Cell type-specific inhibition of keratinocyte collagenase-1 expression by basic fibroblast growth factor and keratinocyte growth factor. A common receptor pathway.

Howard G Welgus,Brian K Pilcher,William C Parks,Jennifer Gaither-Ganim

doi:10.1074/jbc.272.29.18147

Howard G Welgus, Brian K Pilcher + Show 2 more

Open Access

https://doi.org/10.1074/jbc.272.29.18147

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Abstract

Collagenase-1 is invariantly expressed by migrating basal keratinocytes in all forms of human skin wounds, and its expression is induced by contact with native type I collagen. However, net differences in enzyme production between acute and chronic wounds may be modulated by soluble factors present within the tissue environment. Basic fibroblast growth factor (bFGF, FGF-2) and keratinocyte growth factor (KGF, FGF-9), which are produced during wound healing, inhibited collagenase-1 expression by keratinocytes in a dose-dependent manner. However, KGF was >100-fold more effective than bFGF at inhibiting collagenase-1 expression, suggesting that this differential signaling is transduced via an FGF receptor that binds these ligands with different affinities. Reverse transcriptase-polymerase chain reaction analysis of human keratinocyte mRNA for fibroblast growth factor receptors (FGFRs) revealed expression of only FGFR-2 IIIb, the KGF-specific receptor, which also binds bFGF with low affinity, and FGFR-3 IIIb, which does not bind bFGF or KGF. FGFRs that bind bFGF with high affinity were not detected. Our results suggest that bFGF and KGF inhibit collagenase-1 expression through the KGF cell-surface receptor (FGFR-2 IIIb). Because bFGF induces collagenase-1 in most cell types, cell-specific expression of FGFR family members may dictate the regulation of matrix metalloproteinases in a tissue-specific manner.

Highlights

Collagenase-1 is invariantly expressed by migrating basal keratinocytes in all forms of human skin wounds, and its expression is induced by contact with native type I collagen
We have demonstrated that collagenase-1 expression by basal keratinocytes is induced following contact with native type I collagen,2 and the activity of this enzyme is required for cell migration [9]
To assess if bFGF modulates keratinocyte collagenase-1 production, cells were exposed to increasing concentrations of growth factor for 72 h, and collagenase-1 accumulation in the medium was quantified by Enzyme-linked Immunosorbent Assay (ELISA)

Summary

A COMMON RECEPTOR PATHWAY*

Collagenase-1 is invariantly expressed by migrating basal keratinocytes in all forms of human skin wounds, and its expression is induced by contact with native type I collagen. We have demonstrated that collagenase-1 expression by basal keratinocytes is induced following contact with native type I collagen, and the activity of this enzyme is required for cell migration [9]. KGF is expressed exclusively by cells of mesenchymal origin, such as fibroblasts [24] and microvascular endothelial cells [25], yet it influences epithelial cells by a paracrine signaling mechanism [24, 26, 27] Both bFGF and KGF are expressed during epidermal wound repair [28, 29], and topical application of bFGF to wounds accelerates healing [30]. BFGF and KGF inhibition of keratinocyte collagenase-1 expression probably occurs exclusively through the KGF (FGFR-2 IIIb) receptor

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION