transforming-growth-factor-beta and Keratosis

Photodamage is characterized by degradation of collagen and accumulation of abnormal elastin in the superficial dermis and several matrix metalloproteinases have previously been implicated in this process. Using immunohistochemistry and in situ hybridization, we have studied the localization of two elastolytic matrix metalloproteinases, matrilysin (matrix metalloproteinase-7) and human macrophage metalloelastase (matrix metalloproteinase-12) in solar damage. Human macrophage metalloelastase protein was detected in the superficial dermis in areas of elastotic material. Matrix metalloproteinase-7 was seen in the mid-dermis in regions with less damaged elastic fibers and morphologically better preserved collagen as well as in a band-like pattern below basal keratinocytes in eight of 18 solar elastosis. In samples taken from healthy volunteers 3 d after repeated ultraviolet A or ultraviolet B photoprovocation, occasional immunopositive cells for human macrophage metalloelastase (stromal) or matrix metalloproteinase-7 (sweat gland epithelium) were detected. In samples taken 1 d after ultraviolet B exposure, however, basal keratinocytes were matrix metalloproteinase-7 immunopositive, explaining the linear immunostaining below basal keratinocytes noted particularly in ultraviolet B treated 3 d specimens. Upregulation of metalloelastase was also demonstrated in the skin of hairless mice after repeated ultraviolet exposure. In normal skin, no staining for human macrophage metalloelastase or matrix metalloproteinase-7 was observed in association with elastin. The amount of immunoreactivity for the substrates of matrix metalloproteinase-7, versican, and tenascin, was clearly increased in solar elastosis and photoprovocated skin; versican but not tenascin was detected in the same areas as matrix metalloproteinase-7. Our results suggest that both matrix metalloproteinase-7 and -12 may contribute to remodeling of elastotic areas in sun-damaged skin.

Topics: Adult; Aged; Animals; Chondroitin Sulfate Proteoglycans; Elastin; Gene Expression Regulation, Enzymologic; Humans; Keratosis; Lectins, C-Type; Matrix Metalloproteinase 12; Matrix Metalloproteinase 7; Metalloendopeptidases; Mice; Mice, Hairless; RNA, Messenger; Skin; Sunlight; Tenascin; Transforming Growth Factor beta; Ultraviolet Rays; Versicans

To determine whether a functional type II receptor of transforming growth factor beta (TGF-beta) is required to mediate the growth inhibitory effect of TGF-beta on the skin in vivo, we have generated transgenic mice that overexpress a dominant negative-type II TGF-beta receptor (delta beta RII) in the epidermis. The delta beta RII mice exhibited a thickened and wrinkled skin, and histologically the epidermis was markedly hyperplastic and hyperkeratotic. In vivo labeling with BrdUrd showed a 2.5-fold increase in the labeling index over controls, with labeled nuclei occurring in both basal and suprabasal cells of transgenic epidermis. In heterozygotes, this skin phenotype gradually diminished, and by 10-14 days after birth the transgenic mice were indistinguishable from their normal siblings. However, when F1 mice were mated to homozygosity, perinatal lethality occurred due to the severe hyperkeratotic phenotype, which restricted movement. Cultured primary keratinocytes from delta beta RII mice also exhibited an increased rate of growth in comparison with nontransgenic controls, and were resistant to TGF-beta-induced growth inhibition. These data document the role of the type II TGF-beta receptor in mediating TGF-beta-induced growth inhibition of the epidermis in vivo and in maintenance of epidermal homeostasis.

Topics: Amino Acid Sequence; Animals; Animals, Newborn; Cell Division; Cells, Cultured; Epidermis; Epitopes; Female; Genes, myc; Humans; Hypertrophy; Keratinocytes; Keratosis; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Mice, Transgenic; Mitotic Index; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Skin; Skin Aging; Skin Physiological Phenomena; Transforming Growth Factor beta

Superficial dermabrasion has a proven beneficial effect on photoaged skin, but little is known about the differences between the two major modalities used in dermabrasion, the diamond fraise (DF) and the wire brush (WB).. We compared the clinical, immunohistologic, and biochemical changes after superficial dermabrasion with DF and WB.. Eight photoaged patients (mean age, 68 years; range, 49 to 80 years) underwent facial dermabrasion to the level of the papillary dermis. Clinical assessments were performed at baseline and at 3 and 12 weeks after dermabrasion. Biopsy specimens were taken from both dermabraded halves at the same time points and assessed by routine histologic and immunohistologic examinations, western blot analysis, and radioimmunoassay. Scoring of intracellular and extracellular transforming growth factor-beta 1 was based on a semiquantitative ordinal scale (0 = no staining to 4 = maximum staining) in half-unit increments. The score for each specimen represents the average of values obtained from four high-power fields.. Both methods of dermabrasion resulted in significant resolution of actinic keratoses, lentigines, and wrinkling. No statistical significance was noted between the two methods in regard to clinical efficacy. Significantly fewer milia occurred after DF than after WB. Solar elastosis decreased with both the WB and DF. Immunohistologic examination demonstrated a highly significant increase in papillary dermal fibroblast staining for amino terminal procollagen I (type I pN-collagen) at 3 weeks for both DF and WB compared to baseline. Staining at 12 weeks had decreased from the peak noted at week 3, but was still significantly increased from baseline. Western blotting of type I pN-collagen demonstrated a 5.4-fold (p = 0.01) increase from baseline at 3 weeks and a 4.9-fold (p = 0.002) increase at 12 weeks after dermabrasion with the WB. Similarly, the DF produced a 4.9-fold (p = 0.006) increase at 3 weeks and a 5.1-fold (p = 0.008) increase at 12 weeks after dermabrasion. Western blotting of amino terminal procollagen III (type III pN-collagen) showed a 6.1-fold (p = 0.07) increase from baseline at 3 weeks and a 3.9-fold (p = 0.04) increase at 12 weeks after dermabrasion with the DF. The WB showed a 3.8-fold (p = 0.07) increase from baseline at 3 weeks and a 5.1-fold (p = 0.05) increase at 12 weeks. Transforming growth factor-beta 1 demonstrated a significant increase in extracellular staining with DF (3.3 +/- 0.2) and WB (3.7 +/- 0.2) from baseline (1.2 +/- 0.2, p < 0.001) at 3 weeks.. Superficial dermabrasion with DF and WP appears to be similarly efficacious in the treatment of photoaged skin. Significant increases in type I pN-collagen, type III pN-collagen, and TGF-beta 1 occurred in the papillary dermis after both types of dermabrasion. These results suggest that increased fibroblast activity and consequent collagen I and III synthesis underlie the clinical improvement.

Topics: Aged; Aged, 80 and over; Biopsy; Blotting, Western; Dermabrasion; Dermatologic Surgical Procedures; Diamond; Epidermal Cyst; Equipment Design; Face; Fibroblasts; Humans; Immunohistochemistry; Keratosis; Lentigo; Male; Middle Aged; Peptide Fragments; Procollagen; Skin; Skin Aging; Skin Diseases; Transforming Growth Factor beta