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Eileen M Shore

Publications and source records attributed to Eileen M Shore.

13 recordsLinked to original sources
PubMed2025

Medical guidelines for fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in "The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations" which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

ACVR1↗
PubMed2005

Developmental anomalies of the cervical spine in patients with fibrodysplasia ossificans progressiva are distinctly different from those in patients with Klippel-Feil syndrome: clues from the BMP signaling pathway.

STUDY DESIGN: A radiographic analysis of the cervical spine of 70 patients diagnosed with fibrodysplasia ossificans progressiva (FOP) and 33 diagnosed with Klippel-Feil (KF) syndrome was conducted. OBJECTIVES: The objectives of this study were to describe cervical spine abnormalities in patients with FOP, to compare and contrast those findings with the malformations in patients with KF syndrome, and to examine the possible etiology of these abnormalities. SUMMARY OF BACKGROUND DATA: Congenital features of diseases often provide seminal clues to underlying etiology and developmental pathways. While progressive metamorphosis of connective tissue to heterotopic bone is the most dramatic and disabling feature of FOP, less severe congenital anomalies of the skeleton are also present. Vertebral fusions observed in KF are consistent with defects in embryonic segmentation. METHODS: The cervical spine plain films of 70 FOP patients and 33 KF patients with documented congenital abnormalities were reviewed. RESULTS: Generalized neck stiffness and decreased range of motion were noted in most children with FOP. In the FOP patient group, characteristic anomalies, including large posterior elements, tall narrow vertebral bodies,and fusion of the facet joints between C2 and C7, were observed. Most notably, these characteristic anomalies of the cervical spine in patients with FOP were distinctly different from those of 33 patients with KF that were examined but were strikingly similar to those seen in mice with homozygous deletions of the gene-encoding noggin, a bone morphogenetic protein (BMP) antagonist. CONCLUSIONS: FOP patients exhibit a characteristic set of congenital spine malformations. While the noggin gene (NOG) is not mutated in patients who have FOP, these findings extend a growing body of evidence implicating overactivity of the BMP signaling pathway in the molecular pathogenesis of FOP.

Adolescent↗
PubMed2005

Fibrodysplasia ossificans progressiva (FOP), a disorder of ectopic osteogenesis, misregulates cell surface expression and trafficking of BMPRIA.

UNLABELLED: FOP is a disorder in which skeletal muscle is progressively replaced with bone. FOP lymphocytes, a model system for exploring the BMP pathway in these patients, exhibit a defect in BMPRIA internalization and increased activation of downstream signaling, suggesting that altered BMP receptor trafficking underlies ectopic bone formation in this disease. INTRODUCTION: Fibrodysplasia ossificans progressiva (FOP) is a severely disabling disorder characterized by progressive heterotopic ossification of connective tissues. Whereas the genetic defect and pathophysiology of this condition remain enigmatic, BMP4 mRNA and protein are overexpressed, and mRNAs for a subset of secreted BMP antagonists are not synthesized at appropriate levels in cultured lymphocytes from FOP patients. These data suggest involvement of altered BMP signaling in the disease. In this study, we investigate whether the abnormality is associated with defective BMP receptor function in lymphocytes. MATERIALS AND METHODS: Cell surface proteins were quantified by fluorescence-activated cell sorting (FACS). Protein phosphorylation was assayed by immunoprecipitation and immunoblotting. Protein synthesis and degradation were examined by [35S]methionine labeling and pulse-chase assays. mRNA was detected by RT-PCR. RESULTS: FOP lymphocytes expressed 6-fold higher levels of BMP receptor type IA (BMPRIA) on the cell surface compared with control cells and displayed a marked reduction in ligand-stimulated internalization and degradation of BMPRIA. Moreover, in control cells, BMP4 treatment increased BMPRIA phosphorylation, whereas BMPRIA showed ligand-insensitive constitutive phosphorylation in FOP cells. Our data additionally support that the p38 mitogen-activated protein kinase (MAPK) signaling pathway is a major BMP signaling pathway in these cell lines and that expression of inhibitor of DNA binding and differentiation 1 (ID-1), a transcriptional target of BMP signaling, is enhanced in FOP cells. CONCLUSIONS: These data extend our previous observations of misregulated BMP4 signaling in FOP lymphocytes and show that cell surface overabundance and constitutive phosphorylation of BMPRIA are associated with a defect in receptor internalization. Altered BMP receptor trafficking may play a significant role in FOP pathogenesis.

Bone Morphogenetic Protein 4↗
PubMed2004

Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva.

Flare-ups of fibrodysplasia ossificans progressiva are most commonly triggered by soft tissue trauma. After observing severe flare-ups of fibrodysplasia ossificans progressiva in two half-sisters with culture-confirmed influenza B infections, we hypothesized that influenza-like viral illnesses also can trigger fibrodysplasia ossificans progressiva flare-ups. To address this hypothesis, we designed a questionnaire to assess whether patients with fibrodysplasia ossificans progressiva experienced influenza symptoms during the 2000 to 2001 influenza season, and whether these symptoms were correlated with flare-ups of the condition. The questionnaire was sent to patients with fibrodysplasia ossificans progressiva worldwide. Of the 264 patients surveyed, 123 (47%) responded. The survey revealed that the risk of a disease flare-up of fibrodysplasia ossificans progressiva during an influenza-like viral illness was increased at least threefold and possibly much more. The survey data strongly supported the hypothesis that influenza-like viral illnesses are associated with disease flare-ups in patients who have fibrodysplasia ossificans progressiva. Influenza-like viral illnesses may be a source of previously unrecognized muscle injury leading to heterotopic ossification and permanent loss of mobility in these patients. These findings have important implications for understanding and preventing environmental triggers of disease activity in this population of patients genetically susceptible to progressive heterotopic ossification.

Adolescent↗
PubMed2003

Progressive osseous heteroplasia in the face of a child.

We describe a rare case of progressive osseous heteroplasia of the face in a child. Biopsy showed osteoma cutis superficially with ectopic bone formation in the deeper tissues including skeletal muscle. Analysis of DNA from peripheral blood leukocytes showed mutations in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1), confirming the diagnosis of progressive osseous heteroplasia.

Child↗
PubMed2003

Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa-1: clues to a vascular origin of heterotopic ossification?

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable genetic disorder, which is characterized pathologically by sporadic episodes of explosive growth of mesenchymal cells in skeletal muscle followed by cellular differentiation to heterotopic bone through an endochondral process. This study examined the histological origin and differentiation state of stromal cells in early FOP lesions and investigated the association between the phenotype of these FOP cells and bone formation. Interestingly, FOP lesional stromal cells were found to display characteristics of the smooth muscle (SM) cell lineage and are therefore potentially of vascular origin. These cells co-express multiple SM lineage markers along with multiple proteins associated with bone formation including the obligate osteogenic transcription factor Runx2/Cbfa-1. It is hypothesized that the stromal cells of early FOP lesions may be locally recruited vascular cells or cells of the bone marrow stroma and that these cells maintain the potential (given the correct environmental stimuli) to differentiate along an endochondral ossification pathway.

Biopsy↗
PubMed2003

Bone morphogenetic protein-4 regulation in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva is a rare genetic disorder in which connective tissues are replaced with heterotopic bone through an endochondral process. Bone morphogenetic protein-4 messenger ribonucleic acid and protein levels are elevated in the cells of patients with fibrodysplasia ossificans progressiva, but the molecular mechanism of this steady-state elevation is unknown. Nuclear run-on assays and messenger ribonucleic acid stability assays were done to examine the molecular mechanisms of increased bone morphogenetic protein-4 messenger ribonucleic acid. The bone morphogenetic protein-4 transcription rate in patient cells was found to be enhanced fivefold to sevenfold over normal control cells, suggesting that elevated steady-state levels of this transcript were attributable at least in part to an enhancement in transcription initiation. The stability of bone morphogenetic protein-4 messenger ribonucleic acid was found to be similar for patient and control cells and to have an extremely brief half-life, with bone morphogenetic protein-4 messenger ribonucleic acid almost completely decayed (75%) by 40 minutes. This unusually brief half-life suggests that a high fidelity control over temporal expression of the bone morphogenetic protein 4-message can be maintained. The data document that enhanced transcription rather than increased messenger ribonucleic acid stability is responsible for the elevation in steady-state levels of bone morphogenetic protein-4 messenger ribonucleic acid, and suggest that an inappropriate enhancement of the rate of bone morphogenetic protein-4 transcription plays a critical role in the molecular pathophysiology of fibrodysplasia ossificans progressiva.

Adult↗
PubMed2003

Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva is a disabling genetic disorder characterized by congenital skeletal malformations and progressive heterotopic ossification. New episodes of ossification are heralded by preosseous inflammatory lesions replete with B and T lymphocytes that overexpress bone morphogenetic protein-4. NF-kappaB is an inflammatory mediator that plays a critical role in developmental skeletogenesis and in suppression of bone morphogenetic protein-4 expression. Because of its multiple roles in inflammation, skeletogenesis, and bone morphogenetic protein-4 regulation, NF-kappaB may play an important functional role in the pathogenesis of fibrodysplasia ossificans progressiva. To clarify the potential role of NF-kappaB in the pathophysiologic features of fibrodysplasia ossificans progressiva, the role of NF-kappaB in regulating bone morphogenetic protein-4 signaling in patient-derived lymphoblastoid cell lines was examined. General NF-kappaB activity and specific NF-kappaB suppression of bone morphogenetic protein-4 expression were not altered in fibrodysplasia ossificans progressiva. In addition, despite the proximity of the gene for the p50 subunit of NF-kappaB (NFKB1 on long arm of chromosome 4) to the recently mapped locus for fibrodysplasia ossificans progressiva, a detailed linkage exclusion analysis in four multigenerational families with the disorder excluded NFKB1 as the causative gene for fibrodysplasia ossificans progressiva. These data exonerate NF-kappaB as the critical molecular and genetic pathogenic mediator in fibrodysplasia ossificans progressiva and, therefore, implicate a defect in another regulatory pathway as the cause for bone morphogenetic protein-4 overexpression in the disease.

Alleles↗
PubMed2003

Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis.

BACKGROUND: Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by congenital malformations of the great toes and by progressive heterotopic bone formation. Bone morphogenetic protein-4 (BMP-4) messenger ribonucleic acid (mRNA) and protein are uniquely overexpressed in lymphocytes and lesional cells from patients who have fibrodysplasia ossificans progressiva. However, the BMP-4 gene is not mutated in fibrodysplasia ossificans progressiva. The activities of BMPs are specified in part by the formation of morphogen gradients that are further regulated by an array of secreted antagonists. Recent studies have indicated that BMP-4 upregulates the expression of the BMP antagonists noggin, gremlin, and follistatin, thereby establishing an autoregulatory feedback loop. Therefore, a defect in the feedback pathway between BMP-4 and one or more of its extracellular antagonists could contribute to the elevated BMP-4 activity characteristic of fibrodysplasia ossificans progressiva. METHODS: Basal and BMP-4-induced expression of noggin, gremlin, follistatin, and chordin mRNA were investigated in control and fibrodysplasia ossificans progressiva lymphoblastoid cell lines with use of reverse transcriptase-polymerase chain reaction and Northern analysis. RESULTS: In the absence of exogenous BMP-4 stimulation (basal state), steady-state levels of all of the BMP antagonists that were investigated were similar in fibrodysplasia ossificans progressiva and control cell lines. Upon stimulation with recombinant human BMP-4, control lymphoblastoid cell lines exhibited a marked increase in expression of noggin and gremlin mRNA. Fibrodysplasia ossificans progressiva cells, however, showed a dramatically attenuated response to BMP-4 stimulation compared with that of controls. CONCLUSIONS: These data indicate a paresis of a BMP-antagonist response, suggesting the loss of a negative feedback mechanism by which cells normally regulate the magnitude and boundaries of ambient morphogenetic signals. This paresis may account in part for the increased BMP-4 activity in fibrodysplasia ossificans progressiva.

Bone Morphogenetic Protein 4↗
PubMed2003

In vivo somatic cell gene transfer of an engineered Noggin mutein prevents BMP4-induced heterotopic ossification.

BACKGROUND: The formation of the skeleton requires inductive signals that are balanced with their antagonists in a highly regulated negative feedback system. Inappropriate or excessive expression of BMPs (bone morphogenetic proteins) or their antagonists results in genetic disorders affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP signaling mediated through binding to its receptors is a critical step in the induction of abnormal ossification. Therefore, we hypothesized that engineering more effective inhibitors of this BMP-signaling process may lead to the development of therapies for such conditions. METHODS: BMP4-induced heterotopic ossification was used as a model for testing the ability of the BMP antagonist Noggin to block de novo bone formation, either by local or systemic delivery. Since Noggin naturally acts locally, a Noggin mutein, hNOGDeltaB2, was engineered and was shown to circulate systemically, and its ability to block heterotopic ossification was tested in a mouse model with use of adenovirus-mediated somatic cell gene transfer. RESULTS: A mouse model of BMP4-induced heterotopic ossification was developed. Local delivery of wild-type NOG inhibited heterotopic ossification, but systemic administration was ineffective. In contrast, systemic delivery of the adenovirus encoding hNOGDeltaB2 resulted in systemic levels that persisted for more than two weeks and were sufficient to block BMP4-induced heterotopic ossification. CONCLUSIONS: BMP4-induced heterotopic ossification can be prevented in vivo either by local delivery of wild-type Noggin or after somatic cell gene transfer of a Noggin mutein, hNOGDeltaB2. Furthermore, the data in the present study provide proof of concept that a naturally occurring factor can be engineered for systemic delivery toward a desirable pharmacological outcome. CLINICAL RELEVANCE: Blocking bone formation is clinically relevant to disorders of heterotopic ossification in humans, such as fibrodysplasia ossificans progressiva. Furthermore, development of BMP antagonists as therapeutic agents may provide modalities for the treatment of other pathologic conditions that arise from aberrant expression of BMPs and/or from a lack of their antagonists.

Adenoviridae↗
PubMed2002

Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.

BACKGROUND: Progressive osseous heteroplasia (POH), an autosomal dominant disorder, is characterized by extensive dermal ossification during childhood, followed by disabling and widespread heterotopic ossification of skeletal muscle and deep connective tissue. Occasional reports of mild heterotopic ossification in Albright's hereditary osteodystrophy (AHO) and a recent report of two patients with AHO who had atypically extensive heterotopic ossification suggested a common genetic basis for the two disorders. AHO is caused by heterozygous inactivating mutations in the GNAS1 gene that result in decreased expression or function of the alpha subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase. METHODS: We tested the hypothesis that GNAS1 mutations cause POH, using the polymerase chain reaction to amplify GNAS1 exons and exon-intron boundaries in 18 patients with sporadic or familial POH. RESULTS: Heterozygous inactivating GNAS1 mutations were identified in 13 of the 18 probands with POH. The defective allele in POH is inherited exclusively from fathers, a result consistent with a model of imprinting for GNAS1. Direct evidence that the same mutation can cause either POH or AHO was observed within a single family, in which the phenotype correlated with the parental origin of the mutant allele. CONCLUSIONS: Paternally inherited inactivating GNAS1 mutations cause POH. This finding extends the range of phenotypes derived from haplo insufficiency of GNAS1, provides evidence that imprinting is a regulatory mechanism for GNAS1 expression, and suggests that Gsalpha is a critical negative regulator of osteogenic commitment in nonosseous connective tissues.

Base Sequence↗
PubMedDate not supplied

Heterotopic ossification.

Heterotopic ossification, the formation of bone in soft tissue, requires inductive signaling pathways, inducible osteoprogenitor cells, and a heterotopic environment conducive to osteogenesis. Little is known about the molecular pathogenesis of this condition. Research into two rare heritable and developmental forms, fibrodysplasia ossificans progressiva and progressive osseous heteroplasia, has provided clinical, pathologic, and genetic insights. In fibrodysplasia ossificans progressiva, overexpression of bone morphogenetic protein 4 and underexpression of multiple antagonists of this protein highlight the potential role of a potent morphogenetic gradient. Research on fibrodysplasia ossificans progressiva also has led to the identification of the genetic cause of progressive osseous heteroplasia: inactivating mutations in the alpha subunit of the gene coding for the stimulatory G protein of adenylyl cyclase. Better understanding of the complex developmental and molecular pathology of these disorders may lead to more effective strategies to prevent and treat other, more common forms of heterotopic ossification.

Adolescent↗