An inducible knock-in mouse model of fibrodysplasia ossificans progressiva shows spontaneous formation of heterotopic ossification

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder caused by mutations in ACVR1, most commonly the R206H variant. These mutations lead to heterotopic ossification (HO) in soft tissues, such as muscles, tendons, and ligaments. While people with FOP appear healthy at birth, they progressively develop HO starting in childhood, resulting in severe disabilities. Heterotopic ossification can be triggered by injuries, flare-ups, or occur spontaneously, and currently, there are limited medical or surgical treatment options available. To address these challenges, we generated a novel inducible Acvr1R206H knock-in mouse model (C57BL/6 background) that accurately replicates both injury- and non-injury-induced (spontaneous) HO. This model was engineered using an inducible CreERT2 system to express the R206H mutation following Cre-mediated recombination. As expected, muscle injury in these mice resulted in the formation of HO via endochondral ossification, a process in which cartilage is converted into bone. When induced by doxycycline administration employing the rt;tetO-Cre system the same Acvr1ARC-R206H floxed allele also led to the development of similar HO upon muscle injury. Furthermore, we developed a protocol to induce non-injury-induced HO in these mice and determined that HO progresses more slowly in the absence of injury. This mouse model holds great potential as a valuable tool to explore cellular processes underlying disease progression and to serve as pre-clinical model to test the efficacy of therapeutic interventions aimed at preventing HO in FOP.