What if I told you that Avon is widely promoting a new product, and proudly proclaiming that it works by causing fibrosis, a pathological process that can distort and scar skin over time? Hard to believe they would do that, right?
Exactly what I thought when I first heard they were claiming that the active ingredient in their new offering, Anew Line and Wrinkle Corrector with AF-33, works by turning on PLOD2, a gene that produces an enzyme that rapidly increases collagen production, and also changes the cross-linking pattern of those collagen fibers. And that this worked to erase wrinkles, rather dramatically, within weeks. With a clinical study to boot. Pretty amazing, right?
Now, Avon doesn’t mention the term fibrosis in the P.R., but they don’t really need to. Because PLOD2 is widely known in medical science as the gene responsible for causing fibrotic collagen fibers, a condition called fibrosis. It’s not a deep buried secret. One study even has the blunt and definitive title “Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis.” Can’t miss that kind of solid evidence by claiming the title is confusing. Multiple confirmatory studies confirm the same thing, and in fact every gene databank I researched identifies PLOD2 as having a role in the pathogenesis of fibrosis.
Fibrosis is a pathologic process, leading to disease and dysfunction
So, what is fibrosis, and why should I be worried about whether my Avon Lady is really “Fibrosis Mary”? Fibrosis refers to a pathologic process whereby connective tissue in your body that is excessive in amount, and/or abnormally stiff or unyielding. It can affect any organ, causing architectural distortion and dysfunction (e.g. pulmonary fibrosis, pancreatic fibrosis, dermal fibrosis). Fibrosis often, but not always, follows chronic inflammation. Fibrotic tissue is like a scar tissue, thick, and rigid, due to excess accumulation of matrix protein (e.g. collagen). A scar is actually a particular type of fibrosis, localized to an area of prior damage. When due to diffuse damage, such an inflammatory or autoimmune process, a more generalized fibrosis may ensue. Over time fibrotic skin contracts, as scars are well known to do. In severe cases this can cause dysfunction (e.g. unable to sip through a straw) as well as an esthetically unappealing appearance.
Just to avoid confusion, there is another term – fibrotic – that refers to a normal process in wound healing. In the initial stages in adult (not fetal) wound healing, sometimes called the fibrotic phase, there is organization of blood clots, and production of fibrotic collagen as the body tries to quickly knit together the edges of a wound, to maintain tissue integrity. This in fact is the likely reason why we have PLOD2 genes in the first place. However, this fibrotic phase is limited in normal healing to the first few weeks, then is replaced by successive stages of healing that is not fibrotic. If you get stuck in the fibrotic phase, you tend to develop fibrosis, or scars. Keloids are a particular kind of excessive scarring, also with a known connection to fibrosis. So, fibrotic processes are part of normal healing but in a particular context, for a short duration. When they persist past that, the usual result is fibrosis.
What does this have to do with wrinkles?
Collagen is a key target in anti-wrinkle therapy, because our skin loses collagen with aging (photoaging in particular) and aged collagen also changes qualitatively as the cross links between collagen fibers may undergo various chemical transformations (such as glycation, contributing to skin problems including poor wound healing in diabetes). This may limit collagen turnover (breaking down old, and building new, a continuous renewal process in healthy skin). But there is a paradox here. Fibrotic skin, and scar tissue, is very hard to degrade. It’s particular pattern of cross links resists the enzymes that break down old collagen. Once you develop skin fibrosis, it’s very hard to remedy. And while fibrosis can erase wrinkles in the short term by pumping skin, in the long term it contracts and in effect locks wrinkles in place.
Scleroderma as an example of skin fibrosis
One disease whose hallmark is severe skin fibrosis is a potentially fatal condition called scleroderma. In Greek, the word scleroderma literally means “hard skin”. The facial manifestations of scleroderma have been termed “the slowly contracting skin of steel”. Another sign of scleroderma is, logically enough, a paucity of wrinkles.
Does AF-33 cause scleroderma? No. Scleroderma is an autoimmune disorder, and skin fibrosis is a downstream event. AF-33, by putting PLOD2 in overdrive, causes a fibrotic process that mimics the fibrotic skin pathology of scleroderma.
Another clue about the relationship between PLOD2 and fibrotic skin comes from studies of fibroblasts from the skin of people with scleroderma. No surprise here — PLOD2 mRNA is highly increased in the fibroblasts of people with scleroderma.
The first thing I noticed was “small mouth syndrome.” That was when I really began to see the tightening. I know it sounds funny, but I found that I couldn’t whistle anymore, because the skin had tightened around my mouth so much…and I also found that using a straw became a bit of a joke…couldn’t close my mouth around the straw, completely. And, I also got that “pinched” nose look. (patient with scleroderma).
Something askew with Anew
So, let’s start putting some of the pieces of this puzzle together. PLOD2 is a gene strongly linked to fibrosis, and Avon has a product containing something called AF-33 which expresses (turns on) PLOD2 so significantly that it “erases” wrinkles in weeks. Furthermore, they tout that it cranks up the production of GAG’s and collagen, and changes collagen cross linking. Which are all known functions of PLOD2’s enzyme product, telopeptide lysyl hydroxylase. (We will go into greater detail on the cross-linking chemistry in a subsequent post).
Would that erase wrinkles quickly? You bet. Crank up the pro-collagen and GAG’s (glycosaminoglycans; big proteins, they draw water to the matrix as well), radically increase collagen production, all leading to plumped up skin in record time. The problem is that the cross-linking of collagen that happens after its production is of the fibrotic type.
Now, suppose you love the effect of Anew (who wouldn’t) and want to continue to use this product not for weeks, but for months, or years. When your body turns on PLOD2 in response to a wound, under most circumstances it will peak in a few weeks to be replaced by “non-scarring” matrix cross-linking enzymes. Will Anew users know when to stop? Or will they continue to infuse their facial skin with fibrogenetic enzymes? And what will be the end result of that? It would seem likely that the collagen, cross linked in the presence of PLOD2’s enzyme, will become hard and stiff. The face will tighten.
Has anyone studied this with AF-33? No. That’s part of what bothers me. If you are inducing PLOD2, a known fibrotic enzyme, wouldn’t it occur to you that you should at least check to see if chronic use results in pathologic fibrosis? If this were a drug (well, actually it is a drug) Avon would be required to test for that, plus a whole lot more. But Avon calls it something else, and then claims that …
This is not dissimilar to what has been shown with other widely used ingredients in cosmetics. Furthermore, there is no evidence that these ingredients with a long history of use in cosmetics increase the propensity to develop scleroderma.
Now this is scary for several reasons. First, check the logic. “These ingredients” = anything that increase GAGs and pro-collagen. But wait, this is an entirely new ingredient. One not in general use. And one specifically associated with the gene whose product leads to fibrosis. Then they scare me further by saying there is “no evidence to suggest it increases the propensity to develop scleroderma.” Nobody said it does. What the medical science literature suggests is that anything that turns on PLOD2 continuously ought to lead to fibrosis. Further, there is evidence that people with scleroderma had high levels of PLOD2 in their fibrotic skin. The answer given by Avon R&D suggests that they don’t understand the difference between the disease (scleroderma) and the process (fibrosis). Someone trained in medicine would never have said this, because he would have known the difference. So, are there no medical scientists involved in the development of this drug? I’m seriously worried.
Avon thumbs their nose at BFT doctors (and you readers)
Which brings us full tilt to the backstory on all this. More pieces to the puzzle. When I first learned about this, I contact Avon to try to gather more information, in the hope that they had done some testing to mitigate the known facts about PLOD-2 and fibrosis. Nobody seemed to want to reply to my e-mails, so I ended up contacting NeoStrata, a cosmetic company that also does ingredient R&D. They had done the original work on AF-33 but then licensed it to Avon.
The people at NeoStrata explained that Avon had done all the work on PLOD-2. They also kindly shared with me a poster presented at a conference. It showed safety studies (none addressing fibrosis; the usual patch test things), skin thickness studies, some nice before and after pictures, and some rather remarkable photomicrographs of skin biopsies from subjects in the clinical trial. One was striking – a slide stained to show abundant GAGs in treated skin. A quick search revealed that the slide (from an AF-33 treated subjects) closely resembled textbook slides showing skin from people in early stages of scleroderma, accumulating pro-collagen and GAGs in their dermis. By the way, the NeoStrata people were very helpful, and very forthcoming. They appropriately referred me to Avon, who they say had carried the work further and had done the PLOD2 studies.
So I tried calling Avon, and was referred to Claudia Schaum in their public relations department. Very nice lady, who tried to be helpful. I sent her the e-mail I had sent to NeoStrata, she forwarded it to the research folks at Avon. After several days of delay, she sent me the reply (a few sentences, abstracted above). I found it disturbing, as I said above, and replied back with some additional facts (a short form of this post). Plus this …
Does Avon have a medical director that I can speak to by telephone? A simple collegial conversation would go a long way toward assisting me in sorting through all this. Or can I at least speak with the executive in charge of research and development? Thank you in advance for your continuing assistance.
I was roundly ignored. No reply. No call, no e-mail, not even an acknowledgement. As far as BFT is concerned, there is no “Avon calling”.
I have been a medical executive at Johnson & Johnson, and other medical companies. When physicians or scientists inquired about products, they always received the full attention of the medical affairs department. My conclusion is that Avon believes they can just ignore this. I find this response extremely short-sighted, and frankly arrogant. There are numerous concerns arising from this, not just about Avon, but about the industry in general.
Beyond AF-33, the most flagrant example to date, we here at BFT have some general concerns about anti-wrinkle ingredients that crank on collagen with no concern about whether it is of the fibrotic (inflammatory context) type, or non-fibrotic (anti-inflammatory) type. This is just the introductory piece. We are going to turn this into a series of in-depth explorations of this topic. We are going to do some bench lab work of our own, and try to find some more pieces to this puzzle.
Meanwhile, I think there is enough evidence already present to raise an alarm about this particular Avon Anew product. And about Avon itself – doe they really not know that it makes them look ridiculous to tout PLOD2 (the fibrosis gene) as a way to erase wrinkles? Or do they do they not even know what the medical science literature so clearly says on the topic? Or that their users are just too ignorant to care about fibrosis? Or, do they just feel that they are so big and powerful that they can do whatever they want, with no sense of responsibility to the scientific, medical, or user community?
Let’s see how this story plays out. More to come.
1. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. van der Slot, A.J., Zuurmond, A.M., Bardoel, A.F., Wijmenga, C., Pruijs, H.E., Sillence, D.O.,Brinckmann, J., Abraham, D.J., Black, C.M., Verzijl, N., DeGroot, J., Hanemaaijer, R., TeKoppele, J.M., Huizinga, T.W., Bank, R.A. J. Biol. Chem. (2003)
2. Collagen Cross-Links. Eyre, D.R., Wu. J. Top Curr Chem (2005) 247: 207–229
3. Differential expression of human lysyl hydroxylase genes, lysine hydroxylation, and cross-linking of type I collagen during osteoblastic differentiation in vitro. Uzawa, K., Grzesik, W.J., Nishiura, T., Kuznetsov, S.A., Robey, P.G., Brenner, D.A., Yamauchi, M. J. Bone Miner. Res. (1999)
4. Fox-2 protein regulates the alternative splicing of scleroderma-associated lysyl hydroxylase 2 messenger RNA. Seth P, Yeowell HN. Arthritis Rheum. 2010 Apr;62(4):1167-75.
5. Functional diversity of lysyl hydroxylase 2 in collagen synthesis of human dermal fibroblasts. Wu, J., Reinhardt, D.P., Batmunkh, C., Lindenmaier, W., Far, R.K., Notbohm, H., Hunzelmann, N., Brinckmann, J. Exp. Cell Res. 2006
6. Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: important pathogenetic steps in early and late stage of systemic scleroderma? Brinckmann J, Kim S, Wu J, Reinhardt DP, Batmunkh C, Metzen E, Notbohm H, Bank RA, Krieg T, Hunzelmann N. Matrix Biol. (2005) 24(7):459-68.
7. Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts. Walker LC, Overstreet MA, Yeowell HN. Matrix Biol. 2005 Jan;23(8):515-23.
8. Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. van der Slot AJ, Zuurmond AM, van den Bogaerdt AJ, Ulrich MM, Middelkoop E, Boers W, Karel Ronday H, DeGroot J, Huizinga TW, Bank RA. Matrix Biol. 2004 Jul;23(4):251-7.