The major
pathological processes of
systemic scleroderma (SSc) comprise
inflammation and microvascular damage in the early or acute progressive stage as well as tissue
fibrosis and
hypoxia in the chronic end stage.
Fibrosis seems to be a general phenomenon characterized by an increase of
hydroxylysine aldehyde derived
collagen cross-links which has been shown in vitro for
systemic scleroderma fibroblasts. In the present study, we analyzed the cross-link pattern and the gene expression of
lysyl hydroxylase 2 (LH2) in the skin of SSc. Furthermore, we determined the modulatory impact of inflammatory
cytokines (
interleukin 4, TNF- alphaand
interleukin 1alpha/beta) and prolonged
hypoxia on the cross-link profile and the gene expression of LH2, respectively. The concentration of
hydroxylysine aldehyde derived cross-links was significantly increased in SSc, while the level of
lysine aldehyde derived cross-links was not changed. Accordingly, a marked increase of the transcriptional level of LH2 was found. In long term dermal fibroblast cultures, only
interleukin 4 induced an increase of
hydroxylysine aldehyde derived cross-links accompanied by a higher gene expression of LH2. Furthermore, prolonged
hypoxia induced a marked increase of the
mRNA level of LH2 in relation to
collagen I. The skin of SSc is characterized by an increase of the transcriptional activity of LH2 leading to an altered cross-link pattern. The changes in the quality of the collagenous matrix can also be obtained in cell culture by the exposure of fibroblasts to
interleukin 4 or prolonged
hypoxia emphasizing the role of this mediator in the acute and the low
oxygen tension in the chronic phase of the disease.