ECTS Abstracts (2015) 1 P396

Inhibition of TGF[beta] Signalling Delays Ossification in Patients with Fibrodysplasia Ossificans Progressiva

Dimitra Micha1, Elise Voermans1,2, Huib W van Essen2, Jesse Drukker1,2, Coen Netelenbos2, Marelise E W Eekhoff2, Gerard Pals1 & Nathalie Bravenboer2


1VU University Medical Center, Clinical Genetics department, Amsterdam, North Holland, The Netherlands; 2VU University Medical Center, Endocrinology department, MOVE Research Institute, Amsterdam, North Holland, The Netherlands.


Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterised by progressive heterotopic ossification. FOP patients only present great toe malformations at birth. However, as they grow older they develop soft tissue lumps as a result of flare-ups causing the irreversible replacement of skeletal muscle tissue with bone tissue leading to cumulative physical immobility. Classical FOP patients possess a mutation (c.617G>A; R206H) in the activin receptor IA (ACVR1)-encoding gene which is associated with dysregulated bone morphogenetic protein (BMP) signalling. Nonetheless, not all FOP patients with this mutation exhibit equal severity in symptom presentation or disease progression, which indicates a strong contribution by environmental factors. Although inflammation is known to be the main trigger of flare-ups the molecular pathway remains largely unknown. Our objective was to study the process of osteogenic differentiation in primary dermal fibroblasts from five FOP patients based on a novel method of growth factor-induced osteogenic transdifferentiation. In all patients, the presence of the classical FOP mutation was confirmed. The osteogenic properties of the cells were evaluated by the mRNA expression of Runt-related transcription factor 2 (Runx2), alkaline phosphatase (Alp), osteocalcin (OC) and the presence of mineralization by Alizarin Red staining. Given the pro-inflammatory role of TGFβ, we also performed pharmacological inhibition of TGFβ signalling by the TGFβ type I receptor inhibitor GW788388. During osteogenic transdifferentiation the expression of Runx2 and Alp over time was higher in FOP cell lines compared to heathy controls (Runx2:p=0.001; Alp:p>0.05). All cell lines exhibited increase in mineralization. Addition of the inhibitor to the osteogenic media resulted in the attenuation of osteogenic differentiation shown by the decrease in expression of osteogenic markers in patients vs untreated cells (Runx2:p=0.045) and mineralisation. We suggest that TGFβ is involved in the molecular pathway of flare-up-induced ossification. Inhibition of this pathway may limit ectopic ossification in FOP.

Disclosure: The authors declared no competing interests.

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