进行性骨化性纤维发育不良的发病机制及药物治疗的研究进展

周怡君; 史册; 孙宏晨

doi:10.1631/jzus.B2300779

Your Location：

Home >

Browse articles >

进行性骨化性纤维发育不良的发病机制及药物治疗的研究进展

Scan QR Code

文章被引用时，请邮件提醒。

Submit

Review | Updated：2025-04-23

进行性骨化性纤维发育不良的发病机制及药物治疗的研究进展
Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2025年26卷第4期页码：317-332
Affiliations：

1.Department of Endodontics, Hospital of Stomatology, Jilin University, Changchun 130021, China
2.Department of Oral Pathology, Hospital of Stomatology, Jilin University, Changchun 130021, China
3.Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun 130021, China
Funds：

the National Natural Science Foundation of China(82370936;81920108012;81970903;82270959);the Jilin University Norman Bethune Program(2023B28);the Department of Finance of Jilin Province(jcsz2023481-37)
DOI：10.1631/jzus.B2300779
中图分类号：
CSTR：
收稿日期：2023-10-29，

修回日期：2024-01-12，

网络出版日期：2025-04-23，

纸质出版日期：2025-04-23
Accepted：

周怡君,史册,孙宏晨.进行性骨化性纤维发育不良的发病机制及药物治疗的研究进展[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(04):317-332.

Yijun ZHOU, Ce SHI, Hongchen SUN. Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(4): 317-332.
周怡君,史册,孙宏晨.进行性骨化性纤维发育不良的发病机制及药物治疗的研究进展[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2025,26(04):317-332. DOI： 10.1631/jzus.B2300779.

Yijun ZHOU, Ce SHI, Hongchen SUN. Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva[J]. Journal of zhejiang university-science b (biomedicine & biotechnology), 2025, 26(4): 317-332. DOI： 10.1631/jzus.B2300779.

摘要

进行性骨化性纤维发育不良（FOP）是一种罕见的遗传性疾病，它以先天性双侧大脚趾畸形和全身软组织进行性、广泛性和不可逆的异位骨化（HO）为特征，最终可导致严重残疾。FOP主要由活化素A受体1（ACVR1，也被称为活化素受体样激酶2，即ALK2）的突变引起，该受体属于骨形态发生蛋白（BMP）I型受体。然而，FOP中复杂的HO形成机制尚未完全明确，这阻碍了治疗药物的开发。手术切除骨化组织常会导致HO的复发和扩大，而目前尚无药物可完全预防、停止或逆转FOP中HO的进展。目前，研究人员正在深入研究各个阶段FOP的发病机制，并开发候选药物，包括saracatinib、palovarotene和rapamycin等。本文就FOP的发病机制及治疗药物的研究进展进行综述，以期为进一步研究和开发新的治疗方法提供参考。

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital bilateral malformation of the large toe and progressive

extensive

and irreversible heterotopic ossification (HO) of soft tissues throughout the body

leading to severe disabilities. FOP is caused primarily by mutations in activin A receptor type 1 (

ACVR1

)

also known as activin-like kinase 2 (

ALK2

)

which encodes a receptor belonging to the bone morphogenetic protein (BMP) type I family. However

the continuous and complex process of HO in FOP is not yet fully understood

which has impeded the development of therapeutic drugs. Despite surgical removal of HO

which often results in recurrence and expansion of ossification

there is currently no definitive drug treatment available to completely prevent

halt

or reverse the progression of HO in FOP. Currently

researchers are intensively studying the pathogenesis of FOP at various stages and developing promising drug candidates

including saracatinib

palovarotene

and rapamycin. This review provides an overview of progress in understanding the mechanism of FOP and the development of therapeutic drugs

with the goal of providing insights for further research and the development of new treatment methods.

关键词

Keywords

references

Aykul S , Corpina RA , Goebel EJ , et al. , 2020 . Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop . eLife , 9 : e54582 . https://doi.org/10.7554/eLife.54582 https://doi.org/10.7554/eLife.54582

Aykul S , Huang L , Wang LL , et al. , 2022 . Anti-ACVR1 antibodies exacerbate heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) by activating FOP-mutant ACVR1 . J Clin Invest , 132 ( 12 ): e153792 . https://doi.org/10.1172/jci153792 https://doi.org/10.1172/jci153792

Babiker HM , Byron SA , Hendricks WPD , et al. , 2019 . E6201, an intravenous MEK1 inhibitor, achieves an exceptional response in BRAF V600E-mutated metastatic malignant melanoma with brain metastases . Invest New Drugs , 37 ( 4 ): 636 - 645 . https://doi.org/10.1007/s10637-018-0668-8 https://doi.org/10.1007/s10637-018-0668-8

Barruet E , Morales BM , Cain CJ , et al. , 2018 . NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification . JCI Insight , 3 ( 22 ): e122958 . https://doi.org/10.1172/jci.insight.122958 https://doi.org/10.1172/jci.insight.122958

Blueprint Medicines Corporation , 2019 . Safety, tolerability, pharmacokinetics, and food effect of BLU-782 in healthy adults . ClinicalTrials.gov ID NCT 03858075 . https://clinicaltrials.gov/study/NCT03858075 https://clinicaltrials.gov/study/NCT03858075

Brennan TA , Lindborg CM , Bergbauer CR , et al. , 2018 . Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP) . Bone , 109 : 259 - 266 . https://doi.org/10.1016/j.bone.2017.08.023 https://doi.org/10.1016/j.bone.2017.08.023

Cai J , Orlova VV , Cai X , et al. , 2015 . Induced pluripotent stem cells to model human fibrodysplasia ossificans progressiva . Stem Cell Rep , 5 ( 6 ): 963 - 970 . https://doi.org/10.1016/j.stemcr.2015.10.020 https://doi.org/10.1016/j.stemcr.2015.10.020

Capdeville R , Buchdunger E , Zimmermann J , et al. , 2002 . Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug . Nat Rev Drug Discov , 1 ( 7 ): 493 - 502 . https://doi.org/10.1038/nrd839 https://doi.org/10.1038/nrd839

Chaikuad A , Alfano I , Kerr G , et al. , 2012 . Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva . J Biol Chem , 287 ( 44 ): 36990 - 36998 . https://doi.org/10.1074/jbc.M112.365932 https://doi.org/10.1074/jbc.M112.365932

Chakkalakal SA , Uchibe K , Convente MR , et al. , 2016 . Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 R206H fibrodysplasia ossificans progressiva (FOP) mutation . J Bone Miner Res , 31 ( 9 ): 1666 - 1675 . https://doi.org/10.1002/jbmr.2820 https://doi.org/10.1002/jbmr.2820

Chen YY , Stubbs MC , Pusey M , et al. , 2020 . Characterization of INCB00928, a potent and selective ALK2 inhibitor for the treatment of anemia . Blood , 136 ( Suppl 1 ): 52 . https://doi.org/10.1182/blood-2020-136138 https://doi.org/10.1182/blood-2020-136138

Chiu W , Lin TY , Chang YC , et al. , 2021 . An update on gene therapy for inherited retinal dystrophy: experience in leber congenital amaurosis clinical trials . Int J Mol Sci , 22 ( 9 ): 4534 . https://doi.org/10.3390/ijms22094534 https://doi.org/10.3390/ijms22094534

Convente MR , Chakkalakal SA , Yang EJ , et al. , 2018 . Depletion of mast cells and macrophages impairs heterotopic ossification in an Acvr1 R206H mouse model of fibrodysplasia ossificans progressiva . J Bone Miner Res , 33 ( 2 ): 269 - 282 . https://doi.org/10.1002/jbmr.3304 https://doi.org/10.1002/jbmr.3304

Cuny GD , Yu PB , Laha JK , et al. , 2008 . Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors . Bioorg Med Chem Lett , 18 ( 15 ): 4388 - 4392 . https://doi.org/10.1016/j.bmcl.2008.06.052 https://doi.org/10.1016/j.bmcl.2008.06.052

de Ruiter R , Groot T , Schoenmaker T , et al. , 2022 . Fibroblasts from patients with fibrodysplasia ossificans progressiva exhibit increased activin a production . J Bone Miner Res , 37 : 320 - 320 .

de Ruiter RD , Wisse LE , Schoenmaker T , et al. , 2023 . TGF-beta induces activin a production in dermal fibroblasts derived from patients with fibrodysplasia ossificans progressiva . Int J Mol Sci , 24 ( 3 ): 2299 . https://doi.org/10.3390/ijms24032299 https://doi.org/10.3390/ijms24032299

del Zotto G , Antonini F , Azzari I , et al. , 2018 . Peripheral blood mononuclear cell immunophenotyping in fibrodysplasia ossificans progressiva patients: evidence for monocyte DNAM1 up‐regulation . Cytometry B Clin Cytom , 94 ( 4 ): 613 - 622 . https://doi.org/10.1002/cyto.b.21594 https://doi.org/10.1002/cyto.b.21594

Dey D , Bagarova J , Hatsell SJ , et al. , 2016 . Two tissue-resident progenitor lineages drive distinct phenotypes of heterotopic ossification . Sci Transl Med , 8 ( 366 ): 366ra163 . https://doi.org/10.1126/scitranslmed.aaf1090 https://doi.org/10.1126/scitranslmed.aaf1090

Engers DW , Frist AY , Lindsley CW , et al. , 2013 . Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5- a ] pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe . Bioorg Med Chem Lett , 23 ( 11 ): 3248 - 3252 . https://doi.org/10.1016/j.bmcl.2013.03.113 https://doi.org/10.1016/j.bmcl.2013.03.113

Engers DW , Bollinger SR , Felts AS , et al. , 2020 . Discovery, synthesis and characterization of a series of 7-aryl-imidazo [1,2-a ] pyridine-3-ylquinolines as activin-like kinase (ALK) inhibitors. Bioorg Med Chem Lett , 30 ( 18 ): 127418 . https://doi.org/10.1016/j.bmcl.2020.127418 https://doi.org/10.1016/j.bmcl.2020.127418

Fortin J , Tian RX , Zarrabi I , et al. , 2020 . Mutant ACVR1 arrests glial cell differentiation to drive tumorigenesis in pediatric gliomas . Cancer Cell , 37 ( 3 ): 308 - 323.e12 . https://doi.org/10.1016/j.ccell.2020.02.002 https://doi.org/10.1016/j.ccell.2020.02.002

Gámez B , Rodríguez-Carballo E , Graupera M , et al. , 2016 . Class I PI-3-kinase signaling is critical for bone formation through regulation of SMAD1 activity in osteoblasts . J Bone Miner Res , 31 ( 8 ): 1617 - 1630 . https://doi.org/10.1002/jbmr.2819 https://doi.org/10.1002/jbmr.2819

Hannon RA , Clack G , Rimmer M , et al. , 2010 . Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial . J Bone Miner Res , 25 ( 3 ): 463 - 471 . https://doi.org/10.1359/jbmr.090830 https://doi.org/10.1359/jbmr.090830

Hao JJ , Ho JN , Lewis JA , et al. , 2010 . In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors . ACS Chem Biol , 5 ( 2 ): 245 - 253 . https://doi.org/10.1021/cb9002865 https://doi.org/10.1021/cb9002865

Hatsell SJ , Idone V , Wolken DMA , et al. , 2015 . ACVR1 R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A . Sci Transl Med , 7 ( 303 ): 303ra137 . https://doi.org/10.1126/scitranslmed.aac4358 https://doi.org/10.1126/scitranslmed.aac4358

Haviv R , Moshe V , de Benedetti F , et al. , 2019 . Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome? Pediatr Rheumatol , 17 : 84 . https://doi.org/10.1186/s12969-019-0386-6 https://doi.org/10.1186/s12969-019-0386-6

Hennequin LF , Allen J , Breed J , et al. , 2006 . N -(5-Chloro-1,3-benzodioxol-4-yl)‍-7-‍[2-‍(4-methylpiperazin-1-yl)ethoxy ] ‍- 5 -

tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine , a novel , highly selective , orally available , dual-specific c-Src/Abl kinase inhibitor . J Med Chem , 49 ( 22 ): 6465 - 6488 . https://doi.org/10.1021/jm060434q https://doi.org/10.1021/jm060434q

Herbert KE , Walkley CR , Winkler IG , et al. , 2007 . Granulocyte colony-stimulating factor and an RARα specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells . Transplantation , 83 ( 4 ): 375 - 384 . https://doi.org/10.1097/01.tp.0000251376.75347.b4 https://doi.org/10.1097/01.tp.0000251376.75347.b4

Hildebrandt S , Kampfrath B , Fischer K , et al. , 2021 . Activina induced SMAD1/5 signaling in an iPSC derived EC model of fibrodysplasia ossificans progressiva (FOP) can be rescued by the drug candidate saracatinib . Stem Cell Rev Rep , 17 ( 3 ): 1039 - 1052 . https://doi.org/10.1007/s12015-020-10103-9 https://doi.org/10.1007/s12015-020-10103-9

Hino K , Horigome K , Nishio M , et al. , 2017 . Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva . J Clin Invest , 127 ( 9 ): 3339 - 3352 . https://doi.org/10.1172/JCI93521 https://doi.org/10.1172/JCI93521

Hino K , Zhao CZ , Horigome K , et al. , 2018 . An mTOR signaling modulator suppressed heterotopic ossification of fibrodysplasia ossificans progressiva . Stem Cell Rep , 11 ( 5 ): 1106 - 1119 . https://doi.org/10.1016/j.stemcr.2018.10.007 https://doi.org/10.1016/j.stemcr.2018.10.007

Hochhaus A , Larson RA , Guilhot F , et al. , 2017 . Long-term outcomes of imatinib treatment for chronic myeloid leukemia . N Engl J Med , 376 ( 10 ): 917 - 927 . https://doi.org/10.1056/NEJMoa1609324 https://doi.org/10.1056/NEJMoa1609324

Hrkac S , Novak R , Salai G , et al. , 2022 . Heterotopic ossification vs. fracture healing: extracellular vesicle cargo proteins shed new light on bone formation . Bone Rep , 16 : 101177 . https://doi.org/10.1016/j.bonr.2022.101177 https://doi.org/10.1016/j.bonr.2022.101177

Hu Y , Hao XQ , Liu CW , et al. , 2021 . Acvr1 deletion in osteoblasts impaired mandibular bone mass through compromised osteoblast differentiation and enhanced sRANKL-induced osteoclastogenesis . J Cell Physiol , 236 ( 6 ): 4580 - 4591 . https://doi.org/10.1002/jcp.30183 https://doi.org/10.1002/jcp.30183

Hwang C , Marini S , Huber AK , et al. , 2019 . Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification . Bone Res , 7 : 36 . https://doi.org/10.1038/s41413-019-0075-6 https://doi.org/10.1038/s41413-019-0075-6

Hwang CD , Pagani CA , Nunez JH , et al. , 2022 . Contemporary perspectives on heterotopic ossification . JCI Insight , 7 ( 14 ): e158996 . https://doi.org/10.1172/jci.insight.158996 https://doi.org/10.1172/jci.insight.158996

IFOPA , 2022 . DS-6016a . https://www.ifopa.org/ds_6016a https://www.ifopa.org/ds_6016a

Incyte Corporation , 2024 . To assess the efficacy, safety, and tolerability of INCB000928 in participants with fibrodysplasia ossificans progressiva (progress) . ClinicalTrials.gov ID NCT 05090891 . https://clinicaltrials.gov/study/NCT05090891 https://clinicaltrials.gov/study/NCT05090891

Jacobsen KL , Wiebe V , Davidson AP , et al. , 2023 . Use of enrofloxacin and hydrotherapy in the management of fibrodysplasia ossificans progressiva (FOP) in a Savannah cat . Top Companion Anim Med , 52 : 100757 . https://doi.org/10.1016/j.tcam.2022.100757 https://doi.org/10.1016/j.tcam.2022.100757

Jia SJ , Meng AM , 2021 . TGFβ family signaling and development . Development , 148 ( 5 ): dev188490 . https://doi.org/10.1242/dev.188490 https://doi.org/10.1242/dev.188490

Jiang JK , Huang XL , Shamim K , et al. , 2018 . Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,‍5- a ] pyrimidines as potent and selective ALK2 inhibitors . Bioorg Med Chem Lett , 28 ( 20 ): 3356 - 3362 . https://doi.org/10.1016/j.bmcl.2018.09.006 https://doi.org/10.1016/j.bmcl.2018.09.006

Kaplan FS , Andolina JR , Adamson PC , et al. , 2018a . Early clinical observations on the use of imatinib mesylate in FOP: a report of seven cases . Bone , 109 : 276 - 280 . https://doi.org/10.1016/j.bone.2017.07.019 https://doi.org/10.1016/j.bone.2017.07.019

Kaplan FS , Zeitlin L , Dunn SP , et al. , 2018b . Acute and chronic rapamycin use in patients with fibrodysplasia ossificans progressiva: a report of two cases . Bone , 109 : 281 - 284 . https://doi.org/10.1016/j.bone.2017.12.011 https://doi.org/10.1016/j.bone.2017.12.011

Kaplan J , Kaplan FS , Shore EM , 2012 . Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting . Gene Ther , 19 ( 7 ): 786 - 790 . https://doi.org/10.1038/gt.2011.152 https://doi.org/10.1038/gt.2011.152

Katagiri T , Tsukamoto S , Kuratani M , et al. , 2023 . A blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders . Nat Commun , 14 : 2960 . https://doi.org/10.1038/s41467-023-38746-5 https://doi.org/10.1038/s41467-023-38746-5

Kawamata M , Suzuki HI , Kimura R , et al. , 2023 . Optimization of Cas9 activity through the addition of cytosine extensions to single-guide RNAs . Nat Biomed Eng , 7 ( 5 ): 672 - 691 . https://doi.org/10.1038/s41551-023-01011-7 https://doi.org/10.1038/s41551-023-01011-7

Kitoh H , 2020 . Clinical aspects and current therapeutic approaches for FOP . Biomedicines , 8 ( 9 ): 325 . https://doi.org/10.3390/biomedicines8090325 https://doi.org/10.3390/biomedicines8090325

Lees-Shepard JB , Stoessel SJ , Chandler JT , et al. , 2022 . An anti-ACVR1 antibody exacerbates heterot ossification by fibro-adipogenic progenitors in fibrodysplasia ossificans progressiva mice . J Clinical Invest , 132 ( 12 ): e153795 . https://doi.org/10.1172/jci153795 https://doi.org/10.1172/jci153795

Lim KH , Han Z , Jeon HY , et al. , 2020 . Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression . Nat Commun , 11 : 3501 . https://doi.org/10.1038/s41467-020-17093-9 https://doi.org/10.1038/s41467-020-17093-9

Luo Y , Alsamarah A , Zhang K , et al. , 2016 . Development of new therapeutic agents for fibrodysplasia ossificans progressiva . Curr Mol Med , 16 ( 1 ): 4 - 11 . https://doi.org/10.2174/1566524016666151222142446 https://doi.org/10.2174/1566524016666151222142446

Mao D , Mi JY , Pan XY , et al. , 2022 . Galunisertib attenuates progression of trauma-induced heterotopic ossification via blockage of Smad2/3 signaling in mice . Eur J Pharmacol , 928 : 175109 . https://doi.org/10.1016/j.ejphar.2022.175109 https://doi.org/10.1016/j.ejphar.2022.175109

Maruyama R , Yokota T , 2018 . Morpholino-mediated exon skipping targeting human ACVR1/ALK2 for fibrodysplasia ossificans progressiva . In: Yokota T, Maruyama R (Eds.), Exon Skipping and Inclusion Therapies: Methods and Protocols . Humana Press , New York , p. 497 - 502 . https://doi.org/10.1007/978-1-4939-8651-4_32 https://doi.org/10.1007/978-1-4939-8651-4_32

Maruyama R , Nguyen Q , Roshmi RR , et al. , 2022 . Allele-selective LNA gapmers for the treatment of fibrodysplasia ossificans progressiva knock down the pathogenic ACVR1 R206H transcript and inhibit osteogenic differentiation . Nucl Acid Ther , 32 ( 3 ): 185 - 193 . https://doi.org/10.1089/nat.2021.0009 https://doi.org/10.1089/nat.2021.0009

Meng XM , Wang HT , Hao JJ , 2022 . Recent progress in drug development for fibrodysplasia ossificans progressiva . Mol Cell Biochem , 477 ( 10 ): 2327 - 2334 . https://doi.org/10.1007/s11010-022-04446-9 https://doi.org/10.1007/s11010-022-04446-9

Mohedas AH , Xing XC , Armstrong KA , et al. , 2013 . Development of an ALK2-biased BMP type I receptor kinase inhibitor . ACS Chem Biol , 8 ( 6 ): 1291 - 1302 . https://doi.org/10.1021/cb300655w https://doi.org/10.1021/cb300655w

Nagar G , Mittal P , Gupta SRR , et al. , 2023 . Multi-omics therapeutic perspective on ACVR1 gene: from genetic alterations to potential targeting . Brief Funct Genomics , 22 ( 2 ): 123 - 142 . https://doi.org/10.1093/bfgp/elac026 https://doi.org/10.1093/bfgp/elac026

Nguyen MH , Atasoylu O , Wu LX , et al. , 2022 . Discovery of novel pyrazolopyrimidines as potent, selective, and orally bioavailable inhibitors of ALK2 . ACS Med Chem Lett , 13 ( 7 ): 1159 - 1164 . https://doi.org/10.1021/acsmedchemlett.2c00206 https://doi.org/10.1021/acsmedchemlett.2c00206

Nikishina IP , Arsenyeva SV , Matkava VG , et al. , 2023 . Successful experience of tofacitinib treatment in patients with fibrodysplasia ossificans progressiva . Pediatr Rheumatol , 21 : 92 . https://doi.org/10.1186/s12969-023-00856-1 https://doi.org/10.1186/s12969-023-00856-1

Ohte S , Yamazaki H , Takahashi O , et al. , 2021 . Inhibitory effects of sesquiterpene lactones from the in donesian marine sponge Lamellodysidea cf. herbacea on bone morphogenetic protein-induced osteoblastic differentiation . Bioorg Med Chem Lett , 35 : 127783 . https://doi.org/10.1016/j.bmcl.2021.127783 https://doi.org/10.1016/j.bmcl.2021.127783

Pacifici M , 2018 . Retinoid roles and action in skeletal development and growth provide the rationale for an ongoing heterotopic ossification prevention trial . Bone , 109 : 267 - 275 . https://doi.org/10.1016/j.bone.2017.08.010 https://doi.org/10.1016/j.bone.2017.08.010

Pierce JL , Perrien DS , 2021 . Do interactions of vitamin D 3 and BMP signaling hold implications in the pathogenesis of fibrodysplasia ossificans progressiva? Curr Osteoporos Rep , 19 ( 3 ): 358 - 367 . https://doi.org/10.1007/s11914-021-00673-z https://doi.org/10.1007/s11914-021-00673-z

Pignolo RJ , Pacifici M , 2021 . Retinoid agonists in the targeting of heterotopic ossification . Cells , 10 ( 11 ): 3245 . https://doi.org/10.3390/cells10113245 https://doi.org/10.3390/cells10113245

Pignolo RJ , Wang HT , Kaplan FS , 2020 . Fibrodysplasia ossificans progressiva (FOP): a segmental progeroid syndrome . Front Endocrinol , 10 : 908 . https://doi.org/10.3389/fendo.2019.00908 https://doi.org/10.3389/fendo.2019.00908

Pignolo RJ , Bedford-Gay C , Cali A , et al. , 2022a . Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective . Orphanet J Rare Dis , 17 : 168 . https://doi.org/10.1186/s13023-022-02224-w https://doi.org/10.1186/s13023-022-02224-w

Pignolo RJ , McCarrick‐‍Walmsley R , Wang HT , et al. , 2022b . Plasma‍‐‍soluble biomarkers for fibrodysplasia ossificans progressiva (FOP) reflect acute and chronic inflammatory states . J Bone Miner Res , 37 ( 3 ): 475 - 483 . https://doi.org/10.1002/jbmr.4492 https://doi.org/10.1002/jbmr.4492

Pignolo RJ , Hsiao EC , al Mukaddam M , et al. , 2023 . Reduction of new heterotopic ossification (HO) in the open‐label, phase 3 MOVE trial of palovarotene for fibrodysplasia ossificans progressiva (FOP) . J Bone Miner Res , 38 ( 3 ): 381 - 394 . https://doi.org/10.1002/jbmr.4762 https://doi.org/10.1002/jbmr.4762

Qureshi AT , Dey D , Sanders EM , et al. , 2017 . Inhibition of mammalian target of rapamycin signaling with rapamycin prevents trauma-induced heterotopic ossification . Am J Pathol , 187 ( 11 ): 2536 - 2545 . https://doi.org/10.1016/j.ajpath.2017.07.010 https://doi.org/10.1016/j.ajpath.2017.07.010

Rugo HS , André F , Yamashita T , et al. , 2020 . Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer . Ann Oncol , 31 ( 8 ): 1001 - 1010 . https://doi.org/10.1016/j.annonc.2020.05.001 https://doi.org/10.1016/j.annonc.2020.05.001

Sánchez-Duffhues G , Williams E , Benderitter P , et al. , 2019 . Development of macrocycle kinase inhibitors for ALK2 using fibrodysplasia ossificans progressiva-derived endothelial cells . JBMR Plus , 3 ( 11 ): e10230 . https://doi.org/10.1002/jbm4.10230 https://doi.org/10.1002/jbm4.10230

Sanvitale CE , Kerr G , Chaikuad A , et al. , 2013 . A new class of small molecule inhibitor of BMP signaling . PLoS ONE , 8 ( 4 ): e62721 . https://doi.org/10.1371/journal.pone.0062721 https://doi.org/10.1371/journal.pone.0062721

Sato T , Sekimata K , Sakai N , et al. , 2020 . Structural basis of activin receptor-like kinase 2 (R206H) inhibition by bis-heteroaryl pyrazole-based inhibitors for the treatment of fibrodysplasia ossificans progressiva identified by the integration of ligand-based and structure-based drug design approaches . ACS Omega , 5 ( 20 ): 11411 - 11423 . https://doi.org/10.1021/acsomega.9b04245 https://doi.org/10.1021/acsomega.9b04245

Schoenmaker T , Zwaak J , Loos BG , et al. , 2023 . Transcriptomic differences underlying the activin-A induced large osteoclast formation in both healthy control and fibrodysplasia ossificans progressiva osteoclasts . Int J Mole Sci , 24 ( 7 ): 6822 . https://doi.org/10.3390/ijms24076822 https://doi.org/10.3390/ijms24076822

She DM , Zhang KQ , 2018 . Fibrodysplasia ossificans progressiva in China . Bone , 109 : 101 - 103 . https://doi.org/10.1016/j.bone.2017.11.016 https://doi.org/10.1016/j.bone.2017.11.016

Shi ST , Cai J , de Gorter DJJ , et al. , 2013 . Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva . PLoS ONE , 8 ( 7 ): e69096 . https://doi.org/10.1371/journal.pone.0069096 https://doi.org/10.1371/journal.pone.0069096

Shimono K , Morrison TN , Tung WE , et al. , 2010 . Inhibition of ectopic bone formation by a selective retinoic acid receptor α-agonist: a new therapy for heterotopic ossification? J Orthop Res , 28 ( 2 ): 271 - 277 . https://doi.org/10.1002/jor.20985 https://doi.org/10.1002/jor.20985

Shimono K , Tung WE , Macolino C , et al. , 2011 . Potent inhib ition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med , 17 ( 4 ): 454 - 460 . https://doi.org/10.1038/nm.2334 https://doi.org/10.1038/nm.2334

Shore EM , Xu MQ , Feldman GJ , et al. , 2006 . A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva . Nat Genet , 38 ( 5 ): 525 - 527 . https://doi.org/10.1038/ng1783 https://doi.org/10.1038/ng1783

Smilde BJ , Botman E , de Ruiter R , et al. , 2022 . Monitoring and management of fibrodysplasia ossificans progressiva: current perspectives . Orthop Res Rev , 14 : 113 - 120 . https://doi.org/10.2147/orr.s337491 https://doi.org/10.2147/orr.s337491

Song GA , Kim HJ , Woo KM , et al. , 2010 . Molecular consequences of the ACVR1 R206H mutation of fibrodysplasia ossificans progressiva . J Biol Chem , 285 ( 29 ): 22542 - 22553 . https://doi.org/10.1074/jbc.M109.094557 https://doi.org/10.1074/jbc.M109.094557

Stanley A , Tichy ED , Kocan J , et al. , 2022 . Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva . npj Regen Med , 7 : 5 . https://doi.org/10.1038/s41536-021-00201-8 https://doi.org/10.1038/s41536-021-00201-8

Strong AL , Spreadborough PJ , Pagani CA , et al. , 2020 . Small molecule inhibition of non-canonical (TAK1-mediated) BMP signaling results in reduced chondrogenic ossification and heterotopic ossification in a rat model of blast-associated combat-related lower limb trauma . Bone , 139 : 115517 . https://doi.org/10.1016/j.bone.2020.115517 https://doi.org/10.1016/j.bone.2020.115517

Tirone M , Giovenzana A , Vallone A , et al. , 2019 . Severe heterotopic ossification in the skeletal muscle and endothelial cells recruitment to chondrogenesis are enhanced by monocyte/macrophage depletion . Front Immunol , 10 : 1640 . https://doi.org/10.3389/fimmu.2019.01640 https://doi.org/10.3389/fimmu.2019.01640

Towler OW , Shore EM , 2022 . BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP) . Dev Dyn , 251 ( 1 ): 144 - 157 . https://doi.org/10.1002/dvdy.387 https://doi.org/10.1002/dvdy.387

Ullrich T , Arista L , Weiler S , et al. , 2022 . Discovery of a novel 2-aminopyrazine-3-carboxamide as a potent and selective inhibitor of activin receptor-like kinase-2 (ALK2) for the treatment of fibrodysplasia ossificans progressiva . Bioorg Med Chem Lett , 64 : 128667 . https://doi.org/10.1016/j.bmcl.2022.128667 https://doi.org/10.1016/j.bmcl.2022.128667

Upadhyay J , Xie LQ , Huang L , et al. , 2017 . The expansion of heterotopic bone in fibrodysplasia ossificans progressiva is activin A-dependent . J Bone Miner Res , 32 ( 12 ): 2489 - 2499 . https://doi.org/10.1002/jbmr.3235 https://doi.org/10.1002/jbmr.3235

Valer JA , Sánchez-de-Diego C , Gámez B , et al. , 2019 . Inhib ition of phosphatidylinositol 3-kinase α (PI3α) prevents heterotopic ossification. EMBO Mol Med , 11 ( 9 ): e10567 . https://doi.org/10.15252/emmm.201910567 https://doi.org/10.15252/emmm.201910567

Ventura F , Williams E , Ikeya M , et al. , 2021 . Challenges and opportunities for drug repositioning in fibrodysplasia ossificans progressiva . Biomedicines , 9 ( 2 ): 213 . https://doi.org/10.3390/biomedicines9020213 https://doi.org/10.3390/biomedicines9020213

Wang HT , Lindborg C , Lounev V , et al. , 2016 . Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling . J Bone Miner Res , 31 ( 9 ): 1652 - 1665 . https://doi.org/10.1002/jbmr.2848 https://doi.org/10.1002/jbmr.2848

Wang HT , de Cunto CL , Pignolo RJ , et al. , 2021 . Spatial patterns of heterotopic ossification in fibrodysplasia ossificans progressiva correlate with anatomic temperature gradients . Bone , 149 : 115978 . https://doi.org/10.1016/j.bone.2021.115978 https://doi.org/10.1016/j.bone.2021.115978

Wang HT , Zhang Q , Kaplan FS , et al. , 2022 . Clearance of sen escent cells from injured muscle abrogates heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva. J Bone Miner Res , 37 ( 1 ): 95 - 107 . https://doi.org/10.1002/jbmr.4458 https://doi.org/10.1002/jbmr.4458

Ware AD , Brewer N , Meyers C , et al. , 2019 . Differential vascularity in genetic and nonhereditary heterotopic ossification . Int J Surg Pathol , 27 ( 8 ): 859 - 867 . https://doi.org/10.1177/1066896919857135 https://doi.org/10.1177/1066896919857135

Wentworth KL , Masharani U , Hsiao EC , 2019 . Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva . Br J Clin Pharmacol , 85 ( 6 ): 1180 - 1187 . https://doi.org/10.1111/bcp.13823 https://doi.org/10.1111/bcp.13823

Wentworth KL , Lalonde RL , Groppe JC , et al. , 2022 . Functional testing of b one morphogenetic protein (BMP) pathway variants identified on whole‐exome sequencing in a patient with delayed‐onset fibrodysplasia ossificans progressiva (FOP) using ACVR1 R206H ‐specific human cellular and zebrafish models . J Bone Miner Res , 37 ( 11 ): 2058 - 2076 . https://doi.org/10.1002/jbmr.4711 https://doi.org/10.1002/jbmr.4711

Weston AD , Hoffman LM , Underhill TM , 2003 . Revisiting the role of retinoid signaling in skeletal development . Birth Defects Res Part C Embryo Today , 69 ( 2 ): 156 - 173 . https://doi.org/10.1002/bdrc.10010 https://doi.org/10.1002/bdrc.10010

Williams E , Bagarova J , Kerr G , et al. , 2021 . Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva . JCI Insight , 6 ( 8 ): e95042 . https://doi.org/10.1172/jci.insight.95042 https://doi.org/10.1172/jci.insight.95042

Witten MR , Wu LX , Lai CT , et al. , 2022 . Inhibition of ALK2 with bicyclic pyridyllactams . Bioorg Med Chem Lett , 55 : 128452 . https://doi.org/10.1016/j.bmcl.2021.128452 https://doi.org/10.1016/j.bmcl.2021.128452

Xiong HY , Veedu RN , Diermeier SD , 2021 . Recent advances in oligonucleotide therapeutics in oncology . Int J Mol Sciences , 22 ( 7 ): 3295 . https://doi.org/10.3390/ijms22073295 https://doi.org/10.3390/ijms22073295

Yamamoto H , Sakai N , Ohte S , et al. , 2021 . Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva . Bioorg Med Chem Lett , 38 : 127858 . https://doi.org/10.1016/j.bmcl.2021.127858 https://doi.org/10.1016/j.bmcl.2021.127858

Yamamoto M , Stoessel SJ , Yamamoto S , et al. , 2022 . Overexpression of wild‐type ACVR1 in fibrodysplasia ossificans progressiva mice rescues perinatal lethality and inhibits heterotopic ossification . J Bone Miner Res , 37 ( 11 ): 2077 - 2093 . https://doi.org/10.1002/jbmr.4617 https://doi.org/10.1002/jbmr.4617

Yamazaki H , Ohte S , Rotinsulu H , et al. , 2020 . Screening for small molecule inhibitors of BMP-induced osteoblastic differentiation from indonesian marine invertebrates . Mar Drugs , 18 ( 12 ): 606 . https://doi.org/10.3390/md18120606 https://doi.org/10.3390/md18120606

Yang JW , Kitami M , Pan HC , et al. , 2021 . Augmented BMP signaling commits cranial neural crest cells to a chondrogenic fate by suppressing autophagic β‍-catenin degradation . Sci Signal , 14 ( 665 ): eaaz9368 . https://doi.org/10.1126/scisignal.aaz9368 https://doi.org/10.1126/scisignal.aaz9368

Yang YS , Kim JM , Xie J , et al. , 2022 . Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery . Nat Commun , 13 : 6175 . https://doi.org/10.1038/s41467-022-33956-9 https://doi.org/10.1038/s41467-022-33956-9

Yang YS , Lin CJ , Ma H , et al. , 2023 . AAV-mediated targeting of the activin A-ACVR1 R206H signaling in fibrodysplasia ossificans progressiva . Biomolecules , 13 ( 9 ): 1364 . https://doi.org/10.3390/biom13091364 https://doi.org/10.3390/biom13091364

Ye ZQ , Wang SY , Shan C , et al. , 2023 . The serum levels of activin A and bone morphogenetic protein-4 and-6 in patients with fibrodysplasia ossificans progressiva . Orphanet J Rare Dis , 18 : 111 . https://doi.org/10.1186/s13023-023-02708-3 https://doi.org/10.1186/s13023-023-02708-3

Yu PB , Deng DY , Lai CS , et al. , 2008a . BMP type I receptor inhibition reduces heterotopic ossification . Nat Med , 14 ( 12 ): 1363 - 1369 . https://doi.org/10.1038/nm.1888 https://doi.org/10.1038/nm.1888

Yu PB , Hong CC , Sachidanandan C , et al. , 2008b . Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism . Nat Chem Biol , 4 ( 1 ): 33 - 41 . https://doi.org/10.1038/nchembio.2007.54 https://doi.org/10.1038/nchembio.2007.54

Zhang YE , 2017 . Non-Smad signaling pathways of the TGF-‍β family . Cold Spring Harb Perspect Biol , 9 ( 2 ): a022129 . https://doi.org/10.1101/cshperspect.a022129 https://doi.org/10.1101/cshperspect.a022129

Zitvogel L , Rusakiewicz S , Routy B , et al. , 2016 . Immunological off-target effects of imatinib . Nat Rev Clin Oncol , 13 ( 7 ): 431 - 446 . https://doi.org/10.1038/nrclinonc.2016.41 https://doi.org/10.1038/nrclinonc.2016.41

浏览量

Downloads

CSCD

工具集

关联资源

暂无数据