TY - JOUR
T1 - TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva
AU - de Ruiter, Ruben D.
AU - Wisse, Lisanne E.
AU - Schoenmaker, Ton
AU - Yaqub, Maqsood
AU - Sánchez-Duffhues, Gonzalo
AU - Eekhoff, E. Marelise W.
AU - Micha, Dimitra
N1 - Funding Information: GSD is sponsored by Fundació La Marató de TV3 (#202038) and the Spanish Ministry of Science through the Ramón y Cajal grant RYC2021-030866-1. Publisher Copyright: © 2023 by the authors.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFβ1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFβ1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFβ1 in both cell groups. We present for the first time TGFβ1 as a triggering factor of Activin A production in FOP. As TGFβ1 can promote the induction of the main driver of FOP, TGFβ1 could also be considered a possible therapeutic target in FOP treatment.
AB - Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the ACVR1 gene. The mutant ACVR1 receptor, when triggered by an inflammatory process, leads to heterotopic ossification of the muscles and ligaments. Activin A has been discovered as the main osteogenic ligand of the FOP ACVR1 receptor. However, the source of Activin A itself and the trigger of its production in FOP individuals have remained elusive. We used primary dermal fibroblasts from five FOP patients to investigate Activin A production and how this is influenced by inflammatory cytokines in FOP. FOP fibroblasts showed elevated Activin A production compared to healthy controls, both in standard culture and osteogenic transdifferentiation conditions. We discovered TGFβ1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGFβ1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNFα and IL6 produced negligible levels of Activin A and TGFβ1 in both cell groups. We present for the first time TGFβ1 as a triggering factor of Activin A production in FOP. As TGFβ1 can promote the induction of the main driver of FOP, TGFβ1 could also be considered a possible therapeutic target in FOP treatment.
KW - ACVR1
KW - BMP
KW - TGF-beta
KW - activin A
KW - cytokines
KW - fibroblasts
KW - fibrodysplasia ossificans progressiva
KW - heterotopic ossification
KW - inflammation
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U2 - https://doi.org/10.3390/ijms24032299
DO - https://doi.org/10.3390/ijms24032299
M3 - Article
C2 - 36768622
SN - 1661-6596
VL - 24
SP - 1
EP - 14
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 3
M1 - 2299
ER -