MDI 301, a non-irritating retinoid, induces changes in human skin that underlie repair.
Previous studies have demonstrated that all-trans retinoic acid (RA) increases collagen production and decreases matrix metalloproteinase (MMP) activity in organ-cultured human skin. Decreased MMP activity is associated with up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1). These changes are accompanied by a hyperplastic response in the epidermis. Here we show that a synthetic picolinic ester-substituted retinoid (designated as MDI 301) has comparable effects to those of RA in regard to these activities. What makes these findings of interest is that RA also stimulates elaboration of several pro-inflammatory cytokines and up-regulates leukocyte adhesion molecules in organ-cultured skin. MDI 301 does not induce such changes or is much less active. In a past study we showed that while RA was irritating to the skin of topically treated hairless mice, MDI 301 was essentially non-irritating under the same conditions [Varani et al. (2003) Arch. Dermatol Res 295:255-262]. Taken in conjunction with the findings from the past study, the present data suggest that MDI 301 will be similar to RA in capacity to repair damaged skin, but will be effective under conditions that are not irritating. These findings, thus, suggest that retinoid efficacy and clinically relevant irritancy are not inextricably linked. Potential for efficacy under conditions in which irritation is not observed is a strong rationale for further development of MDI 301 as a skin-repair agent.
Varani
James
J
Department of Pathology, The University of Michigan, 1301 Catherine Road, Box 0602, Ann Arbor, MI 48109, USA. varani@umich.edu
Fay
Kevin
K
Perone
Patricia
P
D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007641:Keratolytic Agents / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D012176:Retinoids / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D012879:Skin Physiological Phenomena; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D019040:E-Selectin; D007641:Keratolytic Agents; C488463:MDI 301; D012176:Retinoids; D019715:Tissue Inhibitor of Metalloproteinase-1; D018799:Intercellular Adhesion Molecule-1; D014212:Tretinoin; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9