An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva

Hino, Kyosuke; Zhao, Chengzhu; Horigome, Kazuhiko; Nishio, Makoto; Okanishi, Yasue; Nagata, Shinji; Komura, Shingo; Yamada, Yoshihiko; Toguchida, Junya; Ohta, Akira; Ikeya, Motoji

doi:10.1016/j.stemcr.2018.10.007

Cited by 52 publications

(50 citation statements)

References 67 publications

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“…Two of them, a human specific antiactivin antibody (REGN2477, Regeneron, NCT03188666; Regeneron Pharmaceuticals, Tarrytown, NY, USA) and a RARγ agonist (Palovarotene, NCT02279095; Clementia, Montreal, Canada) are currently in clinical trials. In addition, the mTOR inhibitor rapamycin (Sirolimus(42); Rapamune, Pfizer, New York, NY, USA), the repurposed Src inhibitor anticancer drug saracatinib (AstraZeneca Pharmaceuticals, Cambridge, UK) that also inhibits ALK2 signaling, an anti‐ALK2 blocking antibody by Daiichi Sankyo (Tokyo, Japan) and Saitama University (Saitama, Japan), and three ALK2 kinase inhibitors (Blueprint Medicines, Cambridge, MA, USA; La Jolla Pharmaceutical Co, San Diego, CA, USA; BioCryst Pharmaceuticals, Durham, NC, USA) have been publicly reported. Apart from waiting for the outcome of clinical trials where periodic systemic administration is considered, it would be of interest to explore whether these drugs may be useful applied locally, eg, surgery to remove heterotopic bone, or for example, in combinations at a lower dose.…”

Section: Discussionmentioning

confidence: 99%

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Sánchez‐Duffhues

Williams

Benderitter³

et al. 2019

JBMR Plus

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Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to activins, thereby turning them into bone‐inducing agents. To date, there is no cure for FOP. The further development of FOP patient‐derived models may contribute to the discovery of novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood‐derived endothelial colony‐forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo endothelial‐to‐mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Sánchez‐Duffhues

Williams

Benderitter³

et al. 2019

JBMR Plus

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“…In addition, other molecules, such as TGF-β neutralizing antibody (Wang et al, 2018) and transferrin receptor 2 (Rauner et al, 2019), and some drugs, such as insulin (Zhang et al, 2014) and desloratadine (Kusano et al, 2020), could attenuate heterotopic ossification formation induced by BMPs. A previous study also showed that mTOR signaling modulator suppressed heterotopic ossification formation (Hino et al, 2018); metformin exerted a dual negative regulatory effect on mTOR and BMP signal, and it might inhibit heterotopic ossification through an mTOR-BMP crosstalk signaling network (Wu et al, 2019). Recently, synthetic retinoid agonists, as a new option, has shown promise because it inhibited BMP-mediated heterotopic ossification formation in animal models (Sinha et al, 2016), and retinoid agonist therapy is being examined in patients with a rare, genetic form of heterotopic ossification (Lowery and Rosen, 2018).…”

Section: Discussionmentioning

confidence: 90%

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

Dai

Liu

et al. 2020

Front. Cell Dev. Biol.

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Although the mineralization in tendon tissue has been reported in a series of aging and disease models, the underlying mechanisms remain unknown. This study aimed to describe the appearance of heterotopic ossification in rat Achilles tendon and further verify whether this tissue metaplasia is related to the enhanced osteogenic differentiation of tendon stem/progenitor cells (TSPCs) owing to the higher expression of bone morphogenetic proteins (BMP-2/4/7) with aging. The male SD rats, aged 4, 8, and 20 months (M), were used. The analyses of ossification and BMP expression in tendon were tested by radiological view (X-ray and CT), histological staining [hematoxylin and eosin (HE), Alcian blue, and Alizarin red], immunohistochemistry, and Western blot. The osteogenic differentiation potential and BMP expression of TSPCs were examined by Alizarin red S staining and real-time PCR. TSPCs were treated with BMP-2 or noggin, and the osteogenic differentiation potential was also examined. X-ray and CT showed the appearance of heterotopic ossification in tendon, and the volume and density of ossification was increased with aging. Histological staining showed the appearance of calcified region surrounded by chondrocyte-like cells and the increased osteogenesis-related gene and BMP expression in ossified tendon with aging. Moreover, the osteogenic differentiation potential and BMP expression in TSPCs isolated from ossified tendon were increased with aging. Additionally, BMP-2 increased the calcium nodule formation and osteogenesis-related gene expression in TSPCs. The addition of noggin inhibited BMP-induced enhancement of osteogenic differentiation. Thus, these findings suggested that the enhanced osteogenic differentiation of TSPCs contributes to the increased heterotopic ossification in aged tendon, which might be induced by the higher expression of BMPs with aging.

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“…Hopefully, an effective treatment will be available to halt the formation of HO in the near future. To date, four potential drugs are tested in a clinical trial: Palovarotene, Garatosmab, Rapamycin and Saracatinib (32)(33)(34)(35). Once found effective in preventing HO formation, surgical treatment might be an option to unlock joints or to safely operate an FOP patient for any other condition under an umbrella of one (or a combination) of these drugs.…”

Section: Discussionmentioning

confidence: 99%

When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature

et al. 2020

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Fibrodysplasia ossificans progressiva (FOP) is a rare disease in which heterotopic ossification (HO) is formed in muscles, tendons and ligaments. Traumatic events, including surgery, are discouraged as this is known to trigger a flare-up with risk of subsequent HO. Anesthetic management for patients with FOP is challenging. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. We report a patient with FOP suffering from life-threatening antibiotic resistant bacterial infected ulcers of the right lower leg and foot. The anesthetic, surgical and postoperative challenges and considerations are discussed. In addition, the literature on limb surgeries of FOP patients is systemically reviewed. The 44 year-old female patient was scheduled for a through-knee amputation. Airway and pulmonary evaluation elicited severe abnormalities, rendering standard general anesthesia a rather complication-prone approach in this patient. Thus, regional anesthesia, supplemented with intravenous analgosedation and N 2 O-inhalation were performed in this case. The surgery itself was securely planned to avoid any unnecessary tissue damage. Postoperatively the patient was closely monitored for FOP activity by ultrasound and [ 18 F]PET/CT-scan. One year after surgery, a non-significant amount of HO had formed at the operated site. The

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An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva

Cited by 52 publications

References 67 publications

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells

Higher BMP Expression in Tendon Stem/Progenitor Cells Contributes to the Increased Heterotopic Ossification in Achilles Tendon With Aging

When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature

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