Interplay of Iron Metallobiology, Metalloproteinases, and FXIII, and Role of Their Gene Variants in Venous Leg Ulcer

The iron metallobiology has long been suspected as a causal agent in venous leg ulcer (VLU) pathophysiology. However, it was demonstrated only recently that visible iron deposits cause lesions in only some individuals due to functional iron and related gene variants. In this article, the mechanism by which dysregulated iron cycle leads to local iron overload that could generate free radicals or activate a proteolytic hyperactivity on the part of matrix metalloproteinases (MMPs) or else downregulate tissue inhibitors of MMPs is reviewed. Also reviewed is the interplay of other vital factors such as coagulation factor XIII (FXIII), which influences tissue remodeling and angiogenesis, leading to impaired healing of the lesion, whether there exists altered interaction with MMPs or in presence of particular unfavorable single nucleotide polymorphisms.