Background: Fibrodysplasia Ossificans Progressiva (FOP) is a genetic disease characterized by heterotopic ossification (HO). The disease is caused by a mutation in the Activin receptor type 1 (ACVR1) gene, resulting in highly enhanced responsiveness to ligands including Activin-A. Binding of Activin-A to the mutated ACVR1 receptor induces osteogenic differentiation in osteoblast-like cells. The metabolism and composition of HO formed in FOP patients is comparable to skeletal bone in healthy subjects. Bone remodeling requires the coupled action of osteoblast and osteoclast activity. Whether this coupling is affected in FOP is unknown.

Objective: To investigate the effect of the FOP mutation and Activin-A on osteoclast formation.

Methods: Periodontal ligament fibroblasts (PLF) induced osteoclast formation was studied by coculturing control and FOP PLF with CD14-positive (CD14+) osteoclast precursors from healthy donors without or with Activin-A. Gene expression and osteoclast formation was assessed. Osteoclast formation in a monoculture was performed by culturing control and FOP CD14+ cells in the presence of M-CSF and RANKL without or with Activin-A. Cell proliferation and osteoclast formation was analyzed.

Results: Activin-A inhibited osteoclast formation induced by control and FOP PLFs. In these cultures Activin-A downregulated M-CSF and DC-STAMP expression. Similarly Activin-A inhibited osteoclastogenesis in monocultures from control and FOP CD14+ cells. This inhibition was probably due to a decreased proliferation of the CD14+ cells.

Conclusion: Our study shows that Activin-A can inhibit osteoclast formation both in a PLF induced coculture system as well as in an M-CSF and RANKL induced CD14+ monoculture system. This inhibition seems to be mediated via a direct effect on the osteoclast precursors regardless of the presence of the FOP mutation.