Hypertrophic scarring (HS) is an overcompensation of wound healing that increases the risk of cosmetic disfigurement and functional impairment. No gold standard has been established for the treatment or prevention of HS. Our study aims to elucidate the expression and function of lumican in the pathogenesis of HS as well as the underlying mechanism involved in this procedure. An animal model of HS (rabbit ear) was established, and the Ad-lumican vectors were locally injected. Primary fibroblasts isolated from patients with hypertrophic burn scars were used in vitro. Histological and molecular changes in HS pathogenesis were evaluated. The results showed that lumican is significantly reduced in HS tissues and fibroblasts from HS patients as compared to normal skin or cells. Lumican levels were further suppressed in response to TGF-beta stimulation. However, lumican upregulation effectively thinned the scar area and inhibited fibroblast proliferation and the cell cycle. Meanwhile, Ad-lumican administration suppressed the deposition of extracellular matrix, such as collagen and CTGF. Ad-lumican injected animals or fibroblasts presented comparable integrin alpha(2)beta(1) expression while greatly reduced phosphorylation of FAK compared to the negative control. Moreover, Ad-lumican administration largely enhanced the binding of lumican to integrin alpha(2)beta(1) and may thus inhibit the signaling propagation of collagen-integrin alpha(2)beta(1). Overall, the restoration of lumican levels contributed to suppressing the HS progression by inhibiting collagen-integrin alpha(2)beta(1)-FAK signaling. (C) 2016 Elsevier Inc. All rights reserved.