Collagen Target May Lead To Treatment Of Wounds, Wrinkles and Fragile Skin

David Granville, BSc, PhD, FAHA Professor, University of British Columbia Scholar of the Royal Society of Canada Director, GEM Facility, Centre for Heart Lung Innovation, St. Paul's Hospital Founder and CSO, viDA Therapeutics, Inc. Vancouver, BC, CanadaMedicalResearch.com Interview with:
David Granville, BSc, PhD, FAHA
Professor, University of British Columbia
Scholar of the Royal Society of Canada
Director, GEM Facility, Centre for Heart Lung Innovation, St. Paul’s Hospital Founder and CSO, viDA Therapeutics, Inc.
Vancouver, BC, Canada

Medical Research: What is the background for this study? What are the main findings?

Dr. Granville: My background is in cardiovascular research. In particular, how age affects blood vessels and how age affects mechanisms of blood vessel and heart injury and repair. We became interested in skin aging during a study in which we were studying the role of a protein degrading enzyme known as Granzyme B in atherosclerosis (hardening of the arteries) and aging. In these studies, we were using a genetic mouse model that is prone to accelerated aging, and knocked out Granzyme B. Although we were initially focused on the blood vessels, we also found that Granzyme B-deficient mice exhibited younger-looking skin. As we started to look into this, we became aware that UV light can induce the skin cells to produce Granzyme B. As sunlight is believed to be responsible for 80-90% of preventable skin aging, we generated a solar-simulated light box (with the similar ratios of UVA/UVB to sunlight) to assess whether Granzyme B played a role in UV-induced skin aging (aka photoaging). We exposed the mice to repetitive, low dose UV three times per week for 20 weeks. After 20 weeks we observed that Granzyme B deficient mice exhibited fewer wrinkles. We then wanted to look histologically and biochemically into how Granzyme B was affecting skin morphology. Granzyme B deficient mice exhibited greater collagen density compared to mice that possessed Granzyme B. As we looked into the mechanism in more detail, we determined that Granzyme B was cleaving a protein known as decorin. Decorin is responsible for collagen fibrillogenesis and assembling collagen into tight bundles. Loss of decorin is associated with a loss of collagen tensile strength. Interestingly, decorin also protects collagen from destruction by a protein-degrading enzyme known as MMP1. We showed in the study that by breaking down decorin, Granzyme B renders collagen susceptible to MMP1-mediated degradation. In addition, we showed that Granzyme B-fragmentation of another protein, fibronectin, led to the upregulation of MMP1 in skin fibroblasts. In summary, the paper showed that UV induced Granzyme B expression in the skin and showed that this enzyme contributes to the breakdown of extracellular matrix proteins and formation of wrinkles.

A link to the Aging Cell publication: http://onlinelibrary.wiley.com/doi/10.1111/acel.12298/pdf

Medical Research: What should clinicians and patients take away from your report?

Dr. Granville: While the media and public tend to focus on the perhaps the most obvious cosmetic implications of our findings, we believe Granzyme B plays a pathologic role (ie. clinically) in the skin in the impairment of tissue injury and repair. By preventing Granzyme B our work suggests that we can improve tissue repair/remodelling and increase the integrity and tensile strength of skin. This could have large implications with respect to skin thinning and skin tearing that is highly prevalent in the elderly and long-term care facilities. Our prior studies also suggest a role in chronic wound healing (ie. diabetic wound healing, pressure ulcers/bed sores). I am also working with viDA Therapeutics to develop Granzyme B inhibitors for topical applications. Granzyme B is highly elevated in a number of autoimmune skin conditions. One in particular that we are quite excited about is discoid lupus erythematosus (DLE). Granzyme B is abundant in DLE. Given DLE is often induced and/or promoted by sunlight and involves scarring, hair loss, microvascular damage and other features where we know Granzyme B plays a role, we believe there is a high liklihood that we could modify/reduce the formation of scarring in these patients. viDA is anticipating clinical trials to commence by the end of 2016.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Granville: Obviously avoidance of sunlight is the best way to prevent skin aging/damage, but sometimes it is unavoidable. Likewise, we also have evidence that repetitive exposure to smoking can induce the expression of Granzyme B. Our future research is focused on further validating Granzyme B as a therapeutic target and developing drugs to prevent skin damage and restore skin (and other tissue) integrity.

Citation:

Parkinson, L. G., Toro, A., Zhao, H., Brown, K., Tebbutt, S. J. and Granville, D. J. (2014), Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation. Aging Cell. doi: 10.1111/acel.12298