Name: Atebrioz (zilurgisertib) in Fibrodysplasia ossificans progressiva: Pathophysiology
Published: 2026-09-27T12:28:00-04:00

Constitutive and ligand-hyperresponsive ACVR1 signaling

“Protein modeling predicted destabilization of the GS domain, consistent with enhanced activation of ACVR1 signaling as the underlying pathogenesis of the ectopic chondrogenesis, osteogenesis, and joint fusion of FOP” (opens the source at this quote in a new tab)
“The GS domain is a specific binding site for FKBP12, a highly conserved inhibitory protein that prevents leaky activation of type I receptors in the absence of ligand.” (opens the source at this quote in a new tab)

Aberrant responsiveness of mutant ACVR1 to activin A

“We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation.” (opens the source at this quote in a new tab)
“When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A.” (opens the source at this quote in a new tab)

“Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling.” (opens the source at this quote in a new tab)

“recent data suggest that ACVR1[R206H] activation by activin A induces receptor clustering, homo-oligomerization, and autophosphorylation, thus triggering dysregulated BMP pathway signaling” (opens the source at this quote in a new tab)

Endochondral sequence of heterotopic bone formation

“Early pre-osseous FOP lesions consist of an intense aggregation of mononuclear inflammatory cells including lymphocytes, macrophages, and mast cells in the perivascular spaces of edematous muscle” (opens the source at this quote in a new tab)
“Following the catabolic phase of muscle cell death, a highly anabolic fibroproliferative phase (often mistaken for aggressive juvenile fibromatosis) consists, in part, of Sca1+/PDGFRα+/Tie2+/CD34- fibroadipogenic progenitor (FAP) cells that differentiate through an endochondral pathway into mature heterotopic bone” (opens the source at this quote in a new tab)

Role of inflammation and triggers

“Loss of autoinhibition of the mutant receptor results in dysregulated BMP pathway signaling and is necessary for the myriad developmental features of FOP but may not be sufficient to induce the episodic flare-ups that lead to disabling post-natal HO and that are a hallmark of the disease. Evidence from all levels of investigation in humans and animal models strongly support that the innate immune system plays a key role in inducing episodes of HO.” (opens the source at this quote in a new tab)

“depletion of mast cells or macrophages impairs injury-induced HO in Acvr1[R206H/+] mice and reduces HO volume by <50% with depletion of each cell population independently and ~75% with combined depletion of both cell populations” (opens the source at this quote in a new tab)

Hypoxia and mTOR signaling amplify BMP pathway activity

“Hypoxia-inducible factor-1α (HIF-1α) integrates the cellular response to both hypoxia and inflammation and increases the intensity and duration of BMP signaling in FOP. Inhibition of HIF-1α by genetic or pharmacologic means restores BMP signaling to normoxic levels in human FOP cells and profoundly reduces HO in a constitutively active Acvr1[Q207D/+] mouse model of FOP” (opens the source at this quote in a new tab)
“a mechanistic target of rapamycin (mTOR) signaling upstream of HIF-1α was identified as a critical pathway for hypoxia sensing in the aberrant chondrogenesis of FOP and unveiled a crucial role of the mTOR axis in FOP pathogenesis” (opens the source at this quote in a new tab)

Tissues spared from heterotopic ossification

“Several skeletal muscles including the diaphragm, intrinsic muscles of the tongue, and extra-ocular muscles are spared from HO in FOP. Cardiac muscle and smooth muscle are also notably spared from HO” (opens the source at this quote in a new tab)

ACVR1 as a therapeutic target

“The discovery of the genetic variants in ACVR1 that cause FOP established a critical milestone in understanding FOP, revealed a highly conserved therapeutic target in the BMP signaling pathway, and propelled the development of novel inhibitors of ACVR1-mediated BMP pathway signaling.” (opens the source at this quote in a new tab)