Matrix Metalloproteinases of Epithelial Origin in Facial Sebum of Patients with Acne and their Regulation by Isotretinoin

Abstract

Acne vulgaris is a skin disorder of the sebaceous follicles, involving hyperkeratinization and perifollicular inflammation. Matrix metalloproteinases (MMP) have a predominant role in inflammatory matrix remodeling and hyperproliferative skin disorders. We investigated the expression of MMP and tissue inhibitors of MMP (TIMP) in facial sebum specimens from acne patients, before and after treatment with isotretinoin. Gelatin zymography and Western-blot analysis revealed that sebum contains proMMP-9, which was decreased following per os or topical treatment with isotretinoin and in parallel to the clinical improvement of acne. Sebum also contains MMP-1, MMP-13, TIMP-1, and TIMP-2, as assessed by ELISA and western blot, but only MMP-13 was decreased following treatment with isotretinoin. The origin of MMP and TIMP in sebum is attributed to keratinocytes and sebocytes, since we found that HaCaT keratinocytes in culture secrete proMMP-2, proMMP-9, MMP-1, MMP-13, TIMP-1, and TIMP-2. SZ95 sebocytes in culture secreted proMMP-2 and proMMP-9, which was also confirmed by microarray analysis. Isotretinoin inhibited the arachidonic acid-induced secretion and mRNA expression of proMMP-2 and -9 in both cell types and of MMP-13 in HaCaT keratinocytes. These data indicate that MMP and TIMP of epithelial origin may be involved in acne pathogenesis, and that isotretinoin-induced reduction in MMP-9 and -13 may contribute to the therapeutic effects of the agent in acne.

Isotretinoin treatment reduces acne lesions but not directly lesional acne inflammation

“…In addition, retinoids inhibit inflammatory Th17 and promote regulatory T-cell (Treg) responses (7). Isotretinoin treatment also downregulates the expression of matrix metalloproteinases 9 and 13, which play a central role in inflammatory matrix remodelling (8). Furthermore, all retinoids stimulate the release of IL-10, granulocyte-macrophage-stimulating factor (GM-CSF) and monocyte chemotactic protein-1 (MCP-1) by monocytes and macrophages in vitro (9).…”

Augmentation of Gene Expression and Production of Promatrix Metalloproteinase 2 by Propionibacterium acnes-Derived Factors in Hamster Sebocytes and Dermal Fibroblasts: A Possible Mechanism for Acne Scarring

“…10) Recently, we have reported that hamster sebocytes constitutively produce proMMP-2, which is immunologically similar to human proMMP-2. 20) In the present study, we demonstrated that hamster dermal fibroblasts as well as sebocytes constitutively and transcriptionally produced proMMP-2 (Figs.…”

“…We have also confirmed that gelatinolytic activity at approximately 92 kDa, which might correspond to proMMP-9, was negligible in sebocytes and dermal fibroblasts (data not shown). Since keratinocytes, monocytes, and dermal fibroblasts in hu-mans play important roles for MMP-mediated cutaneous ECM degradation in acne, 10,11,17,18) these results suggest that hamster sebocytes as well as dermal fibroblasts are useful for the investigation of sebaceous and pilosebaceous ECM remodeling in acne lesion.…”

“…9) Regarding the relationship between MMPs and acne pathology, Papakonstantinou et al 10) reported the existence of MMP-9/gelatinase B and MMP-13/collagenase 3 in sebum obtained from acne patients. In addition, a DNA microarray by Trivedi et al 11) revealed that gene expression and production of MMP-1/collagenase 1 are up-regulated in the skin from acne patients.…”

Differential Expression of Matrix Metalloproteinases in the Serum of Patients with Mucopolysaccharidoses

“…The gelatinolytic activity of MMPs was determined by gelatin zymography analysis using sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) under denaturing but nonreducing conditions (Papakonstantinou et al 2005). In brief, 10 ml of serum samples from patients and healthy subjects were diluted 1:100 and 6 ml of the diluted samples were applied on an 8% SDS-PAGE containing 0.1% gelatin (25 mA, 2 h, at room temperature).…”