2020
DOI: 10.1186/s13023-020-01406-8
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Prophylactic treatment of rapamycin ameliorates naturally developing and episode -induced heterotopic ossification in mice expressing human mutant ACVR1

Abstract: Background Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease characterized by heterotopic ossification (HO) in soft tissues and caused by a mutation of the ACVR1A/ALK2 gene. Activin-A is a key molecule for initiating the process of HO via the activation of mTOR, while rapamycin, an mTOR inhibitor, effectively inhibits the Activin-A-induced HO. However, few reports have verified the effect of rapamycin on FOP in clinical perspectives. Methods We investigated the effect of rapamyc… Show more

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Cited by 14 publications
(13 citation statements)
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“…Preclinical evidence suggests that mTOR plays a significant role in the early pathophysiology of FOP. 47 After promising experiments in mice, 48 a clinical trial has been set up in Japan to evaluate efficacy and safety in FOP patients (UMIN000028429).…”
Section: Current Management and Treatmentmentioning
confidence: 99%
“…Preclinical evidence suggests that mTOR plays a significant role in the early pathophysiology of FOP. 47 After promising experiments in mice, 48 a clinical trial has been set up in Japan to evaluate efficacy and safety in FOP patients (UMIN000028429).…”
Section: Current Management and Treatmentmentioning
confidence: 99%
“…Literature data supports that the use of rapamycin, an Hif1a inhibitor, prevented HO formation in animal models [45]. Rapamycin is a macrolide immunosuppressant, which inhibits the mechanistic target of rapamycin (mTOR) protein kinase [45,46]. It blocks the mTOR pathway, preventing HIF-1α translation without affecting its transcription.…”
Section: Treatment Optionsmentioning
confidence: 91%
“…Despite its wide application on patients following kidney and liver transplant, its side effects are well-known, including hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, glucose intolerance, insulin resistance and diabetes, anemia, thrombocytopenia, dermatological and gastrointestinal disorders, sinusitis, respiratory and urinary infections, and testicular dysfunction [45]. Maekawa et al studied the use of rapamycin on ACVR1 mutant mice and pointed out that this macrolide decreased the occurrence of HO and reduced the amount of recurrent HO following surgical resection [46]. Recent data shows that, in knock-out HIF-1α mice, HO progenitor cells are diminished [47].…”
Section: Treatment Optionsmentioning
confidence: 99%
“…The establishment of FOP-ACVR1 conditional transgenic mice (FOP mice) was reported previously, in which the expression of mutant ACVR1 gene is induced by the administration of doxycycline [ 10 ]. Female mice 13- to 17-weeks old were used in the experiments, and HO was induced by a pinch injury as previously described [ 21 ]. From 7 days before the pinch injury, mice were fed water supplemented with 2 mg/mL doxycycline and 10 mg/mL sucrose, and the left gastrocnemius muscle was pinched using tissue forceps for 5 s. Tissue samples were collected 14 days after the pinch injury from mice euthanized using carbon dioxide (CO 2 ).…”
Section: Methodsmentioning
confidence: 99%