Hyaluronan: More than just a wrinkle filler

Glycobiology, 2016, vol. 26, no. 6, 553–559 doi: 10.1093/glycob/cww033 Advance Access Publication Date: 9 March 2016 Review Review Hyaluronan: More than just a wrinkle filler Edward V Maytin1,2,3 2 Department of Dermatology, and 3Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH 44195, USA 1 To whom correspondence should be addressed: Tel: +1-216-445-6676; Fax: +1-216-444-9198; e-mail: Received 19 February 2016; Revised 2 March 2016; Accepted 2 March 2016 Abstract Dermatology is a field that strives not only to alleviate skin disease (therapeutics) but also to improve the perception of wellness (cosmetics). Thus, in this special issue of Glycobiology, it seems appropriate to discuss the biology of a glycosaminoglycan, called hyaluronic acid (hyaluronan, or HA), that has become the most popular agent today for intradermal injections to improve wrinkles and other cosmetic defects. HA is a simple linear polymer in which a simple disaccharide is repeated thousands of time, thereby creating a huge hydrophilic molecule that confers a large volume of hydration and contributes to the turgor and flexibility of healthy skin. Beyond cosmetic considerations, however, HA also has important biological and physiological functions that were largely under-appreciated until recently. New research has confirmed that HA is dynamically produced by most skin cells, not only fibroblasts (the cells that make most of the skin’s extracellular matrix) but also by keratinocytes in the outer protective layer (epidermis). For both fibroblasts and keratinocytes, HA plays a regulatory role in controlling cell physiology through interaction of extracellular HA with a major cellsurface receptor, CD44. This interaction mediates intracellular signaling both directly and indirectly, through CD44 interactions with the cytoskeleton and with EGF and TGFβ receptors. Furthermore, degradation of HA by specific hyaluronidase enzymes produces HA fragments that can help to regulate inflammatory processes. In this review, current knowledge about the role of HA in skin inflammation and wound healing are reviewed and possible future applications of such knowledge discussed. Key words: fibrosis, glycosaminoglycan, inflammation, skin, wound healing Introduction While in Dermatology Residency training at the Massachusetts General Hospital in the late 1980s, my exposure to glycobiology was extremely limited. I knew that leg ulcers in diabetic patients were somehow caused by hyperglycemia, and that staining of skin biopsy specimens with alcian blue would reveal a mysterious “ground substance” containing glycoproteins and glycosaminoglycans. Two decades later, as an academic dermatologist, I learned that one of these glycosaminoglycans, hyaluronic acid (HA), or hyaluronan, had become the most popular material for soft tissue augmentation by cosmetic dermatologists (Cohen et al. 2013; Gilbert, Hui, Meehan, et al. 2012; Gilbert, Hui, Waldorf, et al. 2012). This was news to me, since for the preceding two decades bovine collagen had been the principal agent used for wrinkle revision. Unlike the highly allergenic collagens, HA is a non-immunogenic molecule, a “pristine” polysaccharide polymer completely devoid of protein epitopes (Gilbert, Hui, Meehan, et al. 2012). Another advantage of HA is that if problems arise, it can be easily removed by digestion with an enzyme, hyaluronidase (Hirsch et al. 2007). Interestingly, since HA is relatively invisible (both optically and immunologically speaking), it was very helpful earlier in its development as a clear biopolymer for use in ophthalmological procedures such as cataract replacement (Pape and Balazs 1980; Vatne and Syrdalen 1986). By the mid-2000s, when HA-based products such as Restylane, Perlane and Juvederm were enjoying newfound fame among dermatologists and plastic surgeons (Gilbert, Hui, Waldorf, et al. 2012), I was at least aware that HA was important. However, when I moved from Boston to the Midwest in 2000 to set up a new skin biology laboratory at the Cleveland Clinic, I had © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: 553 554 never even heard of hyaluronan. As it turned out, my new office was located right next door to Vincent Hascall, a world-renowned expert in HA. While at the NIH Dental Branch in the 1970s and 1980s, Vince had figured out the molecular structure of cartilage, and showed that its unique tissue properties were attributable to a tough, compressible molecular scaffold structure consisting of HA strands bound by a specialized HA-binding proteoglycan called aggrecan (Hascall and Heinegard 1974a,b; Heinegard and Hascall 1974). The protein core of aggrecan is one of a small group of proteins (called “hyaladherins”) now known to bind to the HA polysaccharide and to alter its function (Knudson and Knudson 1993). This pioneering work made Vince famous in the glycobiology world, and from that time onward he became a tireless crusader in the pursuit of knowledge about what he calls “that darn ubiquitous molecule, HA HA HA!” My initial plan for the new laboratory was to study transcription factors that regulate epidermal differentiation, and thereby cure the world of psoriasis, ichthyosis, and other scaly skin diseases. However, whilst struggling to write my first R01 on this topic, I would often take a break and talk to Vince about HA and its role in physiology and disease. Apparently, very little was known about HA in the skin, especially in the epidermis (my tissue of interest). Intrigued, I teamed up with Alberto Passi, a talented glycoscientist on sabbatical from Italy. The experiments we did together (Passi et al. 2004) became preliminary data for an NIH R01 proposal on HA in the skin. That grant was funded, establishing a base for my future work. Parenthetically, I actually never got the R01 funding to work on transcription factors, so my fortuitous encounter with HA was both a career changer and, actually, a research-funding lifesaver. Even to a biochemically challenged dermatologist, it seems obvious that HA should make a good dermal filler. HA is extremely abundant in the dermis under normal circumstances. It is also a major ingredient in moisturizing creams, due to its tremendous hygroscopic (hydrating) properties, which also helps to explain why injected HA-based fillers excel at “plumping up” the dermis. HA consists of a simple non-sulfated 2-sugar subunit, glucuronic acid and N-acetylglucosamine (Figure 1A), which is repeated thousands of times (Figure 1B); for example, a large 2 MDa HA molecule contains 5000 disaccharides (Itano 2008). Though lacking sulfate substitutions, highly charged residues on the sugar moieties confer hydrophilic properties, but, more importantly, the very large molecular size provides a domain that retains large amounts of water. Modern HA-based fillers are created typically by cross-linking the HA chains by conjugation with butanediol d (...truncated)