Age-related reduction of dermal fibroblast size up-regulates multiple matrix metalloproteinases as observed in aged human skin in vivo

Summary

Background

Fragmentation of collagen fibrils, the major structure protein in skin, is a hallmark of dermal aging. Matrix metalloproteinases (MMPs) are largely responsible for fragmentation of collagen fibrils. However, the alteration of all known mammalian MMPs and the mechanism underlying altered expression of MMPs in chronologically aged human skin are less understood.

Objectives

To quantify gene expression of all 23 known mammalian MMPs in sun-protected young and aged human skin in vivo, and investigate the potential mechanism underlying age-related alteration of multiple MMPs.

Methods

MMPs mRNA expression levels and MMPs activity in sun-protected young and aged human skin in vivo were determined by real-time RT-PCR and in situ zymography, respectively. The relative contributions to elevated MMPs in epidermis and dermis were quantified by laser capture microdissection (LCM) coupled real-time RT-PCR. Dermal fibroblast morphology and collagen fibrils fragmentation in human skin in vivo were assessed by second harmonic generation microscopy and atomic force microscopy, respectively. In vitro cell morphology was assessed by CellTracker^® fluorescent dye and Phalloidin staining. Protein levels were determined by ProteinSimple capillary electrophoresis immunoassay.

Results

Among all 23 known mammalian MMPs, multiple MMPs are elevated in aged human skin dermis. Consistent with this finding, increased MMPs activity and collagen fibrils fragmentation were observed in aged skin dermis. As dermal fibroblasts are the major MMPs producing cells in the dermis, reduction of dermal fibroblast size, which is observed in aged human skin, contributes to elevation of age-related multiple MMPs. Reduction of fibroblast size up-regulates c-Jun/c-Fos and activates AP-1, the major regulator of multiple MMPs.

Conclusions

Combined actions of the wide variety of MMPs that are constitutively elevated in aged dermis may be involved in progressive degradation of dermal collagen fibrils. Age-related elevations of multiple MMPs are likely resulted from the reduction of fibroblast size via activation of AP-1.

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