TGF-Beta Induces Activin A Production in Dermal Fibroblasts Derived from Patients with Fibrodysplasia Ossificans Progressiva

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 TGF beta 1 to be an FOP-specific stimulant of Activin A, shown by the upregulation of the INHBA gene and protein expression. Activin A and TGF beta 1 were both induced by BMP4 in FOP and control fibroblasts. Treatment with TNF alpha and IL6 produced negligible levels of Activin A and TGF beta 1 in both cell groups. We present for the first time TGF beta 1 as a triggering factor of Activin A production in FOP. As TGF beta 1 can promote the induction of the main driver of FOP, TGF beta 1 could also be considered a possible therapeutic target in FOP treatment.

Automated summary

FOP is an ultra-rare disease caused by genetic defects in the ACVR1 gene. We found that FOP patients have elevated Activin A production in their fibroblasts, and TGF beta 1 is a specific stimulant of Activin A in FOP. This study is the first to identify TGF beta 1 as a triggering factor of Activin A production in FOP, suggesting it as a possible therapeutic target.