Delayed wound closure in fibromodulin-deficient mice is associated with increased TGF-β3 signaling.

Fibromodulin (FMOD), a small leucine-rich proteoglycan, mediates scarless fetal skin wound repair through, in part, transforming growth factor-β (TGF-β) modulation. Using an adult fmod-null (fmod(-/-)) mouse model, this study further elucidates the interplay between FMOD and TGF-β expression during cutaneous repair and scar formation. Full-thickness skin wounds on fmod(-/-) and wild-type (WT) mice were closed primarily and analyzed. Histomorphometry revealed delayed dermal cell migration leading to delayed wound closure and significantly increased scar size in fmod(-/-) mice relative to WT, which was partially rescued by exogenous FMOD administration. In addition, fmod(-/-) wounds exhibited early elevation (within 24  hours post-wounding) of type I and type II TGF-β receptors as well as unexpectedly high fibroblast expression of TGF-β3, a molecule with reported antifibrotic and antimigratory effects. Consistent with elevated fibroblastic TGF-β3, fmod(-/-) fibroblasts were significantly less motile than WT fibroblasts. fmod(-/-) fibroblasts were also more susceptible to migration inhibition by TGF-β3, leading to profound delays in dermal cell migration. Increased scarring in fmod(-/-) mice indicates that TGF-β3's antimotility effects predominate over its antifibrotic effects when high TGF-β3 levels disrupt early fibroblastic wound ingress. These studies demonstrate that FMOD presence is critical for proper temporospatial coordination of wound healing events and normal TGF-β bioactivity.