TY - JOUR
T1 - Pro-fibrotic phenotype in a patient with segmental stiff skin syndrome via tgf-β signaling overactivation
AU - Fusco, Carmela
AU - Nardella, Grazia
AU - Augello, Bartolomeo
AU - Boccafoschi, Francesca
AU - Palumbo, Orazio
AU - Fusaro, Luca
AU - Notarangelo, Angelantonio
AU - Barbano, Raffaela
AU - Parrella, Paola
AU - Annicchiarico, Giuseppina
AU - De Meco, Carmela
AU - Micale, Lucia
AU - Graziano, Paolo
AU - Castori, Marco
PY - 2020/7/2
Y1 - 2020/7/2
N2 - Transforming growth factor β (TGF-β) superfamily signaling pathways are ubiquitous and essential for several cellular and physiological processes. The overexpression of TGF-β results in excessive fibrosis in multiple human disorders. Among them, stiff skin syndrome (SSS) is an ultrarare and untreatable condition characterized by the progressive thickening and hardening of the dermis, and acquired joint limitations. SSS is distinct in a widespread form, caused by recurrent germline variants of FBN1 encoding a key molecule of the TGF-β signaling, and a segmental form with unknown molecular basis. Here, we report a 12-year-old female with segmental SSS, affecting the right upper limb with acquired thickening of the dermis evident at the magnetic resonance imaging, and progressive limitation of the elbow and shoulder. To better explore the molecular and cellular mechanisms that drive segmental SSS, several functional studies on patient’s fibroblasts were employed. We hypothesized an impairment of TGF-β signaling and, consequently, a dysregulation of the associated downstream signaling. Lesional fibroblast studies showed a higher phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2), increased levels of nuclear factor-kB (NFkB), and a nuclear accumulation of phosphorylated Smad2 via Western blot and microscopy analyses. Quantitative PCR expression analysis of genes encoding key extracellular matrix proteins revealed increased levels of COL1A1, COL3A1, AGT, LTBP and ITGB1, while zymography assay reported a reduced metalloproteinase 2 enzymatic activity. In vitro exposure of patient’s fibroblasts to losartan led to the partial restoration of normal transforming growth factor β (TGF-β) marker protein levels. Taken together, these data demonstrate that in our patient, segmental SSS is characterized by the overactivation of multiple TGF-β signaling pathways, which likely results in altered extracellular matrix composition and fibroblast homeostasis. Our results for the first time reported that aberrant TGF-β signaling may drive the pathogenesis of segmental SSS and might open the way to novel therapeutic approaches.
AB - Transforming growth factor β (TGF-β) superfamily signaling pathways are ubiquitous and essential for several cellular and physiological processes. The overexpression of TGF-β results in excessive fibrosis in multiple human disorders. Among them, stiff skin syndrome (SSS) is an ultrarare and untreatable condition characterized by the progressive thickening and hardening of the dermis, and acquired joint limitations. SSS is distinct in a widespread form, caused by recurrent germline variants of FBN1 encoding a key molecule of the TGF-β signaling, and a segmental form with unknown molecular basis. Here, we report a 12-year-old female with segmental SSS, affecting the right upper limb with acquired thickening of the dermis evident at the magnetic resonance imaging, and progressive limitation of the elbow and shoulder. To better explore the molecular and cellular mechanisms that drive segmental SSS, several functional studies on patient’s fibroblasts were employed. We hypothesized an impairment of TGF-β signaling and, consequently, a dysregulation of the associated downstream signaling. Lesional fibroblast studies showed a higher phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2), increased levels of nuclear factor-kB (NFkB), and a nuclear accumulation of phosphorylated Smad2 via Western blot and microscopy analyses. Quantitative PCR expression analysis of genes encoding key extracellular matrix proteins revealed increased levels of COL1A1, COL3A1, AGT, LTBP and ITGB1, while zymography assay reported a reduced metalloproteinase 2 enzymatic activity. In vitro exposure of patient’s fibroblasts to losartan led to the partial restoration of normal transforming growth factor β (TGF-β) marker protein levels. Taken together, these data demonstrate that in our patient, segmental SSS is characterized by the overactivation of multiple TGF-β signaling pathways, which likely results in altered extracellular matrix composition and fibroblast homeostasis. Our results for the first time reported that aberrant TGF-β signaling may drive the pathogenesis of segmental SSS and might open the way to novel therapeutic approaches.
KW - Fibrosis
KW - Losartan
KW - Pathogenesis
KW - Stiff skin syndrome
KW - TGF-β
UR - http://www.scopus.com/inward/record.url?scp=85088267352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088267352&partnerID=8YFLogxK
U2 - 10.3390/ijms21145141
DO - 10.3390/ijms21145141
M3 - Article
C2 - 32698527
AN - SCOPUS:85088267352
VL - 21
SP - 1
EP - 19
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 14
M1 - 5141
ER -