Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs’ skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.

Understanding the Action of RARγ Agonists on Human Osteochondroma Explants

“…Although these results are promising, it would be too early to reach definitive conclusions regarding the pharmacological effect of RARγ agonists on human osteochondromas, since the number of tested samples was limited. In addition, we also need to be cautious about potential side-effects of RARγ agonists on growing skeletal tissues as suggested previously [32]. However, the findings support the hypothesis that RARγ agonists exert anti-tumor function on osteochondromas and encourages current and future studies on the development of pharmacological therapy for osteochondromas.…”

Propranolol and ascorbic acid in control of fibrodysplasia ossificans progressiva flare-ups due to accidental falls

“…He has suffered several falls due to considerable limitations in the range of motion of limbs, mainly (13,14). Other groups have proposed drugs already in a clinical trial phase, however, their efficacy and side effects can be questioned (15,16). The use of AA only (11) as well as AA plus intravenous bisphosphonates (10), despite some improvement in the patients, did not avoid disease progression.…”

Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

“…Details of skeletal muscle dissection have been previously described ( Lees-Shepard et al, 2018a ). Dissected muscle was dissociated from tamoxifen treated Acvr1 [R206H]FlEx/+ ; Gt(ROSA26)Sor CreERT2/+ mice as described ( Hatsell et al, 2015 ) for tamoxifen regime using the Skeletal Muscle Dissociation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and gentleMACS Octo Dissociator with heaters (Miltenyi Biotec), in accordance with manufacturer instructions.…”

“…FOP-mutant variants of ACVR1 display the neomorphic property of recognizing Activin A (as well as other Activins) as an agonistic ligand, much like a BMP ( Hatsell et al, 2015 ; Hino et al, 2015 ). In mouse FOP, activation of FOP-mutant ACVR1 by Activin A is required for HO, as demonstrated by experiments where inhibition of Activin A, using highly specific monoclonal antibodies, halts both the occurrence and the progression of HO ( Hatsell et al, 2015 ; Lees-Shepard et al, 2018a ; Lees-Shepard et al, 2018b ; Upadhyay et al, 2017 ). Thus, in FOP, the ACVR1[FOP mutant]•Activin A•type II receptor complex, which is stoichiometrically identical to the NSC, acts as a signaling complex.…”