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Dermatoporosis: A new concept in skin aging
European Geriatric Medicine 1 (2010) 216–219
Hot topic in geriatric medicine
Dermatoporosis: A new concept in skin aging G. Kaya *, J.-H. Saurat Department of Dermatology, University of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 4, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 April 2010 Accepted 4 June 2010 Available online 15 September 2010
Dermatoporosis is a new concept proposed to cover different manifestations and implications of chronic cutaneous insufficiency/fragility syndrome. This emerging syndrome extends beyond cosmetics and appearance and is considered to be the functional face of skin aging. With increasing number of elderly population, health care professionals should be aware of the potential epidemics of dermatoporosis. Chronic systemic or topical steroid therapy and chronic exposure to ultraviolet irradiation appear to be the major causes of dermatoporosis. CD44-hyaluronate molecular pathways play an important role in the pathogenesis. Further research and clinical trials are needed to find preventive or therapeutic solutions for dermatoporosis. ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Aging skin Aged Chronic cutaneous insufficiency Cutaneous-deep dissecting hematomas
1. Introduction
(ii) functional aspects such as skin laceration, delayed wound healing and deep dissecting hematoma.
Skin aging has long been considered only as a cosmetic issue. However, with increasing life span, we experience a functional dimension of skin aging, which extends beyond cosmetics and appearance. This dimension is related to the aging-associated gradual loss of hyaluronate (HA), which is a major component of the extracellular matrix of the skin functioning normally as a viscoelastic buffering system between epidermal and dermal structures. Progressive loss of viscoelastic properties of the skin results in an extreme fragility leading to complications such as lacerations, ulcerations and dissecting hematomas. A new concept under the name of dermatoporosis has been proposed to cover different characteristics of this chronic cutaneous insufficiency/fragility syndrome, to understand underlying molecular mechanisms and to develop preventive or therapeutic strategies [1,2,3].
Skin atrophy is the main feature of dermatoporosis. It is predominant on sun-exposed areas such as posterior side of the forearms, dorsum of hands and pretibial zones. The skin is very thin, transparent and shows numerous wrinkles, senile purpura and pseudoscars (see below) (Fig. 1A) Histologically, a thinning of epidermis and dermis, linearization of epidermis with loss of rete ridges and in most of the cases an important dermal elastosis is observed (Fig. 2C and D).
2. Clinical features of dermatoporosis
2.1.2. Senile purpura
First clinical manifestations of dermatoporosis start at around 40–60 years with wrinkles and appearance changes but fullydeveloped disease is seen between 70 and 90 years. Two types of clinical features can be identified:
Senile purpura is a noninflammatory superficial dermal bleeding due to minimal trauma [3]. Decrease of viscoelastic properties of the skin is the main cause for these bleedings. There is normally no vascular lesion in dermatoporotic skin (Fig. 1A).
(i) morphological markers such as skin atrophy, senile purpura and pseudoscars;
* Corresponding author. Tel.: +41 22 372 94 41; fax: +41 22 372 96 93. E-mail address: [email protected] (G. Kaya).
2.1. Morphological markers These markers usually start to be seen at around 70 years of age but can also appear at earlier ages. 2.1.1. Skin atrophy
2.1.3. Pseudoscar Pseudoscar is a spontaneous dermal laceration [4]. Trauma is thought to be the major cause for these lesions. We proposed three main types of pseudoscars: star-shaped, linear or plaque-type (Fig. 1A) [3].
1878-7649/$ – see front matter ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2010.06.002
[(Fig._1)TD$IG]
G. Kaya, J.-H. Saurat / European Geriatric Medicine 1 (2010) 216–219
217
Fig. 1. Clinical features of dermatoporosis. Forearm skin of a stage I dermatoporosis patient shows important atrophy, senile purpura (asterisks) and numerous pseudoscars (arrows) (A). Stage II and III patients display different degrees of skin laceration (B). In stage IV deep dissecting hematoma is observed (C).
2.2. Functional aspects These are the complications of dermatoporosis, which represent an emerging problem in the increasing population of elderly persons. 2.2.1. Skin laceration and delayed wound healing Skin lacerations are irregular superficial tear-like wounds caused by some blunt trauma resulting from extreme skin fragility
(Fig. 1B). Healing of these lesions and deeper chronic wounds is delayed in dermatoporosis patients. 2.2.2. Deep dissecting hematoma This is the most severe complication of dermatoporosis. Deep dissecting hematoma (DDH) is thought to result from a traumainduced massive bleeding between subcutaneous fat and muscle fascia, from fragile and aged vessels localized very close to skin, as a result of extreme skin atrophy (Fig. 1C) [4].
[(Fig._2)TD$IG]
Fig. 2. CD44-/- mice display a skin atrophy reminiscent of dermatoporosis. Skin of CD44-/- mice shows an epidermal end dermal atrophy characterized by thinning and flattening of epidermis, decrease of dermal thickness and high localization of subcutaneous fat (B) when compared to their wild-type counterparts (A). When compared to normal skin (C), dermatoporotic skin shows a decrease in epidermal thickness with loss of rete ridges, loss of collagen and important elastosis (D) (hematoxylin-eosin; original magnification, 10X).
218
G. Kaya, J.-H. Saurat / European Geriatric Medicine 1 (2010) 216–219
3. Etiological classification of dermatoporosis 3.1. Primary dermatoporosis This is the most common type of dermatoporosis and results from chronological aging and long-term and unprotected sun exposure. 3.2. Secondary -iatrogenic- dermatoporosis This type of dermatoporosis which is due to the long-term use of topical and systemic corticosteroids may occur earlier, and be more severe, in patients susceptible to primary dermatoporosis. 4. Clinical staging of dermatoporosis We have proposed the following staging for dermatoporosis, which should be further defined after large scale clinical and epidemiological studies [3]: stage I: this stage is characterized by the presence of extreme skin atrophy, senile purpura and pseudoscars; stage II: in addition to the lesions found in stage I, there are some localized skin lacerations; stage III: skin lacerations are larger (> 3 cm) and may extend to the whole surface of the extremity; stage IV: advanced lesions result in dissecting hematomas and skin necrosis. 5. Mechanisms of skin fragility in dermatoporosis 5.1. Defective functioning of keratinocyte CD44 platform
[(Fig._3)TD$IG]
We previously showed that selective suppression of keratinocyte CD44, major cell surface receptor of HA, results in skin atrophy in mouse (Fig. 2A and B) [5]. This observation has been the root for research on dermatoporosis. HA, a nonsulfated linear
glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine, is the major component of the extracellular matrix [6,7] and is found in high quantities in the skin. HA helps to maintain the normal hydration and viscoelasticity of skin [7]. We have recently shown that CD44 and HA levels were decreased in the dermatoporotic skin when compared to the skin of young individuals (Fig. 3) [8]. We have also shown that UVA or UVB irradiation significantly decreased the content of HA and the expression of its receptor CD44 in mice [9]. We thus explored the molecular mechanisms of skin atrophy induced by keratinocyte CD44 deficiency. We demonstrated that CD44 and erbB1, the receptor of heparin-binding epidermal growth factor (HB-EGF), were physically linked in mouse skin [8]. We therefore proposed the CD44 membrane platform which is composed of CD44v3, a specific isoform of CD44 known to present HB-EGF to its receptors, HB-EGF, matrix metalloproteinase-7 (MMP-7) which cleaves the precursor form of HB-EGF (pro-HBEGF) and erbB1 [8]. We think that quantitative decrease and defective functioning of CD44 platform is the cause of dermatoporosis (Fig. 4). 6. Treatment and prevention Based on the observations indicating the potential role of CD44 platform deficiency in dermatoporosis, we explored the possibility of activating the CD44 platform to reverse skin atrophy. For this purpose we developed hyaluronate fragments (HAF) of defined size and used them as CD44 ligands to activate the CD44-mediated molecular pathways leading to skin hyperplasia. Topical application of HAF of defined size to mouse skin resulted in an epidermal hyperplasia and an increase of epidermal and dermal HA content, by stimulating the molecules of CD44 platform. [8,10]. Topical application of HAF of defined size twice a day for 1 month caused a significant reversal of skin atrophy in dermatoporosis patients [8]. Combination of a topical retinoid, retinaldehyde, which upregulates the CD44 and hyaluronate synthases in mouse skin
Fig. 3. CD44 and HA content of dermatoporotic skin. Epidermis and demis of dermatoporosis patients show a significant decrease of CD44 (B) and HA (D) amounts. Note the membrane expression of CD44 by keratinocytes and the presence of HA in the interkeratinocyte spaces and in the dermis in normal skin (A, C). (A, B: mouse anti-human CD44 antibodies [Bender MedSystems; 2.5 mg/ml]; C, D: biotinylated hyaluronate binding protein (HABP) [Seikagaku Kogyo, Japan; 25 ng/ml]).
[(Fig._4)TD$IG]
G. Kaya, J.-H. Saurat / European Geriatric Medicine 1 (2010) 216–219
219
Fig. 4. Hypothetical model of pathogenesis of dermatoporosis. Epidermal thickness, CD44 platform molecules (CD44v3, HB-EGF, MMP, erbB1), collagen and HA of normal skin (A) decrease by aging, UV exposure and steroid use (B). Minor trauma results in skin lacerations in dermatoporotic skin (C).
[11], with HAF of defined size increased the levels of CD44 and HA in the skin of dermatoporosis patients and corrected the skin atrophy by showing a synergistic effect at both molecular and clinical levels ([12], Kaya et al, manuscript in preparation). These observations suggest that the defects in CD44-mediated molecular pathways play an important role in dermatoporosis and should be considered as a new target for the development of novel therapeutic strategies. HAF of defined size seem to act as antiatrophic factors and appear to be a good candidate for this purpose. Apart from minimizing sun exposure and avoiding topical or systemic corticosteroid use, HAF of defined size could also be used for prevention. Large scale and well-designed randomized clinical trials will be necessary to test the efficacy of such novel candidates for prevention or therapy of this new emerging syndrome. Conflict of interest statement Nothing declared. References [1] Saurat JH. E´ditorial : quand la peau devient insuffisante. Med Hyg 2004;2472: 476.
[2] Saurat JH. Editorial: dermatoporosis: the functional side of skin aging. Dermatology 2007;215:271–2. [3] Kaya G, Saurat JH. Dermatoporosis. A chronic cutaneous insufficiency/fragility syndrome: clinico-pathological features, mechanisms, prevention and potential treatments. Dermatology 2007;215:284–94. [4] Kaya G, Jacobs F, Prins C, Viero D, Kaya A, Saurat JH. Deep dissecting hematoma: an emerging severe complication of dermatoporosis. Arch Dermatol 2008;144:1303–8. [5] Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I. Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev 1997;11:996–1007. [6] Fraser JRE, Laurent TC. Turnover and metabolism of hyaluronan. The biology of hyaluronan. CIBA Found Symp 1989;143:41–59. [7] Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397–404. [8] Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med 2006;3: e493. [9] Calikoglu E, Sorg O, Tran C, Grand D, Carraux P, Saurat JH, et al. UVA and UVB decrease the expression of CD44 and hyaluronate in mouse epidermis which is counteracted by topical retinoids. Photochem Photobiol 2006;82: 1342–7. [10] Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. CD44-dependent mouse skin hyperplasia induced by topical hyaluronate fragments. J Invest Dermatol 2004;123:A2. [11] Kaya G, Grand D, Hotz R, Augsburger E, Carraux P, Didierjean L, et al. Upregulation of CD44 and hyaluronate synthases by topical retinoids in mouse skin. J Invest Dermatol 2005;124:284–7. [12] Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. Synergistic effect of retinaldehyde and hyaluronate fragments in skin hyperplasia. J Invest Dermatol 2006;126:S4.
Hot topic in geriatric medicine
Dermatoporosis: A new concept in skin aging G. Kaya *, J.-H. Saurat Department of Dermatology, University of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 4, Switzerland
A R T I C L E I N F O
A B S T R A C T
Article history: Received 30 April 2010 Accepted 4 June 2010 Available online 15 September 2010
Dermatoporosis is a new concept proposed to cover different manifestations and implications of chronic cutaneous insufficiency/fragility syndrome. This emerging syndrome extends beyond cosmetics and appearance and is considered to be the functional face of skin aging. With increasing number of elderly population, health care professionals should be aware of the potential epidemics of dermatoporosis. Chronic systemic or topical steroid therapy and chronic exposure to ultraviolet irradiation appear to be the major causes of dermatoporosis. CD44-hyaluronate molecular pathways play an important role in the pathogenesis. Further research and clinical trials are needed to find preventive or therapeutic solutions for dermatoporosis. ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.
Keywords: Aging skin Aged Chronic cutaneous insufficiency Cutaneous-deep dissecting hematomas
1. Introduction
(ii) functional aspects such as skin laceration, delayed wound healing and deep dissecting hematoma.
Skin aging has long been considered only as a cosmetic issue. However, with increasing life span, we experience a functional dimension of skin aging, which extends beyond cosmetics and appearance. This dimension is related to the aging-associated gradual loss of hyaluronate (HA), which is a major component of the extracellular matrix of the skin functioning normally as a viscoelastic buffering system between epidermal and dermal structures. Progressive loss of viscoelastic properties of the skin results in an extreme fragility leading to complications such as lacerations, ulcerations and dissecting hematomas. A new concept under the name of dermatoporosis has been proposed to cover different characteristics of this chronic cutaneous insufficiency/fragility syndrome, to understand underlying molecular mechanisms and to develop preventive or therapeutic strategies [1,2,3].
Skin atrophy is the main feature of dermatoporosis. It is predominant on sun-exposed areas such as posterior side of the forearms, dorsum of hands and pretibial zones. The skin is very thin, transparent and shows numerous wrinkles, senile purpura and pseudoscars (see below) (Fig. 1A) Histologically, a thinning of epidermis and dermis, linearization of epidermis with loss of rete ridges and in most of the cases an important dermal elastosis is observed (Fig. 2C and D).
2. Clinical features of dermatoporosis
2.1.2. Senile purpura
First clinical manifestations of dermatoporosis start at around 40–60 years with wrinkles and appearance changes but fullydeveloped disease is seen between 70 and 90 years. Two types of clinical features can be identified:
Senile purpura is a noninflammatory superficial dermal bleeding due to minimal trauma [3]. Decrease of viscoelastic properties of the skin is the main cause for these bleedings. There is normally no vascular lesion in dermatoporotic skin (Fig. 1A).
(i) morphological markers such as skin atrophy, senile purpura and pseudoscars;
* Corresponding author. Tel.: +41 22 372 94 41; fax: +41 22 372 96 93. E-mail address: [email protected] (G. Kaya).
2.1. Morphological markers These markers usually start to be seen at around 70 years of age but can also appear at earlier ages. 2.1.1. Skin atrophy
2.1.3. Pseudoscar Pseudoscar is a spontaneous dermal laceration [4]. Trauma is thought to be the major cause for these lesions. We proposed three main types of pseudoscars: star-shaped, linear or plaque-type (Fig. 1A) [3].
1878-7649/$ – see front matter ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2010.06.002
[(Fig._1)TD$IG]
G. Kaya, J.-H. Saurat / European Geriatric Medicine 1 (2010) 216–219
217
Fig. 1. Clinical features of dermatoporosis. Forearm skin of a stage I dermatoporosis patient shows important atrophy, senile purpura (asterisks) and numerous pseudoscars (arrows) (A). Stage II and III patients display different degrees of skin laceration (B). In stage IV deep dissecting hematoma is observed (C).
2.2. Functional aspects These are the complications of dermatoporosis, which represent an emerging problem in the increasing population of elderly persons. 2.2.1. Skin laceration and delayed wound healing Skin lacerations are irregular superficial tear-like wounds caused by some blunt trauma resulting from extreme skin fragility
(Fig. 1B). Healing of these lesions and deeper chronic wounds is delayed in dermatoporosis patients. 2.2.2. Deep dissecting hematoma This is the most severe complication of dermatoporosis. Deep dissecting hematoma (DDH) is thought to result from a traumainduced massive bleeding between subcutaneous fat and muscle fascia, from fragile and aged vessels localized very close to skin, as a result of extreme skin atrophy (Fig. 1C) [4].
[(Fig._2)TD$IG]
Fig. 2. CD44-/- mice display a skin atrophy reminiscent of dermatoporosis. Skin of CD44-/- mice shows an epidermal end dermal atrophy characterized by thinning and flattening of epidermis, decrease of dermal thickness and high localization of subcutaneous fat (B) when compared to their wild-type counterparts (A). When compared to normal skin (C), dermatoporotic skin shows a decrease in epidermal thickness with loss of rete ridges, loss of collagen and important elastosis (D) (hematoxylin-eosin; original magnification, 10X).
218
G. Kaya, J.-H. Saurat / European Geriatric Medicine 1 (2010) 216–219
3. Etiological classification of dermatoporosis 3.1. Primary dermatoporosis This is the most common type of dermatoporosis and results from chronological aging and long-term and unprotected sun exposure. 3.2. Secondary -iatrogenic- dermatoporosis This type of dermatoporosis which is due to the long-term use of topical and systemic corticosteroids may occur earlier, and be more severe, in patients susceptible to primary dermatoporosis. 4. Clinical staging of dermatoporosis We have proposed the following staging for dermatoporosis, which should be further defined after large scale clinical and epidemiological studies [3]: stage I: this stage is characterized by the presence of extreme skin atrophy, senile purpura and pseudoscars; stage II: in addition to the lesions found in stage I, there are some localized skin lacerations; stage III: skin lacerations are larger (> 3 cm) and may extend to the whole surface of the extremity; stage IV: advanced lesions result in dissecting hematomas and skin necrosis. 5. Mechanisms of skin fragility in dermatoporosis 5.1. Defective functioning of keratinocyte CD44 platform
[(Fig._3)TD$IG]
We previously showed that selective suppression of keratinocyte CD44, major cell surface receptor of HA, results in skin atrophy in mouse (Fig. 2A and B) [5]. This observation has been the root for research on dermatoporosis. HA, a nonsulfated linear
glycosaminoglycan composed of repeating units of D-glucuronic acid and N-acetyl-D-glucosamine, is the major component of the extracellular matrix [6,7] and is found in high quantities in the skin. HA helps to maintain the normal hydration and viscoelasticity of skin [7]. We have recently shown that CD44 and HA levels were decreased in the dermatoporotic skin when compared to the skin of young individuals (Fig. 3) [8]. We have also shown that UVA or UVB irradiation significantly decreased the content of HA and the expression of its receptor CD44 in mice [9]. We thus explored the molecular mechanisms of skin atrophy induced by keratinocyte CD44 deficiency. We demonstrated that CD44 and erbB1, the receptor of heparin-binding epidermal growth factor (HB-EGF), were physically linked in mouse skin [8]. We therefore proposed the CD44 membrane platform which is composed of CD44v3, a specific isoform of CD44 known to present HB-EGF to its receptors, HB-EGF, matrix metalloproteinase-7 (MMP-7) which cleaves the precursor form of HB-EGF (pro-HBEGF) and erbB1 [8]. We think that quantitative decrease and defective functioning of CD44 platform is the cause of dermatoporosis (Fig. 4). 6. Treatment and prevention Based on the observations indicating the potential role of CD44 platform deficiency in dermatoporosis, we explored the possibility of activating the CD44 platform to reverse skin atrophy. For this purpose we developed hyaluronate fragments (HAF) of defined size and used them as CD44 ligands to activate the CD44-mediated molecular pathways leading to skin hyperplasia. Topical application of HAF of defined size to mouse skin resulted in an epidermal hyperplasia and an increase of epidermal and dermal HA content, by stimulating the molecules of CD44 platform. [8,10]. Topical application of HAF of defined size twice a day for 1 month caused a significant reversal of skin atrophy in dermatoporosis patients [8]. Combination of a topical retinoid, retinaldehyde, which upregulates the CD44 and hyaluronate synthases in mouse skin
Fig. 3. CD44 and HA content of dermatoporotic skin. Epidermis and demis of dermatoporosis patients show a significant decrease of CD44 (B) and HA (D) amounts. Note the membrane expression of CD44 by keratinocytes and the presence of HA in the interkeratinocyte spaces and in the dermis in normal skin (A, C). (A, B: mouse anti-human CD44 antibodies [Bender MedSystems; 2.5 mg/ml]; C, D: biotinylated hyaluronate binding protein (HABP) [Seikagaku Kogyo, Japan; 25 ng/ml]).
[(Fig._4)TD$IG]
G. Kaya, J.-H. Saurat / European Geriatric Medicine 1 (2010) 216–219
219
Fig. 4. Hypothetical model of pathogenesis of dermatoporosis. Epidermal thickness, CD44 platform molecules (CD44v3, HB-EGF, MMP, erbB1), collagen and HA of normal skin (A) decrease by aging, UV exposure and steroid use (B). Minor trauma results in skin lacerations in dermatoporotic skin (C).
[11], with HAF of defined size increased the levels of CD44 and HA in the skin of dermatoporosis patients and corrected the skin atrophy by showing a synergistic effect at both molecular and clinical levels ([12], Kaya et al, manuscript in preparation). These observations suggest that the defects in CD44-mediated molecular pathways play an important role in dermatoporosis and should be considered as a new target for the development of novel therapeutic strategies. HAF of defined size seem to act as antiatrophic factors and appear to be a good candidate for this purpose. Apart from minimizing sun exposure and avoiding topical or systemic corticosteroid use, HAF of defined size could also be used for prevention. Large scale and well-designed randomized clinical trials will be necessary to test the efficacy of such novel candidates for prevention or therapy of this new emerging syndrome. Conflict of interest statement Nothing declared. References [1] Saurat JH. E´ditorial : quand la peau devient insuffisante. Med Hyg 2004;2472: 476.
[2] Saurat JH. Editorial: dermatoporosis: the functional side of skin aging. Dermatology 2007;215:271–2. [3] Kaya G, Saurat JH. Dermatoporosis. A chronic cutaneous insufficiency/fragility syndrome: clinico-pathological features, mechanisms, prevention and potential treatments. Dermatology 2007;215:284–94. [4] Kaya G, Jacobs F, Prins C, Viero D, Kaya A, Saurat JH. Deep dissecting hematoma: an emerging severe complication of dermatoporosis. Arch Dermatol 2008;144:1303–8. [5] Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I. Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev 1997;11:996–1007. [6] Fraser JRE, Laurent TC. Turnover and metabolism of hyaluronan. The biology of hyaluronan. CIBA Found Symp 1989;143:41–59. [7] Laurent TC, Fraser JR. Hyaluronan. FASEB J 1992;6:2397–404. [8] Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med 2006;3: e493. [9] Calikoglu E, Sorg O, Tran C, Grand D, Carraux P, Saurat JH, et al. UVA and UVB decrease the expression of CD44 and hyaluronate in mouse epidermis which is counteracted by topical retinoids. Photochem Photobiol 2006;82: 1342–7. [10] Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. CD44-dependent mouse skin hyperplasia induced by topical hyaluronate fragments. J Invest Dermatol 2004;123:A2. [11] Kaya G, Grand D, Hotz R, Augsburger E, Carraux P, Didierjean L, et al. Upregulation of CD44 and hyaluronate synthases by topical retinoids in mouse skin. J Invest Dermatol 2005;124:284–7. [12] Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et al. Synergistic effect of retinaldehyde and hyaluronate fragments in skin hyperplasia. J Invest Dermatol 2006;126:S4.