Treatment Of Fibrodysplasia Ossificans Progressiva Research Articles

Viewing FOP through rosi-colored glasses

Viewing FOP through rosi-colored glasses

Rosiglitazone therapy is associated with major clinical improvements in a patient with fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive heterotopic ossification, increasing disability, and cumulative immobility. Thiazolidinediones, introduced in 1999 for the treatment of diabetes, enhance bone marrow adipogenesis at the expense of new bone formation, and this might be exploited for the treatment of FOP. A 48-year-old woman with severe FOP characterized by continuous flares that she was partially controlling only with high prednisone doses was given rosiglitazone (initially 4 mg and then 8 mg daily) for 14 months. No new flare-ups were observed during rosiglitazone therapy as compared to the five episodes observed during the previous year while on 20 to 25 mg prednisone daily. The steroid dose could be lowered progressively to 5 mg/day, the skin became softer, and the articular mobility improved impressively. This case report seems to suggest that rosiglitazone therapy, possibly in association with small doses of prednisone, is associated with important clinical improvements in patients with FOP.

Is There a Biological Basis for Treatment of Fibrodysplasia Ossificans Progressiva with Rosiglitazone? Potential Benefits and Undesired Effects

Thiazolidinediones (TZDs), among which Rosiglitazone, are known agonists of the peroxisome-proliferator-activated receptor γ (PPARγ) commonly used for treatment of hyperglycemia. A recently published article describing a case report on a patient affected by Fibrodysplasia Ossificans Progressiva (FOP) treated with Rosiglitazone has prompted interest for careful analysis of the rational basis of such treatment. This article reviews the effects of PPARγ agonists in relationship with various pathogenic steps that occur during the course of FOP by reviewing the particularly rich literature on the effects of Rosiglitazone, to underscore their relevance to FOP and to consider possible adverse effects.

Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.

When one skeleton is enough: approaches and strategies for the treatment of fibrodysplasia ossificans progressiva (FOP).

A heterozygous missense mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, is responsible for fibrodysplasia ossificans progressiva (FOP), the most catastrophic disorder of skeletal metamorphosis in humans. The discovery of the FOP gene establishes a crucial milestone in understanding FOP, reveals a highly conserved target in the BMP signaling pathway for drug development and specifically stimulates therapeutic approaches for the development of inhibitors for ACVR1/ALK2 signaling. Effective therapies for FOP, and possibly for more common conditions of heterotopic ossification, will be based on interventions that selectively block promiscuous ACVR1/ALK2 signaling, and/or themolecular triggers, responding cells and tissue microenvironments that facilitate aberrant skeletal metamorphosis in a permissive genetic background of increased BMP pathway activity.

Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP)

Metamorphosis, the transformation of one normal tissue or organ system into another, is a biological process rarely studied in higher vertebrates or mammals, but exemplified pathologically by the extremely disabling autosomal dominant disorder fibrodysplasia ossificans progressiva (FOP). The recurrent single nucleotide missense mutation in the gene encoding activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein type I receptor that causes skeletal metamorphosis in all classically affected individuals worldwide, is the first identified human metamorphogene. Physiological studies of this metamorphogene are beginning to provide deep insight into a highly conserved signaling pathway that regulates tissue stability following morphogenesis, and that when damaged at a highly specific locus (c.617G > A; R206H), and triggered by an inflammatory stimulus permits the renegade metamorphosis of normal functioning connective tissue into a highly ramified skeleton of heterotopic bone. A comprehensive understanding of the process of skeletal metamorphosis, as revealed by the rare condition FOP, will lead to the development of more effective treatments for FOP and, possibly, for more common disorders of skeletal metamorphosis.

Treatment Considerations for the Management of Fibrodysplasia Ossificans Progressiva

The ultimate goal of research on fibrodysplasia ossificans progressiva (FOP) is the development of treatments that will prevent, half, or even reverse the progression of the condition. Despite advances in understanding the pathophysiology of FOP, there are no therapies with scientifically proven benefits for the prevention or treatment of FOP. Insights obtained from the research laboratory and from the treatment of hundreds of patients world wide have allowed us to identify targets for potential therapies. Some of these therapies involve the use of currently available medications, whereas others involve novel therapeutic approaches that are in preclinical testing. In this article, we will review the scientific basis for considering various therapeutic options based on the known pathophysiology of FOP. Because there are presently no proven preventions or treatments for the condition, this article is intended to represent an opinion of the authors that may be helpful to others who face similar situations.

Consideration of Rituximab for fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a severe, progressive disease of the musculoskeletal system. Muscles, tendons and other connective tissues ossify after minor trauma, and patients often become encased in a second immobile skeleton. There is no known cure or treatment for FOP. It has been found that lymphocytes from FOP patients elaborate excess levels of bone morphogenic protein-4 (BMP-4). Given this, it has been suggested that allogenic bone marrow transplantation (BMT) possibly could be a cure for FOP, and drawn attention to a previously unappreciated case of an FOP patient who had successful BMT for aplastic anemia with apparent short- and medium-term arresting of the FOP disease process. However, BMT has non-trivial associated morbidity and mortality. Here, it is noted that if B cells are found to be the lymphocytes responsible for excess BMP-4 production in FOP, use of Rituximab, a monoclonal anti-CD20 antibody which effectively targets B cells, could be a less permanent and less risky treatment alternative for FOP.

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Fibrodysplasia Ossificans Progressiva (FOP) is a severe, comparatively rare disease, characterized by the progressive heterotopic ossification of the muscle, tendon, ligament, and facsia. There is no known effective therapy for this desease. In this syudy, we report two cases of FOP. One of the patients was a 7-year-old boy, suffering from multiple masses on neck and back, and congenital bilateral hallux valgus. We diagnosed him as FOP from his clinical findings. Due to aggravation of the multiple masses, oral etidronate therapy was begun in March 2001. After the therapy, no worsening symptom was observed. Another patient was a 6-year-old boy, complaining of congenital bilateral hallux valgus. Within a couple of years, multiple masses became evident on his neck and back, for which FOP was diagnosed. In this case we did not start etidronate therapy because of no large progression of the masses. The results of this study suggest that etidronate therapy may be helpful for the treatment of FOP.

Multivariate survival analysis with doubly-censored data: application to the assessment of Accutane treatment for fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva is a rare genetic disorder in which the joints of patients become disabled by the formation of heterotopic bone. Data are available on the status of 11 joints of each of 21 patients before, during and after treatment with Accutane. These are compared with data obtained by questionnaire from 40 untreated patients to determine the efficacy of the treatment. Both left- and right-censoring are present in each group, which, together with the multivariate nature of the data and the time-dependent treatment covariate, makes analysis difficult. We consider two alternative parametric models for incorporating within-subject dependence: a marginal model and a frailty model. Both analyses suggest that Accutane treatment is effective. We discuss and illustrate the differences between the two approaches. We also discuss the extent to which the conclusions are compromised by the observational nature of the study.

1138. In Vivo Somatic Cell Gene Transfer of an Engineered Noggin Mutein Prevents BMP4-Induced Heterotopic Ossification in the Mouse: Implications for the Treatment of Fibrodysplasia Ossificans Progressiva and Other Disorders of Heterotopic Ossification in Humans

1138. In Vivo Somatic Cell Gene Transfer of an Engineered Noggin Mutein Prevents BMP4-Induced Heterotopic Ossification in the Mouse: Implications for the Treatment of Fibrodysplasia Ossificans Progressiva and Other Disorders of Heterotopic Ossification in Humans

Effects of Intravenous Etidronate and Oral Corticosteroids in Fibrodysplasia Ossificans Progressiva

There is no known effective therapy for fibrodysplasia ossificans progressiva. Ethane-1-hydroxy-1-diphosphonate has been studied because of its inhibitory effect on bone mineralization and its potential to impair the rapid ossification process observed after acute episodes of fibrodysplasia ossificans progressiva. In an open study, the effects of intravenously administered ethane-1-hydroxy-1-diphosphonate and oral corticosteroids in the treatment of fibrodysplasia ossificans progressiva was evaluated. Thirty-one fibrodysplasia ossificans progressiva attacks were observed in seven patients during the mean followup of 6 years. In 29 attacks, the authors observed a rapid diminution of local inflammation, swelling, and pain during the first 7 days of treatment. However, despite the ethane-1-hydroxy-1-diphosphonate treatment, 10 new ossifications were observed, causing severe deterioration of joint mobility in all affected patients. In 21 attacks, no new ectopic ossification appeared. The radiologic pattern of preexisting ossifications did not change during the treatment. There are no data in the literature describing the percentage of acute episodes leading to an ossification. The results suggest the possibility that intravenous administration of ethane-1-hydroxy-1-diphosphonate and oral steroids may be helpful for the treatment of fibrodysplasia ossificans progressiva, but more control data on the spontaneous resolution of early flareups are needed.

Subject index

More than 50 years ago, Marshal M. Urist detected “heterotopic bone-inducing activity” in demineralized bone matrix. This unique activity was referred to as “bone morphogenetic protein (BMP)” because it was sensitive to trypsin digestion. Purification of the bone-inducing activity from demineralized bone matrix using a bone-inducing assay in vivo indicated that the original “BMP” consisted of a mixture of new members of the transforming growth factor-β (TGF-β) family. The establishment of new in vitro assay systems that reflect the bone-inducing activity of BMPs in vivo have revealed the functional receptors and downstream effectors of BMPs. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic bone formation in soft tissues similar to the event induced by the transplantation of BMPs in skeletal muscle. In patients with FOP, genetic mutations have been identified in the ACVR1 gene, which encodes the BMP receptor ALK2. The mutations in ALK2 associated with FOP are hypersensitive to type II receptor kinases. Recently, activin A, a non-osteogenic member of the TGF-β family, was identified as the ligand of the mutant ALK2 in FOP, and various types of signaling inhibitors for mutant ALK2 are currently under development to establish effective treatments for FOP.