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Abstract Oral isotretinoin in low doses is an effective treatment for facial wrinkling, seemingly with less irritancy than tretinoin . The mechanism of action is related to an increase in the production of collagen. Retinoids are also thought to act by inhibiting metalloproteinases leading to decreased collagen destruction especially collagen types I and III. Matrix metalloproteinases (MMPs) are zinc dependant endopeptidases, which degrades ECM, twenty five members have been discovered till now. MMPs not only degrade the structural components of the ECM in normal and diseased tissues but also many of the growth factors, cytokines, membrane bound precursors, cell adhesion molecules are substrates for MMPs, in addition to cleavage or activation of their zymogen forms. MMPs are not continuously expressed and their activity is regulated at three levels which are: a) gene expression via cytokines, growth factors, b) proenzyme activation and c) inhibition of the active enzyme by endogenous inhibitors (TIMP-1, TIMP-2, TIMP-3, and Summary & Conclusion -175- TIMP-4). There is a tightly regulated balance between these enzymes and their inhibitors. MMP-1 is commonly known as collagenase or collagenase-1. It is being referred to also as fibroblast collagenase or interstitial collagenase. MMP-1 is the only enzyme able to initiate breakdown of the interstitial collagens; collagen type I, collagen type II, and collagen type III .MMP-1 is produced by various types of cells in vitro and in vivo and its expression has been associated with inflammation, wound healing, and tumor invasion, growth, and metastasis . Isotretinoin has been reported to affect MMPs. However, the various reports are contradictory, since there is evidence suggesting that retinoids increase, reduce, or do not affect MMPs. This study was carried for assessment and studying effect of isotretinoin treatment on MMP-1 protein expression in skin. All specimens that were taken after isotretinoin treatment showed a significant increase in MMP- 1 protein expression in both epidermis (in the cytoplasm of most of the keratinocytes) and dermis (in the dermal matrix and the cytoplasm of most fibroblasts). There was also significant Summary & Conclusion -176- increase in epidermal thickness, a significant decrease in number of melanocytes , a significant increase in the collagen fiber content in the papillary dermis and prominent increase in oxytalan fibers in the papillary dermis in most areas. This indicates regeneration of elastic fibers in most areas of papillary dermis. Furthermore, there was a significant positive correlation between MMP-1 protein expression and collagen content in the papillary dermis. The apparent paradox between increased MMP-1 activity which degrade ECM and increased collagen and elastic fiber content may be difficult to interpret. One possibility is that other MMP-1 may not be affected in the same way and may be of more relevance in the collagen balance. Moreover, quantitative measurement by immunohistochemistry may not be an accurate reflection of the functional activity of the enzyme. On the same basis, altered structure of collagen (probably drug-induced) may render it less susceptible to the destructive effect of MMP in spite of increased levels of the latter in the skin. Also, the increased MMP-1 expression may be an event secondary to increased collagen production. Another speculation may be related to the exact type of collagen deposited. MMP-1 seems to be most active on type III collagen more efficiently than type I or II collagen. MMP-1 Summary & Conclusion -177- has not significant activity against type II and IV collagen, while our study did not determine the exact type of collagen deposition. Moreover, the effect may be dose dependent with inhibition of MMP-1 to a minor degree and increased collagen production to a higher degree. Further studies should be done to determine the exact role of isotretinoin on different types and functions of MMPs and their inhibitors (TIMPs) |