Fibrodysplasia ossificans progressiva: a blueprint for metamorphosis

Kaplan, Frederick S.; Lounev, Vitali; Wang, Haitao; Pignolo, Robert J.; Shore, Eileen M.

doi:10.1111/j.1749-6632.2011.06195.x

Cited by 32 publications

(26 citation statements)

References 39 publications

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“…For example, the application of compressive forces in tendon can induce fibrocartilaginous phenotypes, which is lost when the mechanical stimulation is removed3637. Inflammation can also trigger heterotopic endochondral ossification, as established by several studies of traumatic or neurogenic injuries and congenital diseases383940. In addition, a recent study showed that the tendon transcription factor Mkx may also function to inhibit chondrogenic differentiation in tenocytes;41 our study showed downregulation of Mkx expression after adult tendon injury, which may permit cartilage differentiation at the expense of tenogenesis.…”

Section: Discussionmentioning

confidence: 99%

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Howell

Chien

Bell

et al. 2017

Sci Rep

206

324

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To date, the cell and molecular mechanisms regulating tendon healing are poorly understood. Here, we establish a novel model of tendon regeneration using neonatal mice and show that neonates heal via formation of a ‘neo-tendon’ that differentiates along the tendon specific lineage with functional restoration of gait and mechanical properties. In contrast, adults heal via fibrovascular scar, aberrant differentiation toward cartilage and bone, with persistently impaired function. Lineage tracing identified intrinsic recruitment of Scx-lineage cells as a key cellular mechanism of neonatal healing that is absent in adults. Instead, adult Scx-lineage tenocytes are not recruited into the defect but transdifferentiate into ectopic cartilage; in the absence of tenogenic cells, extrinsic αSMA-expressing cells persist to form a permanent scar. Collectively, these results establish an exciting model of tendon regeneration and uncover a novel cellular mechanism underlying regenerative vs non-regenerative tendon healing.

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Section: Discussionmentioning

confidence: 99%

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Howell

Chien

Bell

et al. 2017

Sci Rep

206

324

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“…Given the apparently equivalent consequence of K27M mutations in H3.1 or H3.3 to decrease total cellular levels of H3K27me3, the significant co-occurrence of ACVR1 and HIST1H3B mutations may reflect a specific developmental setting. Surprisingly, some of the same somatic ACVR1 mutations identified in DIPG are found as heterozygous germline mutations causing the congenital malformation syndrome fibrodysplasia ossificans progressiva (FOP), a disease characterized by the formation of heterotopic ossifications in soft tissues at sites of inflammation 82, 83 . FOP is not associated with cancer predisposition, despite the presence of germline mutations that are identical to those found in DIPG.…”

Section: Acvr1/alk2 Mutations; a Selective Role For Bmp Signaling In mentioning

confidence: 99%

Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma

2014

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Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for paediatric HGG ranges from 30%, for tumours arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumourigenesis and chromatin regulation as well as developmental signaling pathways. These new genetic findings provide insights into disease pathogenesis, and the challenges and opportunities for improving patient survival in these largely incurable childhood brain tumours.

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“…The most common mutation is a heterozygous single nucleotide substitution c.617G>A in ACVR1 (located on chromosome 2q23-24) which encodes activin receptor type 1 (ACVR1) also known as activin like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. This mutation leads to a R206H substitution in the glycine-serine region of the cytoplasmic domain of ACVR1, which is highly conserved [1,3,4]. This gain-of-function mutation leads to dysregulated enhanced BMP signaling, responsible for the new bone formation in connective tissue, as occurring in this condition.…”

Section: Discussionmentioning

confidence: 99%

Rare Genetic Cases of Heterotopic Ossification

Mallappa¹,

Vishwanath

Pratt³

et al. 2012

Endocrinol Metab Synd

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Heterotopic Ossification (HO) is formation of normal bone in extraskeletal tissues, such as skin, subcutaneous tissue and deep connective tissue. Heterotopic ossification can be hereditary or nonhereditary in nature. We report two cases of rare hereditary forms of heterotopic ossification namely Fibrodysplasia Ossificans Progressiva (FOP) and Progressive Osseous Heteroplasia (POH). Hereditary forms of heterotopic ossification are progressive and severely debilitating in nature. Though these disorders are rare, awareness and knowledge about these disorders will help in early identification of such unique cases, leading to appropriate referral and management. Case Presentations Case 1A 4 year old Caucasian female was admitted with history of painful soft tissue swelling and induration on her right upper back, posterior neck and torso following an all-terrain vehicle accident that occurred a few weeks before her admission. Patient also reported trouble sitting up and increasing stiffness with ambulation. She had been evaluated in orthopedic clinic a few months previously for scoliosis and suspected Klippel-Feil anomaly. Physical examination revealed extensive tender indurated swellings over upper back and neck. She was also noted to have bilateral hallux valgus (Figure 1). Laboratory data revealed normal electrolytes, blood cell counts, liver enzymes, alkaline phosphatase and LDH levels. CT of her shoulder revealed a bony extension of the left anterior/inferior clavicle ( Figure 1) and was reported as exostosis of the clavicle with nonspecific soft tissue stranding through the lower neck and chest wall musculature, findings inconsistent with KlippelFeil syndrome. Genetic testing for FOP was done because of a strong clinical suspicion and due to the presence of hallux valgus, which revealed a c.617G>A transition in ACVR1 gene, resulting in a missense mutation (p.R206H), commonly associated with FOP [1]. Case 2A 17 year old Caucasian male presented to our endocrinology/bone clinic for evaluation of subcutaneous nodules. The lesions were first noted on his right index finger at two years of age. Over time similar lesions were noted on his right extremity. In the previous year he had noted more lesions in his right hand with extension into the forearm. He also had complaints of mild right wrist joint pain and stiffness with activity. He had undergone surgical removal of the lesions repeatedly (seven times). Family history was negative for ectopic ossifications, rickets, hormone deficiencies or other bone disorders. There was no history of consanguinity.Physical examination showed a well appearing Tanner V adolescent, with no features of Albright Hereditary Osteodystrophy (AHO). Extremity examination was remarkable for 2-4 mm sized bony lesions palpable in the inter-digital space of right index and middle finger and also extending along the radial aspect of the forearm. He was noted to have decreased mobility of the index and middle fingers. Similar lesions were noted on the dorsal aspect of the second digit ...

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Fibrodysplasia ossificans progressiva: a blueprint for metamorphosis

Cited by 32 publications

References 39 publications

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma

Rare Genetic Cases of Heterotopic Ossification

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