Fibrodysplasia (Myositis) Ossificans Progressiva

Convente, Michael R.; Towler, O. Will; Stanley, Alexandra; Brewer, Niambi; Allen, Robyn S.; Kaplan, Frederick S.; Shore, Eileen M.

doi:10.1016/b978-0-12-804182-6.00030-7

Cited by 4 publications

(6 citation statements)

References 224 publications

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“…Yingzi Yang, 1,2 How osteoblast cells are induced during bone development is a central question for understanding the organizational principles underpinning a functional skeletal system. Abnormal osteoblast differentiation leads to a broad range of devastating diseases such as craniosynostosis (premature suture fusion), heterotopic ossification (HO), and osteoporosis.…”

Section: Loss Of Gas Signaling Induces Osteoblast Differentiation In mentioning

confidence: 99%

“…Sandesh Nagamani, 1,2 Dianne Dang, 1 Ingo Grafe, 1 Eric Orwoll, 3 Catherine Pedersen, 3 Reid Sutton, 1,2 and Brendan Lee 1,2 Osteogenesis imperfecta (OI) refers to a phenotypically and genetically heterogeneous group of Mendelian disorders that manifest with increased bone fragility, recurrent fractures, and bone deformities. OI is caused by pathogenic variants in genes that encode: 1) proa1(I) and proa2(I) chains of type I collagen; 2) proteins required for the posttranslational modification and processing of type I collagen; 3) components required for normal mineralization of bone; and 4) transcription and signaling proteins required for the maturation and function of osteoblasts; and 5) genes whose functions are yet to be understood.…”

Section: Safety and Efficacy Of Fresolimumab Therapy In Adults With Omentioning

confidence: 99%

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Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Meeting, September 26–27, 2018: A Meeting in Affiliation With the American Society for Bone and Mineral Research (ASBMR)

Lee

Pacifici

2019

JBMR Plus

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Section: Loss Of Gas Signaling Induces Osteoblast Differentiation In mentioning

confidence: 99%

Section: Safety and Efficacy Of Fresolimumab Therapy In Adults With Omentioning

confidence: 99%

Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Meeting, September 26–27, 2018: A Meeting in Affiliation With the American Society for Bone and Mineral Research (ASBMR)

Lee

Pacifici

2019

JBMR Plus

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“…In the case of FOP, endochondral osteogenesis occurs extra-skeletally, replacing soft connective tissues with bone tissue [1]. Causative missense mutations for FOP occur in the ACVR1 gene, which encodes a type I bone morphogenic protein (BMP) receptor [3], with ACVR1 R206H being the most prominent mutation, occurring in an estimated Biomedicines 2024, 12, 779 2 of 17 97% of FOP patients [4][5][6][7]. The prevalence of FOP has been estimated to be approximately 0.6-1.39 per million inhabitants, with around 900 confirmed cases worldwide [1,[8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Most patients with FOP are born with congenital malformation of the great toe, but otherwise appear normal at birth [1]. Children with FOP start experiencing unpredictable episodes of painful soft tissue swelling, known as flare-ups, around the age of 5, but onset varies per individual [6,11,12,16]. Flare-ups often lead to irreversible HO along the body and joints; however, ectopic bone formation has also been reported in the absence of flare-ups [6,11,12,16].…”

Section: Introductionmentioning

confidence: 99%

“…Children with FOP start experiencing unpredictable episodes of painful soft tissue swelling, known as flare-ups, around the age of 5, but onset varies per individual [6,11,12,16]. Flare-ups often lead to irreversible HO along the body and joints; however, ectopic bone formation has also been reported in the absence of flare-ups [6,11,12,16]. Even though flare-ups and new episodes of HO can be triggered by muscular trauma, they also occur spontaneously, supporting the critical role of the immune system in the pathogenesis of FOP.…”

Section: Introductionmentioning

confidence: 99%

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Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva

Mejias Rivera,

Shore,

Mourkioti

2024

Biomedicines

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Fibrodysplasia ossificans progressiva (FOP) is a debilitating genetic disorder characterized by recurrent episodes of heterotopic ossification (HO) formation in muscles, tendons, and ligaments. FOP is caused by a missense mutation in the ACVR1 gene (activin A receptor type I), an important signaling receptor involved in endochondral ossification. The ACVR1R206H mutation induces increased downstream canonical SMAD-signaling and drives tissue-resident progenitor cells with osteogenic potential to participate in endochondral HO formation. In this article, we review aberrant ACVR1R206H signaling and the cells that give rise to HO in FOP. FOP mouse models and lineage tracing analyses have been used to provide strong evidence for tissue-resident mesenchymal cells as cellular contributors to HO. We assess how the underlying mutation in FOP disrupts muscle-specific dynamics during homeostasis and repair, with a focus on muscle-resident mesenchymal cells known as fibro-adipogenic progenitors (FAPs). Accumulating research points to FAPs as a prominent HO progenitor population, with ACVR1R206H FAPs not only aberrantly differentiating into chondro-osteogenic lineages but creating a permissive environment for bone formation at the expense of muscle regeneration. We will further discuss the emerging role of ACVR1R206H FAPs in muscle regeneration and therapeutic targeting of these cells to reduce HO formation in FOP.

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Molecular Genetics of Fibrodysplasia Ossificans Progressiva

Brewer¹,

Allen²,

Mullins³

et al. 2021

Encyclopedia of Life Sciences

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Fibrodysplasia ossificans progressiva (FOP, MIM# 135100) is an autosomal‐dominant genetic disorder, caused by heterozygous mutations in the ACVR1 gene. While most with FOP have the same single‐nucleotide substitution (c.617G>A; R206H), occasional variant mutations in ACVR1 have also been identified. The defining clinical features of FOP are malformations of the great toes and progressive heterotopic (extraskeletal) ossification (HO). However, the clinical presentations among FOP patients vary and, at least in some cases, there appear to be genotype–phenotype correlations with specific ACVR1 mutations, even among the small number of patients. FOP‐associated ACVR1 mutations are activating mutations that enhance signalling through the BMP‐pSmad1/5 signalling pathway and direct the induction of cartilage and bone cell differentiation to form ectopic bone in postnatal soft connective tissues. Recent studies examining the molecular mechanisms, reveal that the mutant ACVR1 receptors have lost the normal constraints that regulate the activation of the ACVR1 receptor signalling complex. Key Concepts Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of heterotopic ossification. FOP is caused by heterozygous activating mutations in the ACVR1 gene. Most FOP patients share the identical ACVR1 c.617G>A mutation that causes a single amino acid substitution (R206H). Additional variant mutations have been identified in ACVR1 and are associated with distinct clinical manifestations in some cases. ACVR1 is a type I receptor in the BMP signalling pathway, an important pathway in regulating bone formation. FOP mutant ACVR1 receptors have lost regulatory constraints that control how downstream signalling is activated.

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Fibrodysplasia (Myositis) Ossificans Progressiva

Cited by 4 publications

References 224 publications

Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Meeting, September 26–27, 2018: A Meeting in Affiliation With the American Society for Bone and Mineral Research (ASBMR)

Mechanistic and Therapeutic Advances in Rare Skeletal Diseases Meeting, September 26–27, 2018: A Meeting in Affiliation With the American Society for Bone and Mineral Research (ASBMR)

Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva

Molecular Genetics of Fibrodysplasia Ossificans Progressiva

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