The Metamorphosis.
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Bone Morphogenetic Protein 4↗
Biomedical subjects
F S Kaplan
Publications and source records attributed to F S Kaplan.
Acute lymphocytic infiltration in an extremely early lesion of fibrodysplasia ossificans progressiva.
A 2-year-old child with fibrodysplasia ossificans progressiva underwent a muscle biopsy of a very early lesion, and had findings that showed the earliest stage ever seen in the histopathology of fibrodysplasia ossificans progressiva. This very early stage consisted of intense perivascular lymphocytic infiltration into normal appearing skeletal muscle. A nearly identical histopathologic sequence was noted in a cat with phenotypic features similar to those of fibrodysplasia ossificans progressiva in humans. These new findings represent the earliest documented changes that have ever been noted in fibrodysplasia ossificans progressiva, and provide further histopathologic support for the recent discovery that lymphocytes may play a role in the pathogenesis of heterotopic ossification in fibrodysplasia ossificans progressiva.
Animals↗
Characterization of bone morphogenetic protein 4 receptor in fibrodysplasia ossificans progressiva.
Bone morphogenetic protein 4, a potent osteogenic morphogen, has been implicated in fibrodysplasia ossificans progressiva because it is uniquely overexpressed in lymphoblastoid cells and preosseous fibroproliferative lesional cells of patients with fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 signals through a heteromeric complex of serine/ threonine kinase receptors (type I and type II) on the surface of responding cells. Semi-quantitative competitive reverse transcription polymerase chain reaction was used to quantitate steady state levels of messenger ribonucleic acid expression for bone morphogenetic protein 4 and the bone morphogenetic protein receptors. These data confirmed the previous finding of elevated steady state levels of bone morphogenetic protein 4 messenger ribonucleic acid in lymphoblastoid cell lines of affected individuals in a family that exhibited autosomal dominant inheritance of fibrodysplasia ossificans progressiva. There were no differences in the steady state levels of messenger ribonucleic acid for either the Type I or Type II bone morphogenetic protein 4 receptors between affected and unaffected individuals in that same family. The presence of bone morphogenetic protein 4 receptor messenger ribonucleic acid in fibrodysplasia ossificans progressiva lesional tissue and unaffected muscle tissue and demonstrates the deregulation of bone morphogenetic protein 4 messenger ribonucleic acid in fibrodysplasia ossificans progressiva. These data support the hypothesis that the molecular basis of bone morphogenetic protein 4 signaling is abnormal in fibrodysplasia ossificans progressiva.
Bone Morphogenetic Protein 4↗
Differential expression of bone and cartilage related genes in fibrodysplasia ossificans progressiva, myositis ossificans traumatica, and osteogenic sarcoma.
Fibrodysplasia ossificans progressiva, myositis ossificans traumatica, and osteogenic sarcoma are representative genetic, traumatic, and neoplastic disorders of osteogenesis, respectively. However, the pathology, pathophysiology, and natural history of the disorders differ substantially. Gene expression related to bone induction was studied in these disorders. Primary cell lines established from lesional tissues derived from each of these disorders expressed different patterns of protooncogenes, bone morphogenetic protein genes, and bone phenotype specific genes. The osteogenic sarcoma cell line expressed the entire repertoire bone morphogenetic proteins 1 to 7, c-fos and c-jun messenger ribonucleic acids. Myositis ossificans traumatica cells expressed phenotype markers similar to those of the osteogenic sarcoma cells, and expressed bone morphogenetic proteins 1, 4, and 6 and c-fos messenger ribonucleic acids, but not c-jun messenger ribonucleic acid. Fibrodysplasia ossificans progressiva early lesional cells demonstrated specific over-expression of bone morphogenetic protein 4 messenger ribonucleic acid. Differential expression of genes related to osteogenesis have important implications for understanding the earliest molecular events in normal and dysregulated osteogenesis in humans.
Adolescent↗
Embryonic overexpression of the c-Fos protooncogene. A murine stem cell chimera applicable to the study of fibrodysplasia ossificans progressiva in humans.
Murine embryonic overexpression of the c-fos protooncogene leads to early postnatal heterotopic chondrogenesis and osteogenesis with phenotypic features similar to those seen in children who have the disabling heritable disease fibrodysplasia ossificans progressiva. The overexpression of Fos in embryonic stem cell chimeras leads to heterotopic endochondral osteogenesis at least in part through a bone morphogenetic protein 4 mediated signal transduction pathway. In contrast, early fibrodysplasia ossificans progressiva lesions express abundant bone morphogenetic protein 4, without abundant expression of c-Fos, suggesting that the primary molecular defect in fibrodysplasia ossificans progressiva may be independent of the sustained Fos effects on chondrogenesis and osteogenesis. Comparisons of the clinical, molecular, and pathogenetic features of the c-Fos embryonic stem cell chimeras with those of fibrodysplasia ossificans progressiva provide insight into the earliest events in the molecular pathogenesis of genetically induced heterotopic chondrogenesis and osteogenesis. The relevance of the c-Fos embryonic stem cell chimera to the study of the currently untreatable human disease fibrodysplasia ossificans progressiva demonstrates the power of using embryonic stem cell technology for generating gain of function mutations in the study of human bone disease.
Animals↗
Pulmonary and cardiac function in advanced fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva is a rare genetic disease characterized by heterotopic ossification in soft tissues. Severe disability results from progressive immobilization of the limbs, jaw, and chest wall. To determine whether cardiac function is altered in this disease, 25 patients ranging in age from 5 to 55 years (disease duration 1-51 years) were studied. History, physical examination, pulmonary functions, electrocardiography, and echocardiography were performed on each patient. Physical examination of the lungs and heart was unrevealing; no right sided ventricular gallops were heard, and no patient was found to have neck vein distention or peripheral edema. The patients had extremely limited chest expansion (1.9 +/- 0.8 inches), suggesting dependence on diaphragmatic breathing. Lung volumes were severely reduced (mean forced vital capacity 44% +/- 14% of predicted), but flow rates were relatively normal. All patients had normal capillary oxygen saturation. Echocardiography was technically difficult, but no abnormalities of left or right ventricular function were seen. Ten (40%) patients had electrocardiographic evidence of right ventricular dysfunction. Compared with patients without such evidence, these patients were older, had significantly longer disease duration, higher hemoglobin, and more impaired pulmonary function. The results of this study suggest that the presence of severely restrictive chest wall disease is associated with a high incidence of right ventricular abnormalities on electrocardiogram. Whether cor pulmonale will eventually occur remains to be determined.
Adolescent↗
Catastrophic falls in patients who have fibrodysplasia ossificans progressiva.
There have been numerous anecdotal reports of catastrophic falls in patients with fibrodysplasia ossificans progressiva. To determine the incidence of serious morbidity and mortality associated with falls in this patient population, the authors surveyed the 135 patient members of the International Fibrodysplasia Ossificans Progressiva Association and an age and gender matched control group. Eighty-one percent of the fibrodysplasia ossificans progressiva population suffered a fall resulting in injury compared with 44% of the controls. Sixty-seven percent of the falls initiated a painful flareup of fibrodysplasia ossificans progressiva leading to permanent loss of movement in almost all patients. Fifty-four percent of all falls suffered by the fibrodysplasia ossificans progressiva group led to permanent disability compared with 4% of all falls in the control group. Although trauma to the head was a common site of injury in both groups, the injury profile in the fibrodysplasia ossificans progressiva group included traumatic brain injuries, intracranial hemorrhage and death whereas the control group suffered mostly minor soft tissue lacerations. Deficiencies in coordinate gait and protective function likely accounted for the severity of injuries especially to the head in the fibrodysplasia ossificans progressiva population. Precautions are recommended that are intended to minimize the risk of injury without compromising a patient's functional level and independence. These recommendations include limitation of high risk activities, protective head gear, safety improvements in living environments, and augmentation of stabilizing and protective functions.
Accidental Falls↗
Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin.
Retinoids are a plausible family of therapeutic agents for fibrodysplasia ossificans progressiva due to their ability to inhibit differentiation of mesenchymal tissue into cartilage and bone. A prospective study was conducted to assess the efficacy of isotretinoin (13-cis-retinoic acid) in the prevention of heterotopic ossification in patients who had fibrodysplasia ossificans progressiva. Eleven anatomic regions were assessed in each of 21 patients by clinical examination, radiographs, and bone scans. An anatomic region was considered to be involved if there was clinical, radiographic, or radionuclide evidence of orthotopic or heterotopic ossification anywhere in the region. There were 143 involved anatomic regions and 88 uninvolved anatomic regions at the beginning of the study. Only one of the 88 anatomic regions that was completely uninvolved at the beginning of the study became involved during isotretinoin therapy. However, 16 of the 21 patients (76%) had major flare ups develop in 38 of 143 (27%) previously involved anatomic regions while administered isotretinoin therapy. Isotretinoin at steady state doses of 1 to 2 mg/kg per day decreased the incidence of heterotopic ossification at uninvolved anatomic regions compared with an external control group, as long as the medication was started before the appearance of any orthotopic or heterotopic ossification in that anatomic region. The data did not allow the determination of whether isotretinoin was effective or detrimental in preventing disease flareups in regions that had even minimal orthotopic or heterotopic ossification at the time the therapy began. Extreme caution should be exercised when using this medication in patients who have fibrodysplasia ossificans progressiva.
Adolescent↗
Pseudomalignant heterotopic ossification.
Pseudomalignant heterotopic ossification is a rare, self limited connective tissue disorder of unknown origin that may occur atypically during childhood and can simulate either soft tissue sarcoma or fibrodysplasia ossificans progressiva. A complex constellation of diagnostic features usually enable the differentiation of pseudomalignant heterotopic ossification from extraosseous osteosarcoma and fibrodysplasia ossificans progressiva during a time span of approximately 8 to 12 weeks. Orthopaedic surgeons who treat children with connective tissue tumors should be familiar with pseudomalignant heterotopic ossification and its differential diagnosis. The occasional mild and variable expression of fibrodysplasia ossificans progressiva rarely may make it more difficult to distinguish from pseudomalignant heterotopic ossification. It is possible that pseudomalignant heterotopic ossification is a form fruste of fibrodysplasia ossificans progressiva.
Child↗
Progressive osseous heteroplasia. Report of a family.
We report a case of progressive osseous heteroplasia in a female infant who had progressive ossification of the skin and deep connective tissues. Isolated dermal ossification is present in her father and younger sister suggesting an autosomal dominant mode of inheritance with variable expressivity or possible somatic mosaicism. This report of a family with progressive osseous heteroplasia contributes to the understanding of this uncommon genetic disorder, which must be distinguished from fibrodysplasia ossificans progressiva and Albright's hereditary osteodystrophy. The paucity of familial cases of progressive osseous heteroplasia currently limits the use of a genome-wide linkage analysis, but linkage exclusion analysis with promising candidate genes is a possibility.
Adult↗
Osteoporosis. Definition and clinical presentation.
Osteoporosis is a skeletal condition characterized by decreased density (mass/volume) of normally mineralized bone. The reduced bone density leads to decreased mechanical strength, thus making the skeleton more likely to fracture. Postmenopausal osteoporosis (Type I) and age-related osteoporosis (Type II) are the most common primary forms of bone loss seen in clinical practice. Secondary causes of osteoporosis include hypercortisolism, hyperthyroidism, hyperparathyroidism, alcohol abuse, and immobilization. In the development of osteoporosis, there is often a long latent period before the appearance of the main clinical manifestation, pathologic fractures. The earliest symptom of osteoporosis is often an episode of acute back pain caused by a pathologic vertebral compression fracture, or an episode of groin or thigh pain caused by a pathologic hip fracture. In the diagnostic process, the extent and severity of bone loss are evaluated and secondary forms of bone loss are excluded. A careful diagnostic work-up that includes clinical history, physical examination, laboratory evaluation, bone densitometry, and radiographic imaging will allow the clinician to determine the cause of osteoporosis and to institute medical interventions that will stabilize and even reverse this frequently preventable condition.
Back Pain↗
Fibrodysplasia ossificans progressiva: why do some people have two skeletons?
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Adult↗
Bone morphogenetic protein 2/4 in early fibromatous lesions of fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification in distinct anatomic patterns. Early preosseous lesions in FOP are clinically and histologically indistinguishable from the lesions of aggressive juvenile fibromatosis (AJF). Although the genetic defect in FOP is unknown, bone morphogenetic proteins (BMPs) 2 and 4 are plausible candidates genes. To determine if there is a difference in BMP 2/4 expression in the early fibromatous lesions of the two conditions, we performed immunohistochemical studies with a monoclonal antibody to BMP 2/4 on the earliest detectable fibromatous lesions of FOP and compared them with histologically identical lesions resected from children who had AJF. Fibromatous cells from the early FOP lesions exhibited immunostaining for BMP 2/4, whereas histologically indistinguishable fibromatous cells from AJF lesions showed no evidence of BMP 2/4 immunostaining. It is incumbent on all physicians who treat patients with suspected fibromatosis to examine the toes to rule out FOP and to avoid unnecessary diagnostic biopsies because surgical trauma induces further bone formation in patients who have FOP. However, if diagnostic confusion still exists and a biopsy is performed, immunostaining with BMP 2/4 antibody may resolve the diagnostic dilemma between FOP and AJF before the appearance of heterotopic ossification is observed in the FOP lesions. Our data suggest that the BMP 2/4 subfamily of secreted proteins may be involved in the pathogenesis of the FOP lesions.
Alkaline Phosphatase↗
Limb swelling in patients who have fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva is a rare heritable disorder of connective tissue characterized by progressive heterotopic ossification of soft tissues and by congenital malformation of the great toes. Limb swelling has also been noted, yet little is known about this complication of fibrodysplasia ossificans progressiva. To determine the prevalence of limb swelling in this condition, the authors reviewed detailed medical records on 74 patients (25 males, 49 females; age range, 1-49 years) who had a documented history of fibrodysplasia ossificans progressiva. The study population included more than 90% of all patients known to have fibrodysplasia ossificans progressiva in the United States. Acute swelling of the limbs occurred in association with flareups of the condition in nearly all cases. Acute swelling in the upper limbs was focal and nodular in contrast to acute swelling in the lower limbs, which was more diffuse. Acute swelling in the upper limbs occurred in all 74 patients whereas acute swelling in the lower limbs occurred in 47 of the 74 patients (64%). Two of the 74 patients who had acute swelling in the lower limbs (4%) had a documented episode of deep vein thrombophlebitis. Chronic swelling in the upper limbs occurred in 9 of the 74 patients (12%) and was not seen before the age of 12 years. Chronic swelling in the lower limbs occurred in 36 of the 74 patients (49%) and was not seen before the age of 9 years. The intense angiogenesis and edema seen on histopathologic evaluation of preosseous fibrodysplasia ossificans progressiva lesions may play a role in the pathogenesis of the limb swelling. The data show an age related prevalence of limb swelling in fibrodysplasia ossificans progressiva and suggest a model for understanding the complex pathways leading to limb swelling in this disorder.
Adolescent↗
Fibrodysplasia ossificans progressiva (FOP).
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Child, Preschool↗
Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva.
BACKGROUND: Fibrodysplasia ossificans progressiva is a heritable disorder of connective tissue characterized by congenital malformation of the great toes and postnatal formation of ectopic bone. Although the disorder was first described more than 300 years ago, the genetic defect and pathophysiology remain unknown. Bone morphogenetic proteins are potent bone-inducing morphogens that participate in the developmental organization of the skeleton, and increased production of one or more of these proteins has been proposed as the cause of fibrodysplasia ossificans progressiva. METHODS: We studied lymphoblastoid cell lines established from peripheral-blood mononuclear cells of patients with fibrodysplasia ossificans progressiva and fibroblast-like cell lines derived from lesional and nonlesional tissue. We used Northern blot analysis and ribonuclease protection assays to measure the expression of messenger RNA (mRNA) of bone morphogenetic proteins 1 to 7 and immunohistochemical analysis to examine protein expression. RESULTS: Among the bone morphogenetic proteins and mRNAs examined, only bone morphogenetic protein 4 and its mRNA were present in increased levels in cells derived from an early fibroproliferative lesion in a patient with fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 mRNA was expressed in lymphoblastoid cell lines from 26 of 32 patients with fibrodysplasia ossificans progressiva but from only 1 of 12 normal subjects (P<0.001). Bone morphogenetic protein 4 and its mRNA were detected in the lymphoblastoid cell lines from a man with fibrodysplasia ossificans progressiva and his three affected children (two girls and a boy), but not from the children's unaffected mother. No other bone morphogenetic proteins were detected. CONCLUSIONS: Overexpression of a potent bone-inducing morphogen (bone morphogenetic protein 4) in lymphocytes is associated with the disabling ectopic osteogenesis of fibrodysplasia ossificans progressiva.
Bone Morphogenetic Proteins↗
Fibrodysplasia ossificans progressiva in two half-sisters: evidence for maternal mosaicism.
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of connective tissue characterized by congenital malformation of the great toes and by progressive heterotopic ossification of the soft tissues in specific anatomic and temporal patterns. We observed classic findings of FOP in 2 Native American half-sisters with the same unaffected mother and different unaffected fathers. This is the first report of FOP in sibs from different pregnancies with unaffected parents. The findings in this family indicate the possibility of maternal gonadal mosaicism in FOP and provide important new data for genetic counseling in this disease.
Adolescent↗
Fibrodysplasia ossificans progressiva: searching for the skeleton key.
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Animals↗