Signal Transduction: Gain of Activin Turns Muscle into Bone Gonzalo Sanchez-Duffhues, Theodore Fotsis, Peter ten Dijke  Current Biology  Volume 25, Issue 23, Pages R1136-R1138 (December 2015) DOI: 10.1016/j.cub.2015.10.005 Copyright © 2015 Elsevier Ltd Terms and Conditions

Figure 1 Heterotopic ossifications found in FOP patients are similar to those observed in a mouse FOP model. (A) Photo of the skeleton of a man with FOP, from the collections of the Anatomical Museum of the Leiden University Medical Center (LUMC). This photo has been reproduced with permission of LUMC (copyright belongs to LUMC). (B,C) Representative example of in vivo CT images from (B) wild-type mouse and (C) mutant mouse that express the mutant BMP type I receptor ALK2 R206H that is most prevalent among FOP patients. Systemic tamoxifen administration is used for Cre-dependent exchange of the mouse for the corresponding human R206H-encoding exon. Images were taken 4 weeks after tamoxifen treatment of adult mice. Excessive extraneous bone formation in the ALK2 R206H knock-in mouse is highlighted in yellow. Images were generously provided by Dr. A. Economides, Regeneron Pharmaceuticals, Inc., Tarrytown, USA. Current Biology 2015 25, R1136-R1138DOI: (10.1016/j.cub.2015.10.005) Copyright © 2015 Elsevier Ltd Terms and Conditions

Figure 2 A single amino acid change, R206H, in ALK2 converts this BMP receptor into a signaling receptor for the inflammatory cytokine activin, which could be released upon local soft tissue injury. (A) BMP signals through BMP type II and type I receptors. There are three BMP type II receptors, of which activin type II and IIB receptors are shared with activin. ALK2 is one of the four signaling BMP type I receptors to which activin can also bind, but without mediating intracellular SMAD1/5 activation. Activin signals via ALK4-SMAD2/3 (not shown) and inhibits BMP signaling by competing with BMPs for receptor binding. In FOP cells that express mutant R206H ALK2, activin now induces (instead of antagonizing) SMAD1/5 signaling and selective BMPs become more potent. (B) Schematic presentation of potential therapeutic strategies by normalizing the aberrant functions of ALK2 R206H. An activin neutralizing antibody and activin (and BMP) ligand traps ActRIIA-Fc or ActRIIB-Fc and ALK2 kinase inhibitors (LDN-193189, LDN-212854) have been shown to inhibit heterotopic ossification in FOP mouse models. Therapeutic agents that have been shown to stimulate normal bone formation by inhibiting activin, such as activin pro-domains (and also ActRII-Fc), and natural activin antagonists follistatin and inhibin, may now be paradoxically explored for inhibiting heterotopic ossification in FOP. Suppression of the inflammation is currently used to treat FOP patients and antagonizing the ectopic bone formation by the selective retinoic acid receptor gamma (RAR-γ) agonist Palovarotene is currently being evaluated for potential FOP treatment. Current Biology 2015 25, R1136-R1138DOI: (10.1016/j.cub.2015.10.005) Copyright © 2015 Elsevier Ltd Terms and Conditions