skin organotypic the basement membrane was well but was degraded after UVB S. Y. M. of epidermal basement membrane integrity on permeability barrier Dermatol Sci. Full Text Full Text PDF PubMed Scopus Google Scholar studies have that of the BM in organotypic skin is by with and S. Y. M. of epidermal basement membrane integrity on permeability barrier Dermatol Sci. Full Text Full Text PDF PubMed Scopus Google S. H. N. T. S. a and matrix epidermal basement membrane structure and epidermal barrier Dermatol. PubMed Scopus Google Scholar organotypic skin model was also as a of sun-exposed Epidermal HA was in the than in the The of in was increased by with and inhibitors in three skin The of the BM was also by with and inhibitors in the model and the organotypic human skin these suggest that the BM a role in maintaining the epidermal HA level in human In the in the BM is in human as and A. P. H. J. E. J.H. in with and in 1999; PubMed Google J. J.A. J.H. J. E. J. J.H. of extracellular matrix in human of in the basement 1994; PubMed Scopus Google Scholar The presence of negatively charged in the BM is for the permeability of the S. J. K. J.H. is normal in the of and from the basement 2009; PubMed Scopus Google Scholar In content but also HA content in the culture was in the presence of These suggest that in the BM at the the of for the physiological barrier and the of the of HA in the epidermis. In inhibitors of the of in the BM and CD44 at the cell of keratinocytes in the B and was at the cell of keratinocytes in the in the presence of B and CD44 was in sun-exposed skin compared with sun-exposed skin and sun-protected skin, in with the of These suggest that inhibitors the of CD44 and in the epidermis, of HA in the epidermis. In and inhibitors to HA in organotypic human skin after UVB S. Y. M. of epidermal basement membrane integrity on permeability barrier Dermatol Sci. Full Text Full Text PDF PubMed Scopus Google Scholar the of the basement S. M. S. E. role of in of at the dermal-epidermal Dermatol. 2011; 20: PubMed Scopus Google Scholar The of these inhibitors also on the expression of genes related to HA synthesis in the epidermis, and and found to be in the epidermis, the HA content was after the of synthesized HA in the is increased by the expression was in cultured human keratinocytes after UVB irradiation and with aging expression increases after UVB of cultured human I. Itano N. Kimata K. Hanada K. Kon A. Yamaguchi M. Takahashi T. Takagaki K. Up-regulation of hyaluronan synthase genes in cultured human epidermal keratinocytes by UVB irradiation.Arch Biochem Biophys. 2008; 471: 85-93Crossref PubMed Scopus (29) Google Scholar and in M. Sayo T. Yoshida H. A. Kawabata K. Sugiyama Y. Inoue S. Changes in epidermal hyaluronan metabolism following UVB Dermatol Sci. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar the other expression was after UVB irradiation in with a M. T. J. T. V. L. Hyaluronan of irradiation on human Dermatol 2011; PubMed Scopus Google Scholar The molecular of HA is to from at to after UVB in M. Sayo T. Yoshida H. A. Kawabata K. Sugiyama Y. Inoue S. Changes in epidermal hyaluronan metabolism following UVB Dermatol Sci. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar In human skin, the molecular of HA is in sun-protected human skin, is in sun-exposed human H. Nagaoka A. A. M. S. T. R. Sayo T. Okada Y. Takahashi Y. of hyaluronan and increased expression of and with in Dermatol. PubMed Scopus Google Scholar the level of HA is in the skin of older compared with that of L.Y. G. Man M.Q. Elias P.M. matrix interaction with CD44 and keratinocyte and epidermal Dermatol Sci. 2013; Full Text Full Text PDF PubMed Scopus Google for changes in and hyaluronic acid with PubMed Scopus Google Scholar Tammi R.H. Tammi M.I. M. S. basal the metabolism and distribution of hyaluronan in epidermal keratinocyte on PubMed Scopus Google Scholar that the BM at the as a barrier that of HA in the epidermis. the molecular distribution of HA is to to a lower with of the BM at the in sun-exposed facial skin, to a HA content in the to increased transfer the dermis through the in to the via S. R. Sayo T. Inoue S. Hyaluronan in the normal Invest Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Maibach H.I. Tammi M. of synthesized molecular hyaluronan in the epidermal and of human skin in Invest Dermatol. PubMed Scopus Google Scholar, J. C. V. S. M. Y. is mainly in the to the epidermal Invest Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar to the distribution and metabolism of HA in the is in and for with changes of CD44 in from a of CD44 and and hyaluronan binding protein and in and skin of a and of CD44 and with with changes of in epidermis. of in sun-protected skin sun-protected skin sun-exposed skin and sun-exposed skin The content of whole skin from in their and in their was by and are the of on from with of and UVB irradiation on expression of hyaluronan expression levels of and by The HA content in conditioned of human keratinocytes cultured for after UVB irradiation was by are as the of on from and with of matrix and inhibitors on expression in organotypic human of in organotypic human skin model cultured with and inhibitors a compared with the with content was increased by basement membrane in the skin equivalent in the skin equivalent model cultured with matrix and and compared with the with content was increased by basement membrane in the skin equivalent of in the skin equivalent model cultured with matrix and the and inhibitors compared with the The of dermis and conditioned of skin equivalent cultured with and inhibitors by are as the of three with of matrix and on the expression of genes in of skin equivalent expression levels of and in the of skin equivalent treated with by are as the of three with with with

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