Basic science advances promising for acne tx

January 1, 2007

Brooklyn, N.Y. - Fundamental concepts on the pathogenesis of acne vulgaris have not changed significantly over the past 25 years.

However, knowledge of the underlying cellular and molecular mechanisms continues to increase, and that expanding knowledge may be important for identifying new targets for therapeutic intervention, Alan R. Shalita, M.D., says.

Recent accomplishments of several groups of investigators stand out for their potential to have a positive impact on acne therapy in the future, says Dr. Shalita, professor and chairman, SUNY Downstate Medical Center, Brooklyn.

Dr. Shalita cites the development of an immortalized human sebaceous gland cell line by Diane Thiboutot, M.D., and colleagues at Pennsylvania State University as one of the major highlights in recent acne research.

Those investigators confirmed the sebaceous phenotype of their cells using a variety of techniques and also reported the cells reproducibly produced sebum that was biochemically similar to natural sebum with respect to its lipid composition.

"This achievement will enable in vitro studies targeting receptors and genes in the sebaceous gland and so should lead to increased understanding of the factors affecting sebaceous gland activity and how it can be manipulated," Dr. Shalita tells Dermatology Times.

Pattern recognition proteins

At the University of California, Los Angeles, Jenny Kim, M.D., and colleagues have been investigating the roles of pattern recognition proteins (PRP) in acne pathogenesis.

In 2002, they first reported findings of their research implicating a role for the cell surface PRP toll-like receptor 2 (TLR2) in the inflammatory response characterizing acne. In their paper, the researchers described studies that demonstrated Propionibacterium acnes binds to TLR2 and causes the release of proinflammatory cytokines from monocytes. More recently, those researchers have also described involvement of the intracellular PRP nucleotide oligomerization domain (NOD).

"Subsequent studies with adapalene and other synthetic retinoids have demonstrated that those anti-acne agents downregulate expression of TLR2 and thereby block the production of inflammatory cytokines," Dr. Shalita notes.

Pathways of acne scarring

Sewon Kang, M.D., and researchers at the University of Michigan have found that the pathways of inflammation and collagen degradation involved in acne are very similar to the activator protein 1-mediated process that leads to the development of photodamage.

They also demonstrated that retinoids could downregulate those pathways just as they modulate the inflammatory pathways leading to photodamage.

That information provides support for the concept that initiating retinoid treatment early may provide a means for preventing acne scarring, Dr. Shalita notes.

"A study investigating that hypothesis was proposed by Peter Pocchi, M.D., years ago, but the barrier to the success of this strategy will be patient compliance. Patients will need to use their topical retinoid every day and over the long-term in order to limit inflammation-induced matrix degradation and remodeling," Dr. Shalita says.

Dr. Thiboutot has also reported findings from research using gene array profiling techniques to analyze lesional skin of patients with inflammatory acne. In that study, she and her colleagues found hundreds of genes were upregulated in lesional skin versus nonlesional skin. The overexpressed genes were particularly represented by genes involved in pathways modulating inflammation and extracellular matrix remodeling, including the matrix metalloproteinases, IL-9, human beta-defensin 4, protease inhibitors and chemokine ligand 2.

Future directions

Looking toward the horizon, Dr. Shalita expresses hope that a growing number of young scientists will develop an interest in acne research and that positive cooperation between the Food and Drug Administration and clinical researchers will continue to increase.

However, he suggests a need for greater effort to be devoted toward increasing public education about acne in order to dispel prevalent myths and misconceptions about its causes and treatment. In addition, Dr. Shalita urges dermatologists to adapt their practice patterns as new standards evolve.