Editors' ChoiceBone Biology

Explaining bone overgrowth

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Sci. Signal.  08 Sep 2015:
Vol. 8, Issue 393, pp. ec257
DOI: 10.1126/scisignal.aad3723

Fibrodysplasia ossificans progressiva (FOP) is a rare, but deadly, genetic condition that causes growth of bony structures in place of normally soft tissues, such as muscle and ligaments. The causal mutation occurs in the gene encoding the bone morphogenetic protein (BMP) receptor ACVR1. BMP2 is the natural ligand that activates ACVR1, and activin blocks binding of BMP2 to ACVR1, thereby functioning as an antagonist of this receptor. Hatsell et al. suggest that, instead of activating the receptor, the mutated receptor acquires the ability to respond to activin. When expressed in cultured cells, the mutated ACVR1 responded to activin and BMP, its natural ligand. Expression of the mutated gene in adult mice (to avoid its perinatal lethal effects), the animals developed heterotopic ossification, as occurs in FOP, and this pathological ossification required stimulation by the endogenous ligand activin. Small sponges soaked with activin ossified after they were implanted into the animals. Animals expressing the mutated receptor that were treated with a monoclonal antibody to activin A did not show heterotopic ossification. This mutation-induced change in ligand specificity may explain why the ossification in FOP patients is triggered by injury or trauma to tissues—situations that induce high concentrations of activin.

S. J. Hatsell, V. Idone, D. M. A. Wolken, L. Huang, H. J. Kim, L. Wang, X. Wen, K. C. Nannuru, J. Jimenez, L. Xie, N. Das, G. Makhoul, R. Chernomorsky, D. D’Ambrosio, R. A. Corpina, C. J. Schoenherr, K. Feeley, P. B. Yu, G. D. Yancopoulos, A. J. Murphy, A. N. Economides, ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci. Transl. Med. 7, 303ra137 (2015). [Abstract]