Keloids represent a dysregulated cutaneous wound healing process characterized by abnormal proliferation of fibroblasts and excessive deposition of collagen and can form after burns or other skin injuries. Keloid fibroblasts are the primary cells involved in the formation of the wound healing scar, and their elevated proliferation and limited apoptosis lead to excess scarring.  

LY2109761, a transforming growth factor- (TGF-) β receptor inhibitor, reduces tumour cell growth, intravasation, and the metastatic dissemination of hepatocellular carcinoma (HCC) cells through different molecular mechanisms. It also inhibits human hypertrophic scar formation.   

GDF- 9 promoted fibroblast proliferation and migration in keloids via the Smad2/3 pathway, while others have demonstrated that TGF-β/Smad signaling plays an essential role in the development of keloids. In the present study, we focused on changes in the Smad2/3 signaling pathway in response to LY2109761 treatment. When keloid-derived fibroblasts are treated with two concentrations of LY2109761 (5 and 10 μM). The effect of LY2109761 on keloid-derived fibroblast proliferation and apoptosis, suppression of the TGF-β/Smad signaling pathway, and expression of key factors involved in keloid formation was assessed.  

Based on the report which shows that LY2109761 inhibited the Smad signaling pathway in human tumor models it was hypothesized that a similar mechanism was involved in the suppression of keloid-derived fibroblast secretion and proliferation, as well as in the activation of apoptosis. Activated forms of Smad2 and Smad3, p-Smad2 and p-Smad3, were significantly downregulated at 48 h after LY2109761 treatment in a dose-dependent manner.

Silencing of the TGF-β family member GDF-9 in keloid-derived fibroblasts downregulated p-Smad2 and p-Smad3. However, silencing of GDF-9 had no effect on the expression of TGF-β1, LY2109761 clearly suppressed TGF-β1 expression but upregulated GDF-9 expression. Possible reason for this is that GDF-9, as one of the ligands of TGF-β receptors, is produced more to antagonize the inhibitory effect of TGF-β signaling pathway.

The overall effect of LY2109761 on keloid fibroblasts is inhibition, even though GDF-9 was partially elevated. Existing evidence indicates that regulation of TGF-β receptors is a key factor associated with keloid pathogenesis. TGF-β1 is involved in the formation of keloids, and normal fibroblasts produce up to 12-fold higher levels of collagen following treatment with TGF-β1.

Another study also showed that interactions between the TGF-β/Smad and Wnt/β-catenin pathways were associated with the formation of keloids and hypertrophic scars

Source: Anal Cell Pathol (Amst). 2021; 2021: 8883427.