Inhibition of CCN2/CTGF prevents heterotopic ossification in fibrodysplasia ossificans progressiva.

Abstract

Heterotopic ossification (HO) is the aberrant formation of endochondral bone within soft tissues, triggered by trauma, burns, or the congenital disorder fibrodysplasia ossificans progressiva (FOP). In this study, we demonstrate that mesenchymal progenitors (MPs) harboring the ACVR1^wt/R206H mutation exhibit resistance to apoptosis, likely contributing to their pathological accumulation during FOP flare-ups. Transcriptomic analysis of these mutant MPs reveals dysregulation of genes associated with fibrosis and osteogenic differentiation and elevated expression of matricellular signaling proteins, most notably Ccn2/Ctgf. We further show, using both genetic and pharmacological approaches, that Ccn2 induction in ACVR1^wt/R206H MPs is driven by the cooperative interaction between SMAD1 and YAP-TEAD at the Ccn2 promoter. Osteochondrogenic specification of ACVR1^wt/R206H MPs was blocked by the CCN2-neutralizing antibody pamrevlumab. Moreover, pamrevlumab not only partially suppresses activin A-regulated extracellular matrix organization and transforming growth factor β (TGF-β) family transcriptional programs in mutant MPs but also significantly ameliorates ectopic bone formation in an FOP mouse model. Collectively, these findings identify CCN2/CTGF as a critical mediator of HO and support its inhibition as a potential therapeutic strategy for FOP and disorders characterized by pathological ossification.