Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event.

Photobiomodulation with Red and Near-Infrared Light Improves Viability and Modulates Expression of Mesenchymal and Apoptotic-Related Markers in Human Gingival Fibroblasts

“…The third photobiomodulation resulted in the downregulation, similar to CD90 . Endoglin, or CD105 , is a type III coreceptor for TGF-β1, and its overexpression in fibroblasts was reported to affect physiological Smad/Alk1/Alk5 signaling to suppress the synthesis of TGF-β1 and extracellular matrix (ECM) proteins [ 60 ]. Endoglin may induce fibrosis development in different tissues, and its expression is higher in fibroblasts from fibrotic tissue than in non-fibrotic tissue [ 61 ].…”

Raloxifene inhibits the overexpression of TGF-β1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis

“…However, validation of this hypothesis requires additional molecular and biomechanical studies of the cartilage. Furthermore, RAL was shown to decrease the level of TGF-β1 by downregulating ALK1 in human fibroblasts in skin disease [ 49 ]. Nevertheless, it is not known whether RAL has a similar effect on the cartilage in osteoporotic OA.…”

Therapy Development for Epidermolysis Bullosa

“…A key player in EB-associated fibrosis is TGF-ß, a pro-inflammatory cytokine whose pleiotropic effects are highly contextdependent, and which has been shown to be constitutively expressed in RDEB-skin [83,84]. While TGF-ß1 promotes wound healing under normal conditions, excessive TGF-ß1 signaling leads to abnormal ECM deposition and scar formation, as confirmed in a type VII collagen hypomorphic mouse model [85,86]. Thus, modulating the expression of TGF-ß1 was hypothesized to be beneficial in reducing fibrosis.…”

“…In a drug repurposing approach, endoglin (CD105), a type III co-receptor for TGF-1, and raloxifene, an estrogen receptor modulator, were tested in a pre-clinical setting for their potential to attenuate RDEB-associated fibrosis. Indeed, both drugs were shown to modulate profibrotic events, rendering them potential candidates for repositioning both compounds for the treatment of patients with EB [86].…”