Correspondence
Effect of Tretinoin on Collagen Formation in Photodamaged Skin
N Engl J Med 1993; 329:2038-2039December 30, 1993
- Article
To the Editor:
In evaluating the effect of topical tretinoin (retinoic acid) cream on the skin, Griffiths et al. (Aug. 19 issue)1 conclude that tretinoin causes an 80 percent increase in extracellular type I collagen formation in the papillary dermis. Evaluation in terms of the percentage differences in dermal type I collagen formation was based on a subjective scoring system used to assess the intensity and extent of immunostaining of a portion of the procollagen I molecule. Ordinal values of 0 to 5 were used to describe the perceived intensity and extent of staining in prepared immunohistologic tissue sections.
Statements regarding percentage differences in collagen immunostaining as well as collagen formation cannot be made on the basis of these ordinal data. A specimen given a score of 5 cannot be said to show five times the level of immunostaining of a specimen given a score of 1. Although a difference between the two may be described, a percentage difference cannot be quantified.
1 ReferencesS. Elizabeth Whitmore, M.D.
Johns Hopkins University, Baltimore, MD 212871
Griffiths CEM ,Russman AN ,Majmudar G ,Singer RS ,Hamilton TA ,Voorhees JJ . Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 1993;329:530-535
Full Text | Web of Science | Medline
To the Editor:
Griffiths et al. reported that topical treatment of skin with tretinoin resulted in increased production of collagen as assessed by the histologic identification of type I collagen aminopropeptides and a decrease in wrinkling. Studies in animals have yielded similar results. The authors suggest a direct effect of tretinoin on fibroblast collagen synthesis (stimulation) or collagenase production (inhibition). Federspiel et al.1 previously demonstrated that tretinoin increases collagen production in epithelial cells. Griffiths and associates detected increased collagen production in the vicinity of fibroblasts located in the papillary dermis, although numerous previous studies found that the direct application of tretinoin to fibroblasts in vitro decreased collagen accumulation2-4. Tretinoin has been used successfully to treat keloids, a skin condition characterized by the excessive deposition of collagen in scars5. An additional problem in interpreting results relates to the dose and the time of administration. In vitro, tretinoin was used at defined concentrations and for short-term exposures (24 hours or less). In vivo, the dose of tretinoin that penetrated to the papillary dermis was uncertain, and the drug was applied to the skin daily for one year.
The discrepancy between the effect of tretinoin on collagen accumulation in vivo and its effect on fibroblast function in vitro suggests that there are complex cell-to-cell interactions. Such interactions may initially involve a direct effect of tretinoin on the differentiation or the proliferative state of the dermal epithelial cells. Griffiths et al. note that epidermal hyperproliferation preceded clinical improvement. It may be that dermal epithelial cells provide paracrine factors, such as transforming growth factor beta, that stimulate collagen accumulation by fibroblasts. Alternatively, matrix elements produced by epithelial cells may influence fibroblast function.
5 ReferencesMeir Krupsky, M.D.
Ronald H. Goldstein, M.D.
Boston University School of Medicine, Boston, MA 021181
Federspiel SJ ,DiMari SJ ,Howe AM ,Guerry-Force ML ,Haralson MA . Extracellular matrix biosynthesis by cultured fetal rat lung epithelial cells. IV. Effects of chronic exposure to retinoic acid on growth, differentiation, and collagen biosynthesis. Lab Invest 1991;65:441-450
Web of Science | Medline2
Hein R ,Mensing H ,Muller PK ,Braun-Falco O ,Krieg T . Effect of vitamin A and its derivatives on collagen production and chemotactic response to fibroblasts. Br J Dermatol 1984;111:37-44
CrossRef | Web of Science | Medline3
Nelson DL ,Balian G . The effect of retinoic acid on collagen synthesis by human dermal fibroblasts. Coll Relat Res 1984;4:119-128
Medline4
Oikarinen H ,Oikarinen AI ,Tan EM , et al. Modulation of procollagen gene expression by retinoids: inhibition of collagen production by retinoic acid accompanied by reduced type I procollagen messenger ribonucleic acid levels in human skin fibroblast cultures. J Clin Invest 1985;75:1545-1553
CrossRef | Web of Science | Medline5
Janssen de Limpens AM . The local treatment of hypertrophic scars and keloids with topical retinoic acid. Br J Dermatol 1980;103:319-323
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Author/Editor Response
The authors reply:
To the Editor: We appreciate the importance of comments about interpreting the percentage change in collagen synthesis when semiquantitative scales are used. In our paper we stated that the intensity of immunostaining was scored on an ordinal scale ranging from 0 (no staining) to 5 (maximal staining) and that, although subjective, the system was unbiased because the evaluator was blinded to both the treatment assigned and the time when the sample was obtained. However, we acknowledge that ordinal data are not truly quantitative and that therefore it was not possible to determine in exact units of measurement how much procollagen I or collagen I precursor was present before or after tretinoin treatment. Nonetheless, the percentage difference is a helpful and commonly used index for communicating the relative difference between mean values of ordinal data, and when viewed in this context it is considered acceptable.
The often paradoxical in vitro and in vivo effects of tretinoin present a vexing problem for investigators. Undoubtedly, the conditions and cell lines used for in vitro culture are paramount in determining whether tretinoin inhibits or stimulates collagen synthesis. For instance, tretinoin can have very different effects on cell growth in culture, depending on the proliferative state of the cells at the beginning of treatment. This agent inhibits rapidly proliferating cultured keratinocytes, whereas it stimulates the proliferation of keratinocytes whose growth has been inhibited by culture in basal medium1. In vivo, the same paradox is observed, in that retinoids, either topical or systemic, will inhibit the epidermal proliferation characteristic of psoriasis or ichthyoses,2 whereas topical retinoids will promote epidermal proliferation in normal or photodamaged skin3. Dermal cellular constituents -- i.e., fibroblasts -- behave in much the same manner as epidermal keratinocytes. Retinoids may inhibit fibroblast proliferation and enhance collagen synthesis, as observed in scleroderma, for example,4 but stimulate the already depressed fibroblast production of collagen in severely photodamaged skin5.
We concur with Krupsky and Goldstein that some of the effects of tretinoin may be mediated by growth factors, such as transforming growth factor beta produced by dermal cells as well as keratinocytes, and that complex cell-to-cell interactions are operative. Whatever the route, direct or indirect, the evidence remains that tretinoin and probably other retinoids can stimulate collagen accumulation in vivo, and the results of in vitro work should be extrapolated with caution.
5 ReferencesChristopher E.M. Griffiths, M.D.
Ted A. Hamilton, M.S.
John J. Voorhees, M.D.
University of Michigan Medical Center, Ann Arbor, MI 481091
Varani J ,Nickoloff BJ ,Dixit VM ,Mitra RS ,Voorhees JJ . All-trans retinoic acid stimulates growth of adult human keratinocytes cultured in growth factor-deficient medium, inhibits production of thrombospondin and fibronectin, and reduces adhesion. J Invest Dermatol 1989;93:449-454
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Ellis CN ,Voorhees JJ . Etretinate therapy. J Am Acad Dermatol 1987;16:267-291
CrossRef | Web of Science | Medline3
Kligman AM ,Grove GL ,Hirose R ,Leyden JJ . Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986;15:836-859
CrossRef | Web of Science | Medline4
Maurice PD ,Bunker CB ,Dowd PM . Isotretinoin in the treatment of systemic sclerosis. Br J Dermatol 1989;121:367-374
CrossRef | Web of Science | Medline5
Griffiths CEM ,Russman AN ,Majmudar G ,Singer RS ,Hamilton TA ,Voorhees JJ . Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 1993;329:530-535
Full Text | Web of Science | Medline
