Research Article| Volume 90, ISSUE 3, P263-275, June 2018

Cathepsin D contributes to the accumulation of advanced glycation end products during photoaging

Published:February 19, 2018DOI:


      • Advanced glycation endproducts (AGEs) degradation is significantly reduced in photoaged fibroblasts compared to non-photoaged fibroblasts.
      • The activity and expression of cathepsin D is significantly decreased in photoaged fibroblasts compared to non-photoaged fibroblasts.
      • Inhibiting Cathepsin D activity decreases AGEs degradation; whereas Cathepsin D overexpression significantly increases AGEs degradation.
      • AGEs accumulation in photo-damaged skin in vivo is inversely correlated with CatD expression.
      • Cathepsin D plays a major role in intracellular AGEs degradation, which may contribute to accelerated AGEs deposition in photoaged skin.



      The deposition of advanced glycation end products (AGEs) is accelerated in photoaged skin, but the underlying mechanisms remain elusive. Intracellular degradation has been recently considered to play an important role in AGEs removal. Although lysosomal cathepsin D (CatD), B (CatB), L(CatL) and proteasomes are found to degrade internalized AGEs, it remains unknown which protease degrades internalized AGEs in human dermal fibroblasts (HDFs), and whether a decrease in intracellular degradation contributes to enhanced AGEs deposition in photoaged skin.


      This study aims to investigate the specific proteases that contribute to intracellular AGEs degradation in HDFs and regulate AGEs accumulation in photoaged skin.


      Repetitive UVA irradiation was used to induce primary HDF photoaging in vitro. Uptake and degradation of AGE-BSA were verified and compared between photoaged and non-photoaged fibroblasts with flow cytometry, ELISA and confocal microscopy. Proteasomal and lysosomal activity, expression of CatD, CatB and CatL were also investigated between photoaged and non-photoaged fibroblasts. Further, the effect of protease inhibitors and CatD overexpression via lentiviral transduction on AGE-BSA degradation was analyzed. Finally, the correlation between CatD expression and AGEs accumulation in sun-exposed and sun-protected skin of people from different age was studied with immunohistochemistry.


      Fibroblasts underwent photoaging in vitro after repetitive UVA irradiation. AGE-BSA was taken up by both photoaged and non-photoaged fibroblasts, but its degradation was significantly decreased in photoaged cells than that of non-photoaged cells. Although the activity of proteasome, CatB, Cat L and Cat D was significantly reduced in photoaged fibroblasts compared to that of non-photoaged cells, and the expression of CatB, CatL and CatD was profoundly attenuated in photoaged fibroblasts, inhibiting proteasome, CatB and CatL did not affect AGE-BSA degradation in HDFs. In contrast, inhibiting CatD activity dose-dependently decreased AGE-BSA degradation; whereas CatD overexpression significantly increased AGE-BSA degradation. Importantly, AGEs accumulation in photo-damaged skin in vivo was inversely correlated with CatD expression.


      CatD plays a major role in intracellular AGEs degradation. Decreased CatD expression and activity impairs intracellular AGEs degradation in photoaged fibroblasts, which may contribute to accelerated AGEs deposition in photoaged skin. The present study provides a potentially novel molecular basis for antiphotoaging therapy.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Dermatological Science
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Jeanmaire C.
        • Danoux L.
        • Pauly G.
        Glycation during human dermal intrinsic and actinic ageing: an in vivo and in vitro model study.
        Br. J. Dermatol. 2001; 145: 10-18
        • Sato T.
        • Shimogaito N.
        • Wu X.
        • Kikuchi S.
        • Yamagishi S.
        • Takeuchi M.
        Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease.
        Am. J. Alzheimers Dis. Other Demen. 2006; 21: 197-208
        • Lee E.J.
        • Kim J.Y.
        • Oh S.H.
        Advanced glycation end products (AGEs) promote melanogenesis through receptor for AGEs.
        Sci. Rep. 2016; 6: 1-11
        • Corstjens H.
        • Dicanio D.
        • Muizzuddin N.
        • Neven A.
        • Sparacio R.
        • Declercq L.
        • Maes D.
        Glycation associated skin autofluorescence and skin elasticity are related to chronological age and body mass index of healthy subjects.
        Exp. Gerontol. 2008; 43: 663-667
        • Beisswenger P.J.
        • Howell S.
        • Mackenzie T.
        • Corstjens H.
        • Muizzuddin N.
        • Matsui M.S.
        Two fluorescent wavelengths, 440(ex)/520(em) nm and 370(ex)/440(em) nm, reflect advanced glycation and oxidation end products in human skin without diabetes.
        Diabetes Technol. Ther. 2012; 14: 285-292
        • Crisan M.
        • Taulescu M.
        • Crisan D.
        • Cosgarea R.
        • Parvu A.
        • Cãtoi C.
        • Drugan T.
        Expression of advanced glycation end-products on sun-exposed and non-exposed cutaneous sites during the ageing process in humans.
        PLoS One. 2013; 8: e75003
        • Farrar M.D.
        Advanced glycation end products in skin ageing and photoageing: what are the implications for epidermal function?.
        Exp. Dermatol. 2016; 25: 947-948
        • Gkogkolou P.
        • Böhm M.
        Advanced glycation end products: key players in skin aging?.
        Dermatoendocrinology. 2012; 4: 259-270
        • Fisher G.J.
        • Kang S.
        • Varani J.
        • Bata-Csorgo Z.
        • Wan Y.
        • Datta S.
        • Voorhees J.J.
        Mechanisms of photoaging and chronological skin aging.
        Arch. Dermatol. 2002; 138: 1462-1470
        • Xu Q.
        • Hou W.
        • Zheng Y.
        • Liu C.
        • Gong Z.
        • Lu C.
        • Lai W.
        • Maibach H.I.
        Ultraviolet A-induced cathepsin K expression is mediated via MAPK/AP-1 pathway in human dermal fibroblasts.
        PLoS One. 2014; 9: e102732
        • Wondrak G.T.
        • Roberts M.J.
        • Jacobson M.K.
        • Jacobson E.L.
        Photosensitized growth inhibition of cultured human skin cells: mechanism and suppression of oxidative stress from solar irradiation of glycated proteins.
        J. Invest. Dermatol. 2002; 119: 489-498
        • Nowotny K.
        • Grune T.
        Degradation of oxidized and glycoxidized collagen: role of collagen cross-linking.
        Arch. Biochem. Biophys. 2014; 542: 56-64
        • Li R.
        • McCourt P.
        • Schledzewski K.
        • Goerdt S.
        • Moldenhauer G.
        • Liu X.
        • Smedsrød B.
        • Sørensen K.K.
        Endocytosis of advanced glycation end-products in bovine choriocapillaris endothelial cells.
        Microcirculation. 2009; 16: 640-655
        • Grimm S.
        • Ernst L.
        • Grötzinger N.
        • Höhn A.
        • Breusing N.
        • Reinheckel T.
        • Grune T.
        Cathepsin D is one of the major enzymes involved in intracellular degradation of AGE-modified proteins.
        Free Radic. Res. 2010; 44: 1013-1026
        • Grimm S.
        • Horlacher M.
        • Catalgol B.
        • Hoehn A.
        • Reinheckel T.
        • Grune T.
        Cathepsins D and L reduce the toxicity of advanced glycation end products.
        Free Radic. Biol. Med. 2012; 52: 1011-1023
        • Svistounov D.
        • Oteiza A.
        • Zykova S.N.
        • Sørensen K.K.
        • McCourt P.
        • McLachlan A.J.
        • McCuskey R.S.
        • Smedsrød B.
        Hepatic disposal of advanced glycation end products during maturation and aging.
        Exp. Gerontol. 2013; 48: 549-556
        • Sitte N.
        • Huber M.
        • Grune T.
        • Ladhoff A.
        • Doecke W.D.
        • Von Zglinicki T.
        • Davies K.J.
        Proteasome inhibition by lipofuscin/ceroid during postmitotic aging of fibroblasts.
        FASEB J. 2000; 14: 1490-1498
        • Uchiki T.
        • Weikel K.A.
        • Jiao W.
        • Shang F.
        • Caceres A.
        • Pawlak D.
        • Handa J.T.
        • Brownlee M.
        • Nagaraj R.
        • Taylor A.
        Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics).
        Aging Cell. 2012; 11: 1-13
        • Zheng Y.
        • Lai W.
        • Wan M.
        • Maibach H.I.
        Expression of cathepsins in human skin photoaging.
        Skin Pharmacol. Physiol. 2011; 24: 10-21
        • Li J.
        • Cui X.
        • Ma X.
        • Wang Z.
        rBTI reduced β-amyloid-induced toxicity by promoting autophagy-lysosomal degradation via DAF-16 in Caenorhabditis elegans.
        Exp. Gerontol. 2017; 89: 78-86
        • Dammann P.
        • Sell D.R.
        • Begall S.
        • Strauch C.
        • Monnier V.M.
        Advanced glycation end-products as markers of aging and longevity in the long-lived Ansell's mole-rat (Fukomys anselli).
        J. Gerontol. A: Biol. Sci. Med. Sci. 2012; 67: 573-583
        • Xu Q.F.
        • Zheng Y.
        • Chen J.
        • Xu X.Y.
        • Gong Z.J.
        • Huang Y.F.
        • Lu C.
        • Maibach H.I.
        • Lai W.
        Ultraviolet a enhances an enhances cathepsin l expression and activity via JNK pathway in human dermal fibroblasts.
        Chin. Med. J. (Engl.). 2016; 129: 2853-2860
        • Höhn A.
        • König J.
        • Grune T.
        Protein oxidation in aging and the removal of oxidized proteins.
        J. Proteom. 2013; 92: 132-159
        • Catalgol B.
        • Ziaja I.
        • Breusing N.
        • Jung T.
        • Höhn A.
        • Alpertunga B.
        • Schroeder P.
        • Chondrogianni N.
        • Gonos E.S.
        • Petropoulos I.
        • Friguet B.
        • Klotz L.O.
        • Krutmann J.
        • Grune T.
        The proteasome is an integral part of solar ultraviolet a radiation-induced gene expression.
        J. Biol. Chem. 2009; 284: 30076-30086
        • Bulteau A.L.
        • Moreau M.
        • Nizard C.
        • Friguet B.
        Impairment of proteasome function upon UVA- and UVB-irradiation of human keratinocytes.
        Free Radic. Biol. Med. 2002; 32: 1157-1170
        • Lai W.
        • Zheng Y.
        • Ye Z.Z.
        • Su X.Y.
        • Wan M.J.
        • Gong Z.J.
        • Xie X.Y.
        • Liu W.
        Changes of cathepsin B in human photoaging skin both in vivo and in vitro.
        Chin. Med. J. (Engl.). 2010; 123: 527-531
        • Bohley P.
        • Seglen P.O.
        Proteases and proteolysis in the lysosome.
        Experientia. 1992; 48: 151-157
        • Hah Y.S.
        • Noh H.S.
        • Ha J.H.
        • Ahn J.S.
        • Hahm J.R.
        • Cho H.Y.
        • Kim D.R.
        Cathepsin D inhibits oxidative stress-induced cell death via activation of autophagy in cancer cells.
        Cancer Lett. 2012; 323: 208-214
        • Stolzing A.
        • Widmer R.
        • Jung T.
        • Voss P.
        • Grune T.
        Degradation of glycated bovine serum albumin in microglial cells.
        Free Radic. Biol. Med. 2006; 40: 1017-1027
        • Bulteau A.L.
        • Verbeke P.
        • Petropoulos I.
        • Chaffotte A.F.
        • Friguet B.
        Proteasome inhibition in glyoxal-treated fibroblasts and resistance of glycated glucose-6-phosphate dehydrogenase to 20S proteasome degradation in vitro.
        J. Biol. Chem. 2001; 276: 45662-45668
        • Davies M.J.
        Protein oxidation and peroxidation.
        Biochem. J. 2016; 473: 805-825
        • Wille A.
        • Gerber A.
        • Heimburg A.
        • Reisenauer A.
        • Peters C.
        • Saftig P.
        • Reinheckel T.
        • Welte T.
        • Bühling F.
        Cathepsin L is involved in cathepsin D processing and regulation of apoptosis in A549 human lung epithelial cells.
        Biol. Chem. 2004; 385: 665-670
        • Dunlop R.A.
        • Brunk U.T.
        • Rodgers K.J.
        Oxidized proteins: mechanisms of removal and consequences of accumulation.
        IUBMB Life. 2009; 61: 522-527
        • Yoshinaga E.
        • Kawada A.
        • Ono K.
        • Fujimoto E.
        • Wachi H.
        • Harumiya S.
        • Nagai R.
        • Tajima S.
        N(ε)-(carboxymethyl)lysine modification of elastin alters its biological properties: implications for the accumulation of abnormal elastic fibers in actinic elastosis.
        J. Invest. Dermatol. 2012; 132 (Epub 2011 Sep 29): 315-323
        • Klose A.
        • Wilbrand-Hennes A.
        • Brinckmann J.
        • Hunzelmann N.
        Alternate trafficking of cathepsin L in dermal fibroblasts induced by UVA radiation.
        Exp. Dermatol. 2010; 19: e117-e123
        • Igarashi S.
        • Takizawa T.
        • Takizawa T.
        • YasudaY
        • Uchiwa H.
        • Hayashi S.
        • Brysk H.
        • Robinson J.M.
        • Yamamoto K.
        • Brysk M.M.
        • Horikoshi T.
        Cathepsin D, but not cathepsin E, degrades desmosomes during epidermal desquamation.
        Br. J. Dermatol. 2004; 151: 355-361
        • Chen S.H.
        • Arany I.
        • Apisarnthanarax N.
        • Rajaraman S.
        • Tyring S.K.
        • Horikoshi T.
        • Brysk H.
        • Brysk M.M.
        Response of keratinocytes from normal and psoriatic epidermis to interferon-gamma differs in the expression of zinc-alpha(2)-glycoprotein and cathepsin D.
        FASEB J. 2000; 14: 565-571
        • Egberts F.
        • Heinrich M.
        • Jensen J.M.
        • Winoto-Morbach S.
        • Pfeiffer S.
        • Wickel M.
        • Schunck M.
        • Steude J.
        • Saftig P.
        • Proksch E.
        • Schütze S.
        Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation.
        J. Cell. Sci. 2004; 117: 2295-2307
        • Zheng Y.
        • Chen H.
        • Lai W.
        • Xu Q.
        • Liu C.
        • Wu L.
        • Maibach H.I.
        Cathepsin d repairing role in photodamaged skin barrier.
        Skin Pharmacol. Physiol. 2015; 28: 97-102
        • Skrzydlewska E.
        • Sulkowska M.
        • Koda M.
        • Sulkowski S.
        Proteolytic-antiproteolytic balance and its regulation in carcinogenesis.
        World J. Gastroenterol. 2005; 11: 1251-1266