Vitamin A Antagonizes Decreased Cell Growth and Elevated Collagen-Degrading Matrix Metalloproteinases and Stimulates Collagen Accumulation in Naturally.

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Vitamin A Antagonizes Decreased Cell Growth and Elevated Collagen-Degrading Matrix Metalloproteinases and Stimulates Collagen Accumulation in Naturally Aged Human Skin1 James Varani, Roscoe L. Warner, Mehrnaz Gharaee-Kermani, Sem H. Phan Journal of Investigative Dermatology Volume 114, Issue 3, Pages 480-486 (March 2000) DOI: 10.1046/j.1523-1747.2000.00902.x Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Skin connective tissue alterations increase with increasing age and are partially improved by retinol treatment. (a) Histologic sections of skin from persons of varying age were analyzed for the number of fibroblasts in the dermis. Skin samples from n = 11, 10, 11, and 10 persons were analyzed in the four age groups, respectively. *p <0.05 versus 18–29 y old group. ***p <0.001 versus 18–29 y age group. Fibroblasts were also quantitated in 17 persons 80+ y of age who were treated with 1% retinol and its vehicle for 7 d. *p <0.05 versus vehicle-treated skin. (b) Degree of skin connective tissue alteration was assessed on a 1–9 scale (1 = least, 9 = most) in histologic sections from persons of varying age as in A. *p <0.05 versus 18–29 y old group. Connective tissue features were also assessed in 17 persons 80+ y of age who were treated with 1% retinol and its vehicle for 7 d. All values are mean ± SEM. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Histologic features of skin connective tissue are altered in aged skin. Representative histology of skin connective tissue seen in sun-protected skin from a young person (22 y old; a, b) and from 7 d vehicle-treated (c, d) and retinol-treated (e, f) skin from an aged person (86 y old). Formalin-fixed skin sections were stained with hematoxylin and eosin. Scale bar: (a, c, e) 100 μm; (b, d, f) 50 μm. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Fibroblast growth potential is reduced with increasing age and is increased with retinol treatment. Freshly obtained skin samples from persons of varying age were cut into small pieces (15–20 pieces/skin sample) and placed in culture to allow outgrowth of fibroblasts from the tissue. Skin from persons in the four age groups (n = 12, 11, 12, and 10, respectively) was analyzed. Data are presented as the percentage of skin pieces from which fibroblasts were isolated. *p <0.05 versus 18–29 y old group. Fibroblast outgrowth was also determined in skin samples from 17 persons 80+ y of age who were treated with 1% retinol and its vehicle for 7 d. *p <0.05 versus vehicle-treated skin. Values are mean ± SEM. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 MMP levels are increased in skin with increasing age and partially reduced with retinol treatment. Skin samples of persons of varying age were analyzed for expression of three MMP: (a) MMP-1 (interstitial collagenase) (n = 10 persons per age group); (b) MMP-9 (92 kDa gelatinase); and (c) MMP-2 (72 kDa gelatinase) (n = 10, 11, 8, and 8 persons per age group). Values are mean ± SEM. *p <0.05 versus 18–29 y old group. **p <0.01 versus 18–29 y old age group. ***p <0.001 versus 18–29 y old age group. Skin samples from 16 persons 80+ y of age who were treated with 1% retinol and vehicle for 7 d were also analyzed for the three MMP. Values are mean ± SEM. Values for the vehicle-treated 80+ y old individuals were normalized to 1.0 and the other values expressed relative to the normalized values. ***p <0.001, retinol versus vehicle-treated skin. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 MMP-1 protein level is increased in skin from 80 + y old individuals compared with 18–29 y old individuals. MMP-1 protein levels were assessed by western blot analysis in 16 individuals between 18 and 29 y of age and in 16 individuals 80+ y of age. Values are mean ± SEM. *p <0.02 versus 18–29 y old individuals. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Type I and type III procollagen levels are decreased in aged skin. (a) Type I procollagen (α1 chain) levels in skin samples from 18 to 29 y old persons and 80+ y old persons (n = 16 per age group) were determined by western blot analysis. Values are mean ± SEM. *p <0.001 versus 18–29 y old individuals. (b) Representative immunohistology of type I procollagen (α1 chain) and type III procollagen (α1 chain) in skin from young and aged persons. Scale bar: 200 μm. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Retinol treatment increases collagen synthesis in aged (80 + y) skin. (a) Freshly obtained skin samples from nine persons treated with 1% retinol and its vehicle for 7 d were incubated for 24 h with [14C]proline. The amount of radioactivity (counts per minute, cpm) incorporated into the collagen fraction was determined. Values are mean ± SEM. *p <0.05 versus vehicle-treated skin. (b) Freshly obtained skin samples from nine persons treated with 1% retinol and its vehicle for 7 d were incubated in culture medium for 24 h. The amount of type I procollagen secreted into the medium was determined by ELISA. Values from vehicle-treated skin were assigned a number of 1.0 and the values from corresponding retinol-treated skin normalized to this value. Values are mean ± SEM. *p <0.05 versus vehicle-treated skin. (c) Type I procollagen α1 gene expression was measured by in situ hybridization in frozen skin sections from seven persons treated with 1% retinol and its vehicle for 7 d. The number of cells expressing detectable type I procollagen α1 mRNA in three sections from each skin sample were counted. **p <0.01 versus vehicle-treated skin. (Insert: Vehicle-treated and retinol-treated skin from an 87 y old person; scale bar: 150 μm. (d) Type III procollagen α1 gene expression was measured in skin samples from seven persons treated with 1% retinol and its vehicle for 7 d by reverse transcription–PCR. The values of the vehicle-treated skin were assigned a number of 1.0, and values from corresponding retinol-treated skin normalized to this value. Values are mean ± SEM. **p <0.01 versus vehicle-treated skin. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Retinol treatment increases type I procollagen expression in fibroblasts from aged skin. Representative immunohistologic staining of type I procollagen (α1 chain) in vehicle-treated and retinol-treated skin from an 86 y old person. Tissue was frozen in OCT and stained by the immunoperoxidase method; scale bar: 100 μm. Data are representative of n = 6. Journal of Investigative Dermatology 2000 114, 480-486DOI: (10.1046/j.1523-1747.2000.00902.x) Copyright © 2000 The Society for Investigative Dermatology, Inc Terms and Conditions