Hyaluronic acid: A key molecule in skin aging

Taylor & Francis

Hyaluronic acid: A key molecule in skin aging

Eleni Papakonstantinou, Michael Roth, and George Karakiulakis

Additional article information

Abstract

Skin aging is a multifactorial process consisting of two distinct and independent mechanisms: intrinsic and extrinsic aging. Youthful skin retains its turgor, resilience and pliability, among others, due to its high content of water. Daily external injury, in addition to the normal process of aging, causes loss of moisture. The key molecule involved in skin moisture is hyaluronic acid (HA) that has unique capacity in retaining water. There are multiple sites for the control of HA synthesis, deposition, cell and protein association and degradation, reflecting the complexity of HA metabolism. The enzymes that synthesize or catabolize HA and HA receptors responsible for many of the functions of HA are all multigene families with distinct patterns of tissue expression. Understanding the metabolism of HA in the different layers of the skin and the interactions of HA with other skin components will facilitate the ability to modulate skin moisture in a rational manner.

Keywords: hyaluronic acid, hyaluronic acid synthases, hyaluronidases, CD44, RHAMM, skin aging

Skin aging

Human skin aging is a complex biological process, not yet fully understood. It is the result of two biologically independent processes. The first is intrinsic or innate aging, an unpreventable process, which affects the skin in the same pattern as it affects all internal organs. The second is extrinsic aging, which is the result of exposure to external factors, mainly ultraviolet (UV) irradiation, that is also referred to as photoaging.1 Intrinsic skin aging is influenced by hormonal changes that occur with age,2 such as the gradual decreased production of sex hormones from the mid-twenties and the diminution of estrogens and progesterone associated with menopause. It is well established that the deficiency in estrogens and androgens results in collagen degradation, dryness, loss of elasticity, epidermal atrophy and wrinkling of the skin.3

Even though intrinsic and extrinsic skin aging are distinctive processes, they share similarities in molecular mechanisms. For example, reactive oxygen species (ROS), arising from oxidative cell metabolism, play a major role in both processes.4ROS in extrinsic or intrinsic skin aging induce the transcription factor c-Jun via mitogen-activated protein kinases (MAPK), leading to overexpression of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-9 and prevention of the expression of procollagen-1.5 Therefore, elevated levels of degraded collagen and reduced collagen synthesis are pathologies occurring in intrinsically aged as well as photoaged skin.

Skin aging is also associated with loss of skin moisture. The key molecule involved in skin moisture is hyaluronan or hyaluronic acid (HA), a glycosaminoglycan (GAG) with a unique capacity to bind and retain water molecules.6 HA belongs to the extracellular matrix (ECM) molecules. During the past decades the constituents of the skin have been well characterized. In the beginning, most of the studies focused on the cells that comprise the skin layers, such as the epidermis, the dermis and the underlying subcutis. Recently, it is appreciated that ECM molecules that lie between cells, in addition to providing a constructive framework, they exert major effects on cellular function. These ECM molecules, although they appear amorphous by light microscopy, they form a highly organized structure, comprising mainly of GAG, proteoglycans, growth factors and structural proteins such as collagens. Yet, the predominant component of the skin ECM is HA.

Recent reviews have described the involvement of HA with respect to its role in angiogenesis,7reactive oxygen species,8 chondrocytes,9cancer,10,11 lung injury,12,13 immune regulation14,15and skin.16 This review presents in brief recent knowledge in HA biology and function and focuses on its involvement in skin aging.

Hyaluronic acid

Chemistry and physicochemical properties

HA is a non-sulphated GAG and is composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine linked by a glucuronidic β (1→3) bond.17,18 In aqueous solutions HA forms specific stable tertiary structures.19 Despite the simplicity in its composition, without variations in its sugar composition or without branching points, HA has a variety of physicochemical properties. HA polymers occur in a vast number of configurations and shapes, depending on their size, salt concentration, pH, and associated cations.20 Unlike other GAG, HA is not covalently attached to a protein core, but it may form aggregates with proteoglycans.21 HA encompasses a large volume of water giving solutions high viscosity, even at low concentrations.13

Tissue and cell distribution of HA

HA is widely distributed, from prokaryotic,22,23 to eukaryotic cells.24 In humans, HA is most abundant in the skin,25-29 accounting for 50% of the total body HA,30 the vitreous of the eye,31 the umbilical cord,17 and synovial fluid,32,33 but it is also present in all tissues and fluids of the body, such as skeletal tissues,27 heart valves,34 the lung,35-39 the aorta,40the prostate,41 tunica albuginea, corpora cavernosa and corpus spongiosum of the penis.42 HA is produced primarily by mesenchymal cells but also by other cell types.34-38,43

Biological function of HA

Over the past 2 decades there was considerable evidence presented that unraveled the functional role of HA in molecular mechanisms and indicated the potential role of HA for the development of novel therapeutic strategies for many diseases.

Functions of HA include the following: hydration, lubrication of joints, a space filling capacity, and the framework through which cells migrate.34 The synthesis of HA increases during tissue injury and wound healing25,44,45 and HA regulates several aspects of tissue repair, including activation of inflammatory cells to enhance immune response46-48 and the response to injury of fibroblasts49,50 and epithelial cells.51-55 HA also provides the framework for blood vessel formation7,45 and fibroblast migration,56,57 that may be involved in tumor progression.58 The correlation of HA levels on the cell surface of cancer cells with the aggressiveness of tumors has also been reported.59

The size of HA appears to be of critical importance for its various functions described above. HA of high molecular size, usually in excess of 1,000 kDa, is present in intact tissues and is antiangiogenic and immunosuppressive, whereas smaller polymers of HA are distress signals and potent inducers of inflammation and angiogenesis.38,46,60-63

Biosynthesis of HA

HA is synthesized by specific enzymes called HA synthases (HAS). These are membrane bound enzymes that synthesize HA on the inner surface of the plasma membrane64 and then HA is extruded through pore-like structures into the extracellular space.24,65 There are three mammalian enzymes HAS -1, -2 and -3, which exhibit distinct enzymatic properties and synthesize HA chains of various length.66-68

Degradation of HA

HA has a dynamic turnover rate. HA has a half-life of 3 to 5 min in the blood, less than a day in the skin and 1 to 3 weeks in the cartilage.69-71 HA is degraded into fragments of varying size by hyaluronidases (HYAL) by hydrolyzing the hexosaminidic β (1–4) linkages between N-acetyl-D-glucosamine and D-glucuronic acid residues in HA. In humans, six HYAL have been identified so far: HYAL-1, -2, -3, -4, PH-20 and HYALP1.72 The family of HYAL enzymes received little attention until recently73,74 because they are found at extremely low concentrations and they are difficult to purify, characterize and measure their activity, which is high but unstable.16 New procedures have now enabled the isolation and characterization of HYAL.75,76 HYAL-1 is the major HYAL in serum.77 Mutations in the HYAL-1 gene are associated with HYAL deficiency and mucopolysaccharidosis type IX.78 HYAL-2 has very low activity in comparison to plasma HYAL-1 and it hydrolyzes specifically HA of high molecular weight, yielding HA fragments of approximately 20 kDa, which are further degraded to small oligosaccharides by PH-20.79 HYAL-3 is mainly expressed in bone marrow and testis,74 but also in other organs, such as the human lung.37,38 The role of HYAL-3 in the catabolism of HA is not clear and it is suggested that it may contribute to HA degradation by enhancing the activity of HYAL-1.80

HA can also be degraded non-enzymatically by a free-radical mechanism81 in the presence of reducing agents such as ascorbic acid, thiols, ferrous, or cuprous ions, a process that requires the presence of molecular oxygen. Thus, agents that could delay the free-radical-catalyzed degradation of HA may be useful in maintaining the integrity of dermal HA and its moisturizing properties.16

Hyaluronic acid receptors

There is a variety of proteins that bind HA, called hyaladherins, which are widely distributed in the ECM, the cell surface, the cytoplasm and the nucleus.15 Those that attach HA to the cell surface constitute HA receptors. The most prominent among these receptors is the transmembrane glycoprotein “cluster of differentiation 44” (CD44) that occurs in many isoforms, which are the products of a single gene with variable exon expression.82-84 CD44 is found on virtually all cells, except red blood cells, and regulates cell adhesion, migration, lymphocyte activation and homing, and cancer metastasis.

The receptor for HA-mediated motility (RHAMM) is another major receptor for HA, and it is expressed in various isoforms.85-87 RHAMM is a functional receptor in many cell types, including endothelial cells88 and in smooth muscle cells from human pulmonary arteries37 and airways.38 The interactions of HA with RHAMM control cell growth and migration by a complex network of signal transduction events and interactions with the cytoskeleton.89 Transforming growth factor (TGF)-β1, which is a potent stimulator of cell motility, elicits the synthesis and expression of RHAMM and HA, and thus initiates locomotion.90

Hyaluronic acid in skin

The use of biotinylated HA-binding peptide91revealed that not only cells of mesenchymal origin were capable of synthesizing HA and permitted the histolocalization of HA in the dermal compartment of skin and the epidermis.26,92-94 This technique enabled the visualization of HA in the epidermis, mainly in the ECM of the upper spinous and granular layers, whereas in the basal layer HA is predominantly intracellular.26

The function of the skin as a barrier is partly attributed to the lamellar bodies, thought to be modified lysosomes containing hydrolytic enzymes. They fuse with the plasma membranes of mature keratinocytes and they have the ability to acidify via proton pumps and partially convert their polar lipids into neutral lipids. Diffusion of aqueous material through the epidermis is blocked by these lipids synthesized by keratinocytes in the stratum granulosum. This boundary effect corresponds to the level of HA staining. The HA-rich area inferior to this layer may obtain water from the moisture-rich dermis, and the water contained therein cannot penetrate beyond the lipid-rich stratum granulosum. The hydration of the skin critically depends on the HA-bound water in the dermis and in the vital area of the epidermis, while maintenance of hydration essentially depends on the stratum granulosum. Extensive loss of the stratum granulosum in patients with burns may cause serious clinical problems due to dehydration.16

As mentioned above, skin HA accounts for most of 50% of total body HA.30 The HA content of the dermis is significantly higher than that of the epidermis, while papillary dermis has much greater levels of HA than reticular dermis.92 The HA of the dermis is in continuity with the lymphatic and vascular systems. HA in the dermis regulates water balance, osmotic pressure and ion flow and functions as a sieve, excluding certain molecules, enhancing the extracellular domain of cell surfaces and stabilizes skin structures by electrostatic interactions.16 Elevated levels of HA are synthesized during scar-free fetal tissue repair and the prolonged presence of HA assures such scar-free tissue repair.95-97 Dermal fibroblasts provide the synthetic machinery for dermal HA and should be the target for pharmacologic attempts to enhance skin hydration. Unfortunately, exogenous HA is cleared from the dermis and is rapidly degraded.70

Hyaluronic acid synthases in the skin

In the skin, gene expression of HAS-1 and HAS-2 in the dermis and epidermis is differentially upregulated by TGF-β1, indicating that HAS isoforms are independently regulated and that the function of HA is different in the dermis and the epidermis.16,98 The mRNA expression of HAS-2 and HAS-3 can be stimulated by keratinocyte growth factor, which activates keratinocyte migration and stimulates wound healing, leading to the accumulation of intermediate-sized HA in the culture medium and within keratinocytes. The migratory response of keratinocytes in wound healing is stimulated by increased synthesis of HA.99 HAS-2 mRNA is also induced by IL-1β and TNFα in fibroblasts100 and by epidermal growth factor in rat epidermal keratinocytes.101

Dysregulated expression of HA synthases has been reported during tissue injury.102-104 HAS-2 and HAS-3 mRNA are significantly increased after skin injury in mice, leading to increased epidermal HA.104 In juvenile hyaline fibromatosis, which is a rare autosomal recessive disease characterized by deposition of hyaline material and multiple skin lesions, there is a significant decreased expression of HAS-1 and HAS-3, accounting for the reduced synthesis of HA in skin lesions.105 In dermal fibroblasts, where the HAS-2 is the predominant isoform, glucocorticoids inhibit HAS mRNA almost completely, suggesting a molecular basis of the decreased HA in atrophic skin as a result of local treatment with glucocorticoids.16

Hyaluronidases in the skin

In the skin, it has not been established which of the various HYAL controls the turnover of HA in the dermis and the epidermis. The elucidation of the biology of HYAL in the skin may offer novel pharmacological targets to confront age related turnover of HA in skin.

HA receptors in the skin

In the dermis and epidermis HA is co-localized with CD44. However, the exact CD44 variants in the different skin compartments have not yet been elucidated. CD44-HA interactions have been reported to mediate the binding of Langerhans cells to HA in the matrix surrounding keratinocytes by their CD44-rich surfaces, as they migrate through the epidermis.106,107 RHAMM is also expressed in the human skin.28,29 The TGF-β1 induced stimulation of fibroblast locomotion is mediated via RHAMM,90 while overexpression of RHAMM can lead to the transformation of fibroblasts.108

Hyaluronic acid and skin aging

The most dramatic histochemical change observed in senescent skin is the marked disappearance of epidermal HA, while HA is still present in the dermis.92 The reasons for this change in HA homeostasis with aging is unknown. As mentioned above, the synthesis of epidermal HA is influenced by the underlying dermis and is under separate controls from the synthesis of dermal HA.16,98Progressive reduction of the size of the HA polymers in skin as a result of aging has also been reported.109 Thus, the epidermis loses the principle molecule responsible for binding and retaining water molecules, resulting in loss of skin moisture. In the dermis, the major age-related change is the increasing avidity of HA with tissue structures with the concomitant loss of HA extractability. This parallels the progressive cross-linking of collagen and the steady loss of collagen extractability with age.16 All of the above age related phenomena contribute to the apparent dehydration, atrophy and loss of elasticity that characterizes aged skin.

Premature aging of skin is the result of repeated and extended exposure to UV radiation.110,111Approximately 80% of facial skin aging is attributed to UV-exposure.112 UV radiation damage causes initially a mild form of wound healing and is associated at first with an increase of dermal HA. As little as 5 min of UV exposure in nude mice caused enhanced deposition of HA, indicating that UV radiation induced skin damage is an extremely rapid event.16 The initial redness of the skin following exposure to UV radiation may be due to a mild edematous reaction induced by the enhanced HA deposition and histamine release. Repeated and extensive exposures to UV ultimately simulate a typical wound healing response with deposition of scarlike type I collagen, rather than the usual types I and III collagen mixture that gives skin resilience and pliability.16

In the skin, photoaging results in abnormal GAG content and distribution compared with that found in scars, or in the wound healing response, with diminished HA and increased levels of chondroitin sulfate proteoglycans.111 In dermal fibroblasts this reduction in HA synthesis was attributed to collagen fragments, which activate αvβ3-integrins and in turn inhibit Rho kinase signaling and nuclear translocation of phosphoERK, resulting in reduced HAS-2 expression.113 We have recently unraveled some of the biochemical changes that may distinguish photoaging and natural aging. Using photoexposed and photoprotected human skin tissue specimens, obtained from the same patient, we have shown a significant increase in the expression of HA of lower molecular mass in photoexposed skin, as compared with photoprotected skin. This increase of degraded HA was associated with a significant decrease in the expression of HAS-1 and an increased expression of HYAL-1, -2 and -3. Furthermore, the expression of HA receptors CD44 and RHAMM was significantly downregulated in photoexposed, as compared with photoprotected skin. These findings indicate that photoexposed skin, and therefore extrinsic skin aging, is characterized by distinct homeostasis of HA.29 We have also assessed photoprotected skin tissue specimens from adults and juvenile patients and observed that intrinsic skin aging was associated with a significant reduction in the content of HA and downregulation of HAS-1, HAS -2, CD44 and RHAMM.28 Similar results for photoprotected skin have also been reported for both genders for HA, HAS-2 and CD44.114

Conclusion

The available data suggest that HA homeostasis exhibits a distinct profile in intrinsic skin aging, which is totally different of that in extrinsic skin aging. Additional insight needs to be gained in understanding the metabolism of HA in skin layers and the interactions of HA with other skin components. Such information will facilitate the ability to modulate skin moisture in a rational manner and may contribute to the refinement of current drugs and the development of novel treatments for skin aging.

Glossary

Abbreviations:

UV ultraviolet
ROS reactive oxygen species
MMP matrix metalloproteinase
HA hyaluronic acid
GAG glycosaminoglycan
ECM extracellular matrix
HAS hyaluronic acid synthases
HYAL hyaluronidases
CD44 cluster of differentiation 44
RHAMM receptor for HA-mediated motility
TGF transforming growth factor

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Footnotes

Article information

Dermatoendocrinol. 2012 Jul 1; 4(3): 253–258.
PMCID: PMC3583886
PMID: 23467280
1Department of Pharmacology; School of Medicine; Aristotle University of Thessaloniki; Thessaloniki, Greece
2Pulmonary Cell Research-Pneumology; University Hospital Basel; Basel, Switzerland
*Correspondence to: George Karakiulakis, Email: rg.htua.dem@ikarakg
This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
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References

1. Berneburg M, Trelles M, Friguet B, Ogden S, Esrefoglu M, Kaya G, et al. How best to halt and/or revert UV-induced skin ageing: strategies, facts and fiction. Exp Dermatol. 2008;17:228–40. [PubMed] [Google Scholar]
2. Makrantonaki E, Adjaye J, Herwig R, Brink TC, Groth D, Hultschig C, et al. Age-specific hormonal decline is accompanied by transcriptional changes in human sebocytes in vitro. Aging Cell. 2006;5:331–44. doi: 10.1111/j.1474-9726.2006.00223.x. [PubMed] [CrossRef] [Google Scholar]
3. Brincat MP. Hormone replacement therapy and the skin. Maturitas 2000; 35:107–117. 9 Makrantonaki E, Zouboulis CC. Androgens and aging of the skin. Curr Opin Endocrinol Diabetes Obes. 2009;16:240–5.[Google Scholar]
4. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002;138:1462–70. doi: 10.1001/archderm.138.11.1462. [PubMed] [CrossRef] [Google Scholar]
5. Chung JH, Kang S, Varani J, Lin J, Fisher GJ, Voorhees JJ. Decreased extracellular-signal-regulated kinase and increased stress-activated MAP kinase activities in aged human skin in vivo. J Invest Dermatol. 2000;115:177–82. doi: 10.1046/j.1523-1747.2000.00009.x. [PubMed] [CrossRef] [Google Scholar]
6. Baumann L. Skin ageing and its treatment. J Pathol. 2007;211:241–51. doi: 10.1002/path.2098. [PubMed] [CrossRef] [Google Scholar]
7. Slevin M, Krupinski J, Gaffney J, Matou S, West D, Delisser H, et al. Hyaluronan-mediated angiogenesis in vascular disease: uncovering RHAMM and CD44 receptor signaling pathways. Matrix Biol. 2007;26:58–68. doi: 10.1016/j.matbio.2006.08.261. [PubMed] [CrossRef] [Google Scholar]
8. Soltés L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J. Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules. 2006;7:659–68. doi: 10.1021/bm050867v. [PubMed] [CrossRef] [Google Scholar]
9. Knudson CB, Knudson W. Hyaluronan and CD44: modulators of chondrocyte metabolism. Clin Orthop Relat Res. 2004;(Suppl):S152–62. doi: 10.1097/01.blo.0000143804.26638.82. [PubMed] [CrossRef] [Google Scholar]
10. Toole BP, Zoltan-Jones A, Misra S, Ghatak S. Hyaluronan: a critical component of epithelial-mesenchymal and epithelial-carcinoma transitions. Cells Tissues Organs. 2005;179:66–72. doi: 10.1159/000084510. [PubMed] [CrossRef] [Google Scholar]
11. Toole BP, Ghatak S, Misra S. Hyaluronan oligosaccharides as a potential anticancer therapeutic. Curr Pharm Biotechnol. 2008;9:249–52. doi: 10.2174/138920108785161569. [PubMed] [CrossRef] [Google Scholar]
12. Noble PW. Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biol. 2002;21:25–9. doi: 10.1016/S0945-053X(01)00184-6. [PubMed] [CrossRef] [Google Scholar]
13. Turino GM, Cantor JO. Hyaluronan in respiratory injury and repair. Am J Respir Crit Care Med. 2003;167:1169–75. doi: 10.1164/rccm.200205-449PP.[PubMed] [CrossRef] [Google Scholar]
14. Jackson DG. Immunological functions of hyaluronan and its receptors in the lymphatics. Immunol Rev. 2009;230:216–31. doi: 10.1111/j.1600-065X.2009.00803.x. [PubMed] [CrossRef] [Google Scholar]
15. Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011;91:221–64. doi: 10.1152/physrev.00052.2009.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Stern R, Maibach HI. Hyaluronan in skin: aspects of aging and its pharmacologic modulation. Clin Dermatol. 2008;26:106–22. doi: 10.1016/j.clindermatol.2007.09.013. [PubMed] [CrossRef] [Google Scholar]
17. Weissmann B, Meyer K. The structure of hyalobiuronic acid and of hyaluronic acid from umbilical cord. J Am Chem Soc. 1954;76:1753–7. doi: 10.1021/ja01636a010. [CrossRef] [Google Scholar]
18. Weissmann B, Meyer K, Sampson P, Linker A. Isolation of oligosaccharides enzymatically produced from hyaluronic acid. J Biol Chem. 1954;208:417–29.[PubMed] [Google Scholar]
19. Scott JE, Heatley F. Hyaluronan forms specific stable tertiary structures in aqueous solution: a 13C NMR study. Proc Natl Acad Sci U S A. 1999;96:4850–5. doi: 10.1073/pnas.96.9.4850.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Laurent TC. Structure of hyaluronic acid. In: Balazs, EA, ed. Chemistry and Molecular Biology of the Intercellular Matrix, Academic Press: New York, 1970:p. 703. [Google Scholar]
21. Bates EJ, Harper GS, Lowther DA, Preston BN. Effect of oxygen-derived reactive species on cartilage proteoglycan-hyaluronate aggregates. Biochem Int. 1984;8:629–37. [PubMed] [Google Scholar]
22. Lowther DA, Rogers HJ. Biosynthesis of hyaluronate. Nature. 1955;175:435. doi: 10.1038/175435a0. [PubMed] [CrossRef] [Google Scholar]
23. MacLennan AP. The production of capsules, hyaluronic acid and hyaluronidase by 25 strains of group C streptococci. J Gen Microbiol. 1956;15:485–91. doi: 10.1099/00221287-15-3-485. [PubMed] [CrossRef] [Google Scholar]
24. Prehm P. Release of hyaluronate from eukaryotic cells. Biochem J. 1990;267:185–9. [PMC free article][PubMed] [Google Scholar]
25. Juhlin L. Hyaluronan in skin. J Intern Med. 1997;242:61–6. doi: 10.1046/j.1365-2796.1997.00175.x. [PubMed] [CrossRef] [Google Scholar]
26. Tammi R, Ripellino JA, Margolis RU, Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe. J Invest Dermatol. 1988;90:412–4. doi: 10.1111/1523-1747.ep12456530. [PubMed] [CrossRef] [Google Scholar]
27. Armstrong SE, Bell DR. Relationship between lymph and tissue hyaluronan in skin and skeletal muscle. Am J Physiol Heart Circ Physiol. 2002;283:H2485–94. [PubMed] [Google Scholar]
28. Tzellos TG, Sinopidis X, Kyrgidis A, Vahtsevanos K, Triaridis S, Printza A, et al. Differential hyaluronan homeostasis and expression of proteoglycans in juvenile and adult human skin. J Dermatol Sci. 2011;61:69–72. doi: 10.1016/j.jdermsci.2010.10.010.[PubMed] [CrossRef] [Google Scholar]
29. Tzellos TG, Klagas I, Vahtsevanos K, Triaridis S, Printza A, Kyrgidis A, et al. Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes. Exp Dermatol. 2009;18:1028–35. doi: 10.1111/j.1600-0625.2009.00889.x. [PubMed] [CrossRef] [Google Scholar]
30. Reed RK, Lilja K, Laurent TC. Hyaluronan in the rat with special reference to the skin. Acta Physiol Scand. 1988;134:405–11. doi: 10.1111/j.1748-1716.1988.tb08508.x. [PubMed] [CrossRef] [Google Scholar]
31. Meyer K, Palmer JW. The Polysaccharide of the vitreous humor. J Biol Chem. 1934;107:629–34.[Google Scholar]
32. Hamerman D, Schuster H. Hyaluronate in normal human synovial fluid. J Clin Invest. 1958;37:57–64. doi: 10.1172/JCI103585. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
33. Ragan C, Meyer K. The hyaluronic acid of synovial fluid in rheumatoid arthritis. J Clin Invest. 1949;28:56–9. doi: 10.1172/JCI102053.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4:528–39. doi: 10.1038/nrc1391. [PubMed] [CrossRef] [Google Scholar]
35. Papakonstantinou E, Karakiulakis G, Roth M, Block LH. Platelet-derived growth factor stimulates the secretion of hyaluronic acid by proliferating human vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1995;92:9881–5. doi: 10.1073/pnas.92.21.9881. [PMC free article][PubMed] [CrossRef] [Google Scholar]
36. Papakonstantinou E, Roth M, Tamm M, Eickelberg O, Perruchoud AP, Karakiulakis G. Hypoxia differentially enhances the effects of transforming growth factor-beta isoforms on the synthesis and secretion of glycosaminoglycans by human lung fibroblasts. J Pharmacol Exp Ther. 2002;301:830–7. doi: 10.1124/jpet.301.3.830.[PubMed] [CrossRef] [Google Scholar]
37. Papakonstantinou E, Kouri FM, Karakiulakis G, Klagas I, Eickelberg O. Increased hyaluronic acid content in idiopathic pulmonary arterial hypertension. Eur Respir J. 2008;32:1504–12. doi: 10.1183/09031936.00159507. [PubMed] [CrossRef] [Google Scholar]
38. Klagas I, Goulet S, Karakiulakis G, Zhong J, Baraket M, Black JL, et al. Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD. Eur Respir J. 2009;34:616–28. doi: 10.1183/09031936.00070808. [PubMed] [CrossRef] [Google Scholar]
39. Papakonstantinou E, Karakiulakis G. The ‘sweet’ and ‘bitter’ involvement of glycosaminoglycans in lung diseases: pharmacotherapeutic relevance. Br J Pharmacol. 2009;157:1111–27. doi: 10.1111/j.1476-5381.2009.00279.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Papakonstantinou E, Karakiulakis G, Eickelberg O, Perruchoud AP, Block LH, Roth M. A 340 kDa hyaluronic acid secreted by human vascular smooth muscle cells regulates their proliferation and migration. Glycobiology. 1998;8:821–30. doi: 10.1093/glycob/8.8.821. [PubMed] [CrossRef] [Google Scholar]
41. Goulas A, Hatzichristou DG, Karakiulakis G, Mirtsou-Fidani V, Kalinderis A, Papakonstantinou E. Benign hyperplasia of the human prostate is associated with tissue enrichment in chondroitin sulphate of wide size distribution. Prostate. 2000;44:104–10. doi: 10.1002/1097-0045(20000701)44:2<104::AID-PROS2>3.0.CO;2-6. [PubMed] [CrossRef] [Google Scholar]
42. Goulas A, Papakonstantinou E, Karakiulakis G, Mirtsou-Fidani V, Kalinderis A, Hatzichristou DG. Tissue structure-specific distribution of glycosaminoglycans in the human penis. Int J Biochem Cell Biol. 2000;32:975–82. doi: 10.1016/S1357-2725(00)00038-8. [PubMed] [CrossRef] [Google Scholar]
43. Lee JY, Spicer AP. Hyaluronan: a multifunctional, megaDalton, stealth molecule. Curr Opin Cell Biol. 2000;12:581–6. doi: 10.1016/S0955-0674(00)00135-6. [PubMed] [CrossRef] [Google Scholar]
44. Weigel PH, Fuller GM, LeBoeuf RD. A model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healing. J Theor Biol. 1986;119:219–34. doi: 10.1016/S0022-5193(86)80076-5. [PubMed] [CrossRef] [Google Scholar]
45. Slevin M, Kumar S, Gaffney J. Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. J Biol Chem. 2002;277:41046–59. doi: 10.1074/jbc.M109443200.[PubMed] [CrossRef] [Google Scholar]
46. McKee CM, Penno MB, Cowman M, Burdick MD, Strieter RM, Bao C, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest. 1996;98:2403–13. doi: 10.1172/JCI119054. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
47. Horton MR, McKee CM, Bao C, Liao F, Farber JM, Hodge-DuFour J, et al. Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines mig and interferon-inducible protein-10 in mouse macrophages. J Biol Chem. 1998;273:35088–94. doi: 10.1074/jbc.273.52.35088. [PubMed] [CrossRef] [Google Scholar]
48. Teriete P, Banerji S, Noble M, Blundell CD, Wright AJ, Pickford AR, et al. Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44. Mol Cell. 2004;13:483–96. doi: 10.1016/S1097-2765(04)00080-2. [PubMed] [CrossRef] [Google Scholar]
49. Itano N, Atsumi F, Sawai T, Yamada Y, Miyaishi O, Senga T, et al. Abnormal accumulation of hyaluronan matrix diminishes contact inhibition of cell growth and promotes cell migration. Proc Natl Acad Sci U S A. 2002;99:3609–14. doi: 10.1073/pnas.052026799. [PMC free article][PubMed] [CrossRef] [Google Scholar]
50. Bai KJ, Spicer AP, Mascarenhas MM, Yu L, Ochoa CD, Garg HG, et al. The role of hyaluronan synthase 3 in ventilator-induced lung injury. Am J Respir Crit Care Med. 2005;172:92–8. doi: 10.1164/rccm.200405-652OC. [PMC free article][PubMed] [CrossRef] [Google Scholar]
51. Beck-Schimmer B, Oertli B, Pasch T, Wüthrich RP. Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells. J Am Soc Nephrol. 1998;9:2283–90. [PubMed] [Google Scholar]
52. Zoltan-Jones A, Huang L, Ghatak S, Toole BP. Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J Biol Chem. 2003;278:45801–10. doi: 10.1074/jbc.M308168200. [PubMed] [CrossRef] [Google Scholar]
53. Jameson JM, Cauvi G, Sharp LL, Witherden DA, Havran WL. Gammadelta T cell-induced hyaluronan production by epithelial cells regulates inflammation. J Exp Med. 2005;201:1269–79. doi: 10.1084/jem.20042057. [PMC free article][PubMed] [CrossRef] [Google Scholar]
54. Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11:1173–9. doi: 10.1038/nm1315. [PubMed] [CrossRef] [Google Scholar]
55. Jiang D, Liang J, Li Y, Noble PW. The role of Toll-like receptors in non-infectious lung injury. Cell Res. 2006;16:693–701. doi: 10.1038/sj.cr.7310085.[PubMed] [CrossRef] [Google Scholar]
56. Li L, Heldin CH, Heldin P. Inhibition of platelet-derived growth factor-BB-induced receptor activation and fibroblast migration by hyaluronan activation of CD44. J Biol Chem. 2006;281:26512–9. doi: 10.1074/jbc.M605607200. [PubMed] [CrossRef] [Google Scholar]
57. Turley EA. The role of a cell-associated hyaluronan-binding protein in fibroblast behaviour. Ciba Found Symp. 1989;143:121–33, discussion 133-7, 281-5. [PubMed] [Google Scholar]
58. Knudson W. Tumor-associated hyaluronan. Providing an extracellular matrix that facilitates invasion. Am J Pathol. 1996;148:1721–6.[PMC free article] [PubMed] [Google Scholar]
59. Zhang L, Underhill CB, Chen L. Hyaluronan on the surface of tumor cells is correlated with metastatic behavior. Cancer Res. 1995;55:428–33. [PubMed] [Google Scholar]
60. West DC, Hampson IN, Arnold F, Kumar S. Angiogenesis induced by degradation products of hyaluronic acid. Science. 1985;228:1324–6. doi: 10.1126/science.2408340. [PubMed] [CrossRef] [Google Scholar]
61. McKee CM, Lowenstein CJ, Horton MR, Wu J, Bao C, Chin BY, et al. Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappaB-dependent mechanism. J Biol Chem. 1997;272:8013–8. doi: 10.1074/jbc.272.12.8013. [PubMed] [CrossRef] [Google Scholar]
62. Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, et al. Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol. 2000;165:1863–70. [PubMed] [Google Scholar]
63. Papakonstantinou E, Klagas I, Karakiulakis G, Hostettler K, S’ng CT, Kotoula V, et al. Steroids and β2 Agonists Regulate Hyaluronan Metabolism in Asthma Airway Smooth Muscle Cells. Am J Respir Cell Mol Biol. 2012 doi: 10.1165/rcmb.2012-0101OC.In press. [PubMed] [CrossRef] [Google Scholar]
64. Prehm P. Hyaluronate is synthesized at plasma membranes. Biochem J. 1984;220:597–600.[PMC free article] [PubMed] [Google Scholar]
65. Watanabe K, Yamaguchi Y. Molecular identification of a putative human hyaluronan synthase. J Biol Chem. 1996;271:22945–8. doi: 10.1074/jbc.271.38.22945. [PubMed] [CrossRef] [Google Scholar]
66. Weigel PH, Hascall VC, Tammi M. Hyaluronan synthases. J Biol Chem. 1997;272:13997–4000. doi: 10.1074/jbc.272.22.13997. [PubMed] [CrossRef] [Google Scholar]
67. Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, Imagawa M, et al. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem. 1999;274:25085–92. doi: 10.1074/jbc.274.35.25085. [PubMed] [CrossRef] [Google Scholar]
68. Itano N, Kimata K. Mammalian hyaluronan synthases. IUBMB Life. 2002;54:195–9. doi: 10.1080/15216540214929. [PubMed] [CrossRef] [Google Scholar]
69. Fraser JR, Laurent TC, Pertoft H, Baxter E. Plasma clearance, tissue distribution and metabolism of hyaluronic acid injected intravenously in the rabbit. Biochem J. 1981;200:415–24. [PMC free article][PubMed] [Google Scholar]
70. Reed RK, Laurent UB, Fraser JR, Laurent TC. Removal rate of [3H]hyaluronan injected subcutaneously in rabbits. Am J Physiol. 1990;259:H532–5. [PubMed] [Google Scholar]
71. Laurent UB, Dahl LB, Reed RK. Catabolism of hyaluronan in rabbit skin takes place locally, in lymph nodes and liver. Exp Physiol. 1991;76:695–703.[PubMed] [Google Scholar]
72. Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and mechanisms of action. Chem Rev. 2006;106:818–39. doi: 10.1021/cr050247k. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
73. Kreil G. Hyaluronidases--a group of neglected enzymes. Protein Sci. 1995;4:1666–9. doi: 10.1002/pro.5560040902. [PMC free article][PubMed] [CrossRef] [Google Scholar]
74. Csoka AB, Frost GI, Stern R. The six hyaluronidase-like genes in the human and mouse genomes. Matrix Biol. 2001;20:499–508. doi: 10.1016/S0945-053X(01)00172-X. [PubMed] [CrossRef] [Google Scholar]
75. Frost GI, Stern R. A microtiter-based assay for hyaluronidase activity not requiring specialized reagents. Anal Biochem. 1997;251:263–9. doi: 10.1006/abio.1997.2262. [PubMed] [CrossRef] [Google Scholar]
76. Guntenhöner MW, Pogrel MA, Stern R. A substrate-gel assay for hyaluronidase activity. Matrix. 1992;12:388–96. doi: 10.1016/S0934-8832(11)80035-1. [PubMed] [CrossRef] [Google Scholar]
77. Chichibu K, Matsuura T, Shichijo S, Yokoyama MM. Assay of serum hyaluronic acid in clinical application. Clin Chim Acta. 1989;181:317–23. doi: 10.1016/0009-8981(89)90237-4. [PubMed] [CrossRef] [Google Scholar]
78. Natowicz MR, Short MP, Wang Y, Dickersin GR, Gebhardt MC, Rosenthal DI, et al. Clinical and biochemical manifestations of hyaluronidase deficiency. N Engl J Med. 1996;335:1029–33. doi: 10.1056/NEJM199610033351405. [PubMed] [CrossRef] [Google Scholar]
79. Lepperdinger G, Strobl B, Kreil G. HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. J Biol Chem. 1998;273:22466–70. doi: 10.1074/jbc.273.35.22466. [PubMed] [CrossRef] [Google Scholar]
80. Hemming R, Martin DC, Slominski E, Nagy JI, Halayko AJ, Pind S, et al. Mouse Hyal3 encodes a 45- to 56-kDa glycoprotein whose overexpression increases hyaluronidase 1 activity in cultured cells. Glycobiology. 2008;18:280–9. doi: 10.1093/glycob/cwn006. [PubMed] [CrossRef] [Google Scholar]
81. Lapcík L, Jr., Chabrecek P, Stasko A. Photodegradation of hyaluronic acid: EPR and size exclusion chromatography study. Biopolymers. 1991;31:1429–35. doi: 10.1002/bip.360311209.[PubMed] [CrossRef] [Google Scholar]
82. Laurent TC. The chemistry, biology, and medical applications of hyaluronan and its derivatives. London: Portland Press; 1998:621. [Google Scholar]
83. Toole BP. Hyaluronan and its binding proteins, the hyaladherins. Curr Opin Cell Biol. 1990;2:839–44. doi: 10.1016/0955-0674(90)90081-O. [PubMed] [CrossRef] [Google Scholar]
84. Knudson CB, Knudson W. Hyaluronan-binding proteins in development, tissue homeostasis, and disease. FASEB J. 1993;7:1233–41. [PubMed] [Google Scholar]
85. Turley EA. Hyaluronan and cell locomotion. Cancer Metastasis Rev. 1992;11:21–30. doi: 10.1007/BF00047600. [PubMed] [CrossRef] [Google Scholar]
86. Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D, et al. Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility. J Cell Biol. 1992;117:1343–50. doi: 10.1083/jcb.117.6.1343. [PMC free article][PubMed] [CrossRef] [Google Scholar]
87. Yang B, Zhang L, Turley EA. Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. J Biol Chem. 1993;268:8617–23.[PubMed] [Google Scholar]
88. Lokeshwar VB, Selzer MG. Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells. J Biol Chem. 2000;275:27641–9.[PubMed] [Google Scholar]
89. Mohapatra S, Yang X, Wright JA, Turley EA, Greenberg AH. Soluble hyaluronan receptor RHAMM induces mitotic arrest by suppressing Cdc2 and cyclin B1 expression. J Exp Med. 1996;183:1663–8. doi: 10.1084/jem.183.4.1663. [PMC free article][PubMed] [CrossRef] [Google Scholar]
90. Samuel SK, Hurta RA, Spearman MA, Wright JA, Turley EA, Greenberg AH. TGF-beta 1 stimulation of cell locomotion utilizes the hyaluronan receptor RHAMM and hyaluronan. J Cell Biol. 1993;123:749–58. doi: 10.1083/jcb.123.3.749. [PMC free article][PubMed] [CrossRef] [Google Scholar]
91. Ripellino JA, Bailo M, Margolis RU, Margolis RK. Light and electron microscopic studies on the localization of hyaluronic acid in developing rat cerebellum. J Cell Biol. 1988;106:845–55. doi: 10.1083/jcb.106.3.845. [PMC free article][PubMed] [CrossRef] [Google Scholar]
92. Meyer LJ, Stern R. Age-dependent changes of hyaluronan in human skin. J Invest Dermatol. 1994;102:385–9. doi: 10.1111/1523-1747.ep12371800. [PubMed] [CrossRef] [Google Scholar]
93. Wang C, Tammi M, Tammi R. Distribution of hyaluronan and its CD44 receptor in the epithelia of human skin appendages. Histochemistry. 1992;98:105–12. doi: 10.1007/BF00717001.[PubMed] [CrossRef] [Google Scholar]
94. Bertheim U, Hellström S. The distribution of hyaluronan in human skin and mature, hypertrophic and keloid scars. Br J Plast Surg. 1994;47:483–9. doi: 10.1016/0007-1226(94)90031-0. [PubMed] [CrossRef] [Google Scholar]
95. DePalma RL, Krummel TM, Durham LA, 3rd, Michna BA, Thomas BL, Nelson JM, et al. Characterization and quantitation of wound matrix in the fetal rabbit. Matrix. 1989;9:224–31. doi: 10.1016/S0934-8832(89)80054-X. [PubMed] [CrossRef] [Google Scholar]
96. Mast BA, Flood LC, Haynes JH, DePalma RL, Cohen IK, Diegelmann RF, et al. Hyaluronic acid is a major component of the matrix of fetal rabbit skin and wounds: implications for healing by regeneration. Matrix. 1991;11:63–8. doi: 10.1016/S0934-8832(11)80228-3. [PubMed] [CrossRef] [Google Scholar]
97. Longaker MT, Chiu ES, Adzick NS, Stern M, Harrison MR, Stern R. Studies in fetal wound healing. V. A prolonged presence of hyaluronic acid characterizes fetal wound fluid. Ann Surg. 1991;213:292–6. doi: 10.1097/00000658-199104000-00003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
98. Stuhlmeier KM, Pollaschek C. Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. J Biol Chem. 2004;279:8753–60. doi: 10.1074/jbc.M303945200.[PubMed] [CrossRef] [Google Scholar]
99. Karvinen S, Pasonen-Seppänen S, Hyttinen JM, Pienimäki JP, Törrönen K, Jokela TA, et al. Keratinocyte growth factor stimulates migration and hyaluronan synthesis in the epidermis by activation of keratinocyte hyaluronan synthases 2 and 3. J Biol Chem. 2003;278:49495–504. doi: 10.1074/jbc.M310445200. [PubMed] [CrossRef] [Google Scholar]
100. Wilkinson TS, Potter-Perigo S, Tsoi C, Altman LC, Wight TN. Pro- and anti-inflammatory factors cooperate to control hyaluronan synthesis in lung fibroblasts. Am J Respir Cell Mol Biol. 2004;31:92–9. doi: 10.1165/rcmb.2003-0380OC. [PubMed] [CrossRef] [Google Scholar]
101. Pienimaki JP, Rilla K, Fulop C, Sironen RK, Karvinen S, Pasonen S, et al. Epidermal growth factor activates hyaluronan synthase 2 in epidermal keratinocytes and increases pericellular and intracellular hyaluronan. J Biol Chem. 2001;276:20428–35. doi: 10.1074/jbc.M007601200.[PubMed] [CrossRef] [Google Scholar]
102. Yung S, Thomas GJ, Davies M. Induction of hyaluronan metabolism after mechanical injury of human peritoneal mesothelial cells in vitro. Kidney Int. 2000;58:1953–62. doi: 10.1111/j.1523-1755.2000.00367.x. [PubMed] [CrossRef] [Google Scholar]
103. Li Y, Rahmanian M, Widström C, Lepperdinger G, Frost GI, Heldin P. Irradiation-induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types I and III collagen gene expression. Am J Respir Cell Mol Biol. 2000;23:411–8. [PubMed] [Google Scholar]
104. Tammi R, Pasonen-Seppänen S, Kolehmainen E, Tammi M. Hyaluronan synthase induction and hyaluronan accumulation in mouse epidermis following skin injury. J Invest Dermatol. 2005;124:898–905. doi: 10.1111/j.0022-202X.2005.23697.x. [PubMed] [CrossRef] [Google Scholar]
105. Tzellos TG, Dionyssopoulos A, Klagas I, Karakiulakis G, Lazaridis L, Papakonstantinou E. Differential glycosaminoglycan expression and hyaluronan homeostasis in juvenile hyaline fibromatosis. J Am Acad Dermatol. 2009;61:629–38. doi: 10.1016/j.jaad.2009.03.042. [PubMed] [CrossRef] [Google Scholar]
106. Weiss JM, Sleeman J, Renkl AC, Dittmar H, Termeer CC, Taxis S, et al. An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function. J Cell Biol. 1997;137:1137–47. doi: 10.1083/jcb.137.5.1137.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
107. Weiss JM, Renkl AC, Sleeman J, Dittmar H, Termeer CC, Taxis S, et al. CD44 variant isoforms are essential for the function of epidermal Langerhans cells and dendritic cells. Cell Adhes Commun. 1998;6:157–60. doi: 10.3109/15419069809004472.[PubMed] [CrossRef] [Google Scholar]
108. Hall CL, Yang B, Yang X, Zhang S, Turley M, Samuel S, et al. Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell. 1995;82:19–26. doi: 10.1016/0092-8674(95)90048-9. [PubMed] [CrossRef] [Google Scholar]
109. Longas MO, Russell CS, He XY. Evidence for structural changes in dermatan sulfate and hyaluronic acid with aging. Carbohydr Res. 1987;159:127–36. doi: 10.1016/S0008-6215(00)90010-7. [PubMed] [CrossRef] [Google Scholar]
110. Gilchrest BA. A review of skin ageing and its medical therapy. Br J Dermatol. 1996;135:867–75. doi: 10.1046/j.1365-2133.1996.d01-1088.x. [PubMed] [CrossRef] [Google Scholar]
111. Bernstein EF, Underhill CB, Hahn PJ, Brown DB, Uitto J. Chronic sun exposure alters both the content and distribution of dermal glycosaminoglycans. Br J Dermatol. 1996;135:255–62. doi: 10.1111/j.1365-2133.1996.tb01156.x. [PubMed] [CrossRef] [Google Scholar]
112. Uitto J. Understanding premature skin aging. N Engl J Med. 1997;337:1463–5. doi: 10.1056/NEJM199711133372011. [PubMed] [CrossRef] [Google Scholar]
113. Röck K, Grandoch M, Majora M, Krutmann J, Fischer JW. Collagen fragments inhibit hyaluronan synthesis in skin fibroblasts in response to ultraviolet B (UVB): new insights into mechanisms of matrix remodeling. J Biol Chem. 2011;286:18268–76. doi: 10.1074/jbc.M110.201665. [PMC free article][PubMed] [CrossRef] [Google Scholar]
114. Oh JH, Kim YK, Jung JY, Shin JE, Chung JH. Changes in glycosaminoglycans and related proteoglycans in intrinsically aged human skin in vivo. Exp Dermatol. 2011;20:454–6. doi: 10.1111/j.1600-0625.2011.01258.x. [PubMed] [CrossRef] [Google Scholar]

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