Background Gremlin-1 is BMP antagonist that mediates its effects through negative regulation of BMP signalling. BMP signalling is important in development and has been found to be deregulated in various rheumatic diseases. It also has BMP-independant effects that are poorley described. Systemic sclerosis is an autoimmune disease that results in fibrosis of the skin and internal organs. We have previously found elevated levels of gremlin-1 in systemic sclerosis skin biopsies compared to controls. Gremlin-1 genetically reduced mice are protected from kidney fibrosis. It is suggested that fibrosis may be associated with reactivation of development programs.
Objectives The aim of this work was to measure the levels of gremlin-1 and to determine its effects on dermal fibroblasts.
Methods Skin biopsies were taken from systemic sclerosis patients and analysed by PCR for gremlin-1 and 18S as the housekeeing gene. Bleomycin was injected into mice and skin fibrosis developed, control mice received saline. Biopsies were taken and fixed and processed. Laser capture was used to dissect the tissue using a guided laser. Dissected tissue was processed for RNA and qPCR was performed for gremlin-1 and collagen-1. C-Myc tagged human Gremlin-1 was cloned into a vector and empty vector was transfected into human fibroblasts and HEKs. After transfection collagen and alpha-Smooth muscle actin was measured.
Results Elevated levels of gremlin-1 was found in systemic sclerosis skin biopsies. We also found elevated levels of gremlin-1 in skin sections from an animal model of fibrosis, the bleomycin model. Laser capture microdissection found that this was in the dermal proportion of skin and not in the epithelial section. Overexpression of gremlin-1 in a vector system in dermal fibroblasts showed elevated levels of collagen, but not alpha-smooth muscle actin.
Conclusions Gremlin-1 is dsyregulated in systemic sclerosis and in the bleomycin model of fibrosis. Overexpressing gremlin-1 induced higher levels of collagen. Targeting gremlin-1 may represent a novel target in systemic sclerosis.
Disclosure of Interest None declared