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1.
Bone ; 130: 115116, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31655222

RESUMO

RATIONALE: Fibrodysplasia ossificans progressiva (FOP) is primarily a disease of progressive heterotopic ossification (HO) leading to impaired mobility throughout life. An additional diagnostic feature is a characteristic malformation of the great toes. The culpable gene for FOP,ACVR1 (activin A receptor type 1) has a clear effect on the induction of extra-skeletal bone formation. However, this bone morphogenetic protein (BMP) pathway receptor is expressed widely throughout skeletal development and has a seminal role in axial and appendicular chondrogenesis, prompting suspicion of widespread bone and joint defects in those with ACVR1 mutations. MATERIALS AND METHODS: We analyzed baseline whole body (minus skull) computed tomographic (CT) scans of 113 individuals with classic clinical features of FOP and the ACVR1 (R206H) mutation who were enrolled in a non-interventional natural history study ((NCT02322255)) for skeletal malformations, atypical morphology, intra-articular synovial osteochondromatosis, developmental arthropathy, and associated degenerative joint phenotypes. Individuals were evaluated in three age groups: 4-13; 14-25; and 25-56 years old, based on historical models of FOP disease progression. RESULTS: We found widespread evidence of developmental arthropathy throughout the axial and appendicular skeleton in all age groups (61M, 52F; ages: 4-56 years). Asymmetric narrowing and subchondral sclerosis were present throughout the joints of the normotopic skeleton and osteophytes were common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints, and proximal tibio-fibular joints frequently showed partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic. We also found evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacro-iliac joints, and lower limbs. CONCLUSIONS: The effects of ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease. SIGNIFICANCE: FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics.

2.
Orphanet J Rare Dis ; 14(1): 98, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053156

RESUMO

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP. METHODS: All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed. RESULTS: Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm3/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52). CONCLUSIONS: Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients. TRIAL REGISTRATION: This study ( NCT02322255 ) was first posted on 23 December, 2014.


Assuntos
Miosite Ossificante/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ossificação Heterotópica/patologia , Inquéritos e Questionários , Adulto Jovem
3.
Orphanet J Rare Dis ; 14(1): 113, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122250

RESUMO

The original version of this article [1] unfortunately included an error to an author's name. Author Maja Di Rocco was erroneously presented as Maja DiRocco.The correct author name has been included in the author list of this Correction article and is already updated in the original article.

4.
Am J Med Genet A ; 179(7): 1310-1314, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31012264

RESUMO

A 16-year-old girl with a history of nontraumatic swelling of both forearms, osteochondromas of the knees, heterotopic ossification of the neck and back, severe malformations of all digits with hypoplastic or absent nails, alopecia partialis of the scalp, and moderate cognitive impairment was seen for diagnostic evaluation. Whole exome sequencing identified an activating mutation of ACVR1 (c.983G > A; p.Gly328Glu) which confirmed a suspected FOP variant. The delayed diagnosis of an FOP variant in this patient could have been avoided if the significance of severe digital malformations had been recognized, especially in the setting of progressive heterotopic ossification.

6.
Bone ; 109: 56-60, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29320714

RESUMO

Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c.690G>A; E230E) in the causative gene for FOP (ACVR1/ALK2). However, no frameshift, missense, or nonsense mutations in ACVR1, or in the causative gene for POH (GNAS), were found. Although genetic predisposition may play a role in MHO, our data suggest that mutations which occur in known hereditary conditions of HO are not the primary cause.


Assuntos
Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Idoso , Doenças Ósseas Metabólicas/genética , Doenças Ósseas Metabólicas/patologia , Predisposição Genética para Doença , Humanos , Masculino , Miosite Ossificante/genética , Miosite Ossificante/patologia , Análise de Sequência de DNA , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/patologia
7.
J Bone Miner Res ; 33(2): 269-282, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28986986

RESUMO

Heterotopic ossification (HO) is a clinical condition that often reduces mobility and diminishes quality of life for affected individuals. The most severe form of progressive HO occurs in those with fibrodysplasia ossificans progressiva (FOP; OMIM #135100), a genetic disorder caused by a recurrent heterozygous gain-of-function mutation (R206H) in the bone morphogenetic protein (BMP) type I receptor ACVR1/ALK2. In individuals with FOP, episodes of HO frequently follow injury. The first sign of active disease is commonly an inflammatory "flare-up" that precedes connective tissue degradation, progenitor cell recruitment, and endochondral HO. We used a conditional-on global knock-in mouse model expressing Acvr1R206H (referred to as Acvr1cR206H/+ ) to investigate the cellular and molecular inflammatory response in FOP lesions following injury. We found that the Acvr1 R206H mutation caused increased BMP signaling in posttraumatic FOP lesions and early divergence from the normal skeletal muscle repair program with elevated and prolonged immune cell infiltration. The proinflammatory cytokine response of TNFα, IL-1ß, and IL-6 was elevated and prolonged in Acvr1cR206H/+ lesions and in Acvr1cR206H/+ mast cells. Importantly, depletion of mast cells and macrophages significantly impaired injury-induced HO in Acvr1cR206H/+ mice, reducing injury-induced HO volume by ∼50% with depletion of each cell population independently, and ∼75% with combined depletion of both cell populations. Together, our data show that the immune system contributes to the initiation and development of HO in FOP. Further, the expression of Acvr1R206H in immune cells alters cytokine expression and cellular response to injury and unveils novel therapeutic targets for treatment of FOP and nongenetic forms of HO. © 2017 American Society for Bone and Mineral Research.


Assuntos
Receptores de Ativinas Tipo I/genética , Macrófagos/patologia , Mastócitos/patologia , Miosite Ossificante/patologia , Ossificação Heterotópica/patologia , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Contagem de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Mastócitos/metabolismo , Camundongos , Músculo Esquelético/patologia , Mutação/genética , Ossificação Heterotópica/metabolismo , Transdução de Sinais
8.
Bone ; 109: 104-110, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29033382

RESUMO

OBJECTIVE: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder in which heterotopic bone forms in the soft tissues. This often occurs in response to injury or inflammation, leading to joint immobilization and significant disability. There are currently no definitive treatment options for this devastating disease. Although the most dramatic phenotype in FOP is the episodic and progressive heterotopic ossification, patients report a number of symptoms that affect other organ systems. Post-mortem examination of FOP patients may contribute to our understanding of the underlying pathophysiology and complications of this disease. Here, we present the autopsy findings from three patients with FOP. FINDINGS: Autopsy findings in two of the three patients confirmed that the cause of death was cardiorespiratory failure in the setting of severe thoracic insufficiency from heterotopic ossification. Both of these patients also had evidence of right ventricular dilatation likely secondary to thoracic insufficiency. The third patient died from complications of a traumatic head injury after a fall but also had post-mortem evidence of thoracic insufficiency syndrome. All three patients had extensive, widespread heterotopic ossification and joint deformities consistent with FOP. There was extensive ossification of the spinal ligament in these patients, which may contribute to cervical spine rigidity. One patient was diagnosed post-mortem with a brainstem malformation. No additional significant abnormalities were noted in the other organ systems. Finally, we also demonstrate that cadaveric skin fibroblasts can be isolated for use as a potential source for future in vitro cell culture studies. CONCLUSIONS: This autopsy case series provides valuable information about the underlying complications of FOP and contributes significantly to our knowledge of this rare yet debilitating disorder. Thoracic insufficiency syndrome, right heart dysfunction, widespread heterotopic ossification, spinal ligament ossification, and CNS malformations were clearly evident; however, most other non-bone tissues appeared to be spared from gross malformations. Finally, the ability to isolate live cells from cadaveric skin is an important technique that will facilitate future studies, particularly as induced pluripotent stem cells and other cell-based technologies evolve. This case series highlights the importance of post-mortem examinations and their contribution to our current knowledge of disease pathophysiology and comorbidities.


Assuntos
Miosite Ossificante/patologia , Adulto , Cardiomiopatias/patologia , Feminino , Humanos , Pneumopatias/patologia , Pessoa de Meia-Idade , Ossificação Heterotópica/patologia
9.
Bone ; 109: 111-114, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28943457

RESUMO

Fibrodyplasia ossificans progressiva (FOP) is an ultra-rare genetic condition of heterotopic ossification (HO) that results in progressive loss of joint function, ultimately rendering movement impossible. Death is most commonly the result of thoracic insufficiency syndrome, or complications related to recurrent respiratory infections. There are no current treatments for FOP, but early and emerging clinical trials offer hope for this devastating disease. With the recent reporting of a comprehensive global natural history study, scales to assess joint dysfunction, and a more accurate prediction of joint survival, it is now possible to construct a conceptual framework for the clinical staging of FOP. Based on assessment of FOP features in seven areas, it is possible to assign five clinical stages. FOP features include flare-up activity, body regions affected, thoracic insufficiency, other complications, activities of daily living (ADLs), ambulatory status, and the cumulative joint involvement scale (CAJIS) score. Assessments of these features assign an individual with FOP to early/mild, moderate, severe, profound, or late-stage disease. These criteria seek to be flexible enough to be used by clinicians without reliance on advanced imaging or specialized testing, as well as by investigators involved in research or clinical trial studies who would have these tools available. These staging measures for FOP assess the influence of HO and accelerated joint dysfunction (due to congenital abnormalities) on the ability to perform common functional activities, and thus a delay or lack of progression from one stage to the next represents the ultimate test of efficacy for drug trials. This framework will serve both as a prediction tool for FOP progression as well as a critical opportunity to substantiate therapeutic interventions. The staging system proposed here will permit an accurate assessment of severity to appropriately develop or revise clinical plans of care, define operational research criteria, and identify the effectiveness of interventions. Ultimately, this clinical staging will aid the field in moving toward earlier intervention at a stage where disease-modifying therapies may be most efficacious.


Assuntos
Miosite Ossificante/diagnóstico , Humanos , Ossificação Heterotópica/diagnóstico
10.
Bone ; 109: 153-157, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28963080

RESUMO

BACKGROUND: Genesis of a cartilaginous scaffold is an obligate precursor to bone formation in heterotopic endochondral ossification (HEO). We tested the hypothesis that cartilage-derived retinoic acid-sensitive protein (CD-RAP) can serve as a plasma biomarker for the pre-osseous cartilaginous stage of HEO. Palovarotene, a retinoic acid receptor-gamma (RARγ) agonist, has been proposed as a possible treatment for fibrodysplasia ossificans progressiva (FOP) and is a potent inhibitor of HEO in mouse models. Current drug development for FOP mandates the identification of stage-specific biomarkers to facilitate the evaluation of clinical trial endpoints. RESULTS: Here we show in an injury-induced, constitutively-active transgenic mouse model of FOP that CD-RAP levels peaked between day-7 and day-10 during the zenith of histologically-identified chondrogenesis, preceded radiographically apparent HEO, and were diminished by palovarotene. Cross-sectional analysis of CD-RAP levels in plasma samples from FOP patients demonstrated a statistically non-significant trend toward higher levels in the recent flare-up period (three weeks to three months within onset of symptoms). However, in a longitudinal subgroup analysis of patients followed for at least six months after resolution of flare-up symptoms, there was a statistically significant decrease of CD-RAP when compared to levels in the same patients at the time of active or recent exacerbations. CONCLUSIONS: These data support the further exploration of CD-RAP as a stage-specific biomarker of HEO in FOP.


Assuntos
Biomarcadores/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Miosite Ossificante/metabolismo , Miosite Ossificante/patologia , Proteínas de Neoplasias/metabolismo , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/patologia , Adulto , Animais , Estudos Transversais , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Osteogênese/fisiologia , Adulto Jovem
12.
Bone ; 109: 120-123, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29241827

RESUMO

The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7.9%). In both study populations patients with kidney stones were found to be more functionally impaired compared to those without nephrolithiasis. The prevalence of kidney stones in the adult FOP population of the Unites States was 15.8% (9/57 individuals) compared to a sex- and age-weighted prevalence of 4.5% (p=4×10-5) in the general population. Although geographical variation exists, patients with FOP have an approximately three-fold greater prevalence of kidney stones than the general population. This unusually high prevalence may be due to high bone turnover from chronic immobilization, or to unknown mechanistic effects of the activating FOP mutation in activin A receptor, type I/activin-like kinase-2 (ACVR1/ALK2), increasing the disease burden and morbidity in this already disabling condition.


Assuntos
Cálculos Renais/epidemiologia , Miosite Ossificante/epidemiologia , Adulto , Fatores Etários , Feminino , Humanos , Cálculos Renais/etiologia , Cálculos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Miosite Ossificante/complicações , Miosite Ossificante/metabolismo , Nefrolitíase/epidemiologia , Nefrolitíase/etiologia , Nefrolitíase/metabolismo , Prevalência , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários , Adulto Jovem
13.
Bone ; 109: 281-284, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29241828

RESUMO

Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP.


Assuntos
Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Sirolimo/uso terapêutico , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Miosite Ossificante/genética , Miosite Ossificante/metabolismo , Ossificação Heterotópica/genética , Ossificação Heterotópica/metabolismo
14.
Bone ; 109: 201-209, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29288875

RESUMO

Clinical and laboratory observations strongly suggest that the innate immune system induces flare-ups in the setting of dysregulated bone morphogenetic protein (BMP) signaling in fibrodysplasia ossificans progressiva (FOP). In order to investigate the signaling substrates of this hypothesis, we examined toll-like receptor (TLR) activation and bone morphogenetic protein (BMP) signaling in connective tissue progenitor cells (CTPCs) from FOP patients and unaffected individuals. We found that inflammatory stimuli broadly activate TLR expression in FOP CTPCs and that TLR3/TLR4 signaling amplifies BMP pathway signaling through both ligand dependent and independent mechanisms. Importantly, Evolutionarily Conserved Signaling Intermediate in the Toll Pathway (ECSIT) integrates TLR injury signaling with dysregulated BMP pathway signaling in FOP CTPCs. These findings provide novel insight into the cell autonomous integration of injury signals from the innate immune system with dysregulated response signals from the BMP signaling pathway and provide new exploratory targets for therapeutic approaches to blocking the induction and amplification of FOP lesions.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Células do Tecido Conjuntivo/citologia , Células do Tecido Conjuntivo/metabolismo , Miosite Ossificante/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Humanos , Miosite Ossificante/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Receptor 3 Toll-Like/metabolismo
15.
Bone ; 109: 276-280, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28736245

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases. RESULTS: Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. CONCLUSIONS: These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease.


Assuntos
Mesilato de Imatinib/uso terapêutico , Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Receptores de Ativinas Tipo I/genética , Receptores de Ativinas Tipo I/metabolismo , Adolescente , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Mutação/genética , Miosite Ossificante/genética , Miosite Ossificante/metabolismo , Ossificação Heterotópica/genética , Ossificação Heterotópica/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo
16.
Bone ; 109: 259-266, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28851540

RESUMO

BACKGROUND: Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies. RESULTS: Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions. CONCLUSIONS: This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition.


Assuntos
Mastócitos/citologia , Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Animais , Aprepitanto , Cromolina Sódica/uso terapêutico , Modelos Animais de Doenças , Camundongos , Morfolinas/uso terapêutico , Miosite Ossificante/metabolismo , Ossificação Heterotópica/metabolismo
17.
Bone ; 109: 158-161, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28600150

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling genetic disorder characterized by episodic soft tissue swelling (flare-ups) that leads to progressive heterotopic ossification and restricted joint mobility. METHODS: Here we present the first longitudinal patient-reported mobility assessment (PRMA) in FOP based on a simple evaluation tool. At initial presentation and follow-up (1-11year span; median: 6 year span), 64 patients (36 females; 28 males) with classic FOP completed a questionnaire designed to rapidly assess mobility at 15 sites (three axial; six upper limb, and six lower limb). In order to validate this instrument, twenty-one of 64 patients (33%) underwent a cumulative analogue joint involvement scale (CAJIS) evaluation by two physicians within six months of their second self-assessment. RESULTS: We found that: 1) mobility changes were episodic and regional, occurring first in the neck and trunk, followed by the upper limbs and finally the lower limbs; 2) interval improvements in mobility did occur, most notably in the lower limbs (18%), and less so in the upper limbs (12%) and trunk (3%), and 3) patient-reported mobility assessments correlate highly (R2=0.81) with physician-reported CAJIS evaluations. CONCLUSION: This is the first longitudinal PRMA in FOP and provides a simple and valid tool that can be used in the design and evaluation of clinical trials in this progressively disabling disease.


Assuntos
Miosite Ossificante/fisiopatologia , Ossificação Heterotópica/fisiopatologia , Receptores de Ativinas Tipo I/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Miosite Ossificante/metabolismo , Ossificação Heterotópica/metabolismo , Adulto Jovem
18.
Bone ; 109: 124-133, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28627475

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) causes progressive disability due to heterotopic ossification from episodic flare-ups. Using data from 500 FOP patients (representing 63% of all known patients world-wide), age- and joint-specific risks of new joint involvement were estimated using parametric and nonparametric statistical methods. RESULTS: Compared to data from a 1994 survey of 44 individuals with FOP, our current estimates of age- and joint-specific risks of new joint involvement are more accurate (narrower confidence limits), based on a wider range of ages, and have less bias due to its greater comprehensiveness (captures over three-fifths of the known FOP patients worldwide). For the neck, chest, abdomen, and upper back, the estimated hazard decreases over time. For the jaw, lower back, shoulder, elbow, wrist, fingers, hip, knee, ankle, and foot, the estimated hazard increases initially then either plateaus or decreases. At any given time and for any anatomic site, the data indicate which joints are at risk. CONCLUSIONS: This study of approximately 63% of the world's known population of FOP patients provides a refined estimate of risk for new involvement at any joint at any age, as well as the proportion of patients with uninvolved joints at any age. Importantly, these joint-specific survival curves can be used to facilitate clinical trial design and to determine if potential treatments can modify the predicted trajectory of progressive joint dysfunction.


Assuntos
Articulações/patologia , Ossificação Heterotópica/patologia , Adolescente , Adulto , Proteínas Morfogenéticas Ósseas/metabolismo , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Articulações/metabolismo , Masculino , Pessoa de Meia-Idade , Miosite Ossificante/metabolismo , Miosite Ossificante/patologia , Ossificação Heterotópica/metabolismo , Adulto Jovem
19.
Bone ; 109: 28-34, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28688892

RESUMO

In recent years, the mechanisms and clinical significance of vascular calcification have been increasingly investigated. For over a century, however, pathologists have recognized that vascular calcification is a form of heterotopic ossification. In this review, we aim to describe the pathology and molecular processes of vascular ossification, to characterize its clinical significance and treatment options, and to elucidate areas that require further investigation. The molecular mechanisms of vascular ossification involve the activation of regulators including bone morphogenic proteins and chondrogenic transcription factors and the loss of mineralization inhibitors like fetuin-A and pyrophosphate. Although few studies have examined the gross pathology of vascular ossification, the presence of these molecular regulators and evidence of microfractures and cartilage have been demonstrated on heart valves and atherosclerotic plaques. These changes are often triggered by common inflammatory and metabolic disorders like diabetes, hyperlipidemia, and chronic kidney disease. The increasing prevalence of these diseases warrants further research into the clinical significance of vascular ossification and future treatment options.


Assuntos
Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/patologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Animais , Difosfatos/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Humanos , Ossificação Heterotópica/genética , Ligante RANK/genética , Ligante RANK/metabolismo , Calcificação Vascular/genética , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , alfa-2-Glicoproteína-HS/genética , alfa-2-Glicoproteína-HS/metabolismo
20.
Bone ; 109: 218-224, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29170109

RESUMO

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), is caused by mutations in the type I BMP receptor ACVR1 that lead to increased activation of the BMP-pSmad1/5/8 signaling pathway. Recent findings suggest that Activin A (Act A) promiscuously stimulates the bone morphogenetic protein (BMP) signaling pathway in vitro and mediates heterotopic ossification (HO) in mouse models of FOP, but primary data from FOP patient cells are lacking. OBJECTIVE: To examine BMP-pSmad1/5/8 pathway signaling and chondro-osseous differentiation in response to endogenous and exogenous Act A in primary connective tissue progenitor cells [CTPCs; also known as stem cells from human exfoliated deciduous teeth (SHED) cells] from patients with FOP. These cells express the common FOP mutation, ACVR1 (R206H). RESULTS: We found that Act A amplifies dysregulated BMP pathway signaling in human FOP primary CTPCs cells through the Smad1/5/8 pathway and induces chondro-osseous differentiation. Amplification of BMP-pSmad1/5/8 signaling was inhibited by Follistatin and by a neutralizing antibody to Activin A. The increased basal pSmad1/5/8 activity, as well as the hypoxia-induced stimulation of FOP CTPCs cells, were BMP4 and Act A independent. Importantly, either BMP4 or Act A stimulated pSmad1/5/8 pathway signaling but BMP4 signaling was not dependent on Activin A and vice versa. Circulating plasma levels of Act A or BMP4 are similar in controls compared to FOP patients, and suggest the potential for an autocrine or paracrine route for pathological signaling. CONCLUSIONS: The mutated FOP receptor [ACVR1 (R206H)] is hypersensitive to BMP4 and uniquely sensitive (compared to the wild type receptor) to Act A. Both canonical and non-canonical ligands have a synergistic effect on BMP-pSmad1/5/8 signaling in FOP CTPCs and may cooperate to alter the threshold for HO in FOP. Our findings in primary human FOP CTPCs have important implications for the design of clinical trials to inhibit dysregulated BMP pathway signaling in humans who have FOP.


Assuntos
Ativinas/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Miosite Ossificante/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Ossificação Heterotópica/genética , Ossificação Heterotópica/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad1/metabolismo , Proteína Smad5/metabolismo , Proteína Smad8/metabolismo
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