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

Abstract

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.

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

“…Activin A as an inflammatory mediator: Activin A is a member of the TGF-β/BMP family of ligands [ 93 ]. Recently, de Ruiter et al discovered that TGF-β1 stimulates the generation of activin A in dermal fibroblasts obtained from FOP patients, as evidenced by an increase in the inhibin subunit beta A ( INHBA ) gene and protein expression levels, functioning as an upstream activator of activin A generation, specifically in FOP [ 94 ]. These findings suggest that TGF-β may be an additional target along with activin A, as its blockade could hinder, at least in part, the signaling cascade concluding in the HO formation arbitrated by activin A in FOP [ 94 ].…”

“…Recently, de Ruiter et al discovered that TGF-β1 stimulates the generation of activin A in dermal fibroblasts obtained from FOP patients, as evidenced by an increase in the inhibin subunit beta A ( INHBA ) gene and protein expression levels, functioning as an upstream activator of activin A generation, specifically in FOP [ 94 ]. These findings suggest that TGF-β may be an additional target along with activin A, as its blockade could hinder, at least in part, the signaling cascade concluding in the HO formation arbitrated by activin A in FOP [ 94 ]. This is in agreement with previous reports implicating the TGF-β pathway as a strong driver of HO, as HO has been shown to be abated following the circulating repression of TGF-β in FOP mouse models [ 63 ].…”