transforming-growth-factor-beta and Myositis-Ossificans

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily. BMPs play crucial roles in embryogenesis and bone remodeling. Recently, BMP signaling has been found to have diverse effects on different types of tumors. In this review, we summarized the effects of BMP signaling on gynecologic cancer. BMP signaling has tumor-promoting effects on ovarian cancer (OC) and endometrial cancer (EC), whereas it has tumor-suppressing effects on uterine cervical cancer (UCC). Interestingly, EC has frequent gain-of-function mutations in ACVR1, encoding one of the type I BMP receptors, which are also observed in fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Little is known about the relationship between BMP signaling and other gynecologic cancers. Tumor-promoting effects of BMP signaling in OC and EC are dependent on the promotion of cancer stemness and epithelial-mesenchymal transition (EMT). In accordance, BMP receptor kinase inhibitors suppress the cell growth and migration of OC and EC. Since both cancer stemness and EMT are associated with chemoresistance, BMP signaling activation might also be an important mechanism by which OC and EC patients acquire chemoresistance. Therefore, BMP inhibitors are promising for OC and EC patients even if they become resistant to standard chemotherapy. In contrast, BMP signaling inhibits UCC growth in vitro. However, the in vivo effects of BMP signaling have not been elucidated in UCC. In conclusion, BMP signaling has a variety of functions, depending on the types of gynecologic cancer. Therefore, targeting BMP signaling should improve the treatment of patients with gynecologic cancer.

Topics: Bone Morphogenetic Proteins; Epithelial-Mesenchymal Transition; Female; Humans; Myositis Ossificans; Neoplasms; Signal Transduction; Transforming Growth Factor beta

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease caused by heterozygous missense mutations in Activin A receptor type I which is also known as Activin-like kinase 2 (ALK2), a type I receptor of Bone Morphogenetic Proteins(BMP). Patients with FOP usually undergo episodic flare-ups and the heterotopic ossification in soft and connective tissues. Molecular mechanism study indicates that Activin A, the ligand which normally transduces Transforming Growth Factor Beta signaling, abnormally activates BMP signaling through ALK2 mutants in FOP, leading to heterotopic bone formation. To date, effective therapies to FOP are unavailable. However, significant advances have recently been made in the development of FOP drugs. In this article, we review the recent advances in understanding the FOP mechanism and drug development, with a focus on the small-molecular and antibody drugs currently in the clinical trials for FOP treatment.

Topics: Activins; Bone Morphogenetic Proteins; Drug Development; Humans; Ligands; Mutation; Myositis Ossificans; Ossification, Heterotopic; Transforming Growth Factor beta

Heterotopic ossification (HO), a serious disorder of extra-skeletal bone formation, occurs as a common complication of trauma or in rare genetic disorders. Many conserved signaling pathways have been implicated in HO; however, the exact underlying molecular mechanisms for many forms of HO are still unclear. The emerging picture is that dysregulation of bone morphogenetic protein (BMP) signaling plays a central role in the process, but that other conserved signaling pathways, such as Hedgehog (HH), Wnt/β-catenin and Fibroblast growth factors (FGF), are also involved, either through cross-talk with BMP signaling or through other independent mechanisms. Deep understanding of the conserved signaling pathways is necessary for the effective prevention and treatment of HO. In this review, we update and integrate recent progress in this area. Hopefully, our discussion will point to novel promising, druggable loci for further translational research and successful clinical applications.

Topics: Animals; Bone Morphogenetic Proteins; Fibroblast Growth Factors; Humans; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; Transforming Growth Factor beta

Bone is a unique organ because it can be experimentally induced in soft tissues by implanting a single growth factor, bone morphogenetic protein (BMP). Heterotopic bone-inducing activity was found in demineralized bone matrix in 1965. The characterization of this activity in bone enabled the purification and molecular cloning of BMPs and showed that they are members of the transforming growth factor-β (TGF-β) superfamily. Assay systems developed for this bone-inducing activity revealed the molecular mechanisms of the intracellular signaling of members of the superfamily, including BMPs. Moreover, they are being applied to elucidate molecular mechanisms and to develop novel therapeutics for a disease caused by an abnormality in BMP signaling.

Topics: Animals; Bone Morphogenetic Proteins; Humans; Myositis Ossificans; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic bone formation in skeletal muscle tissue. In 2007, FOP was authorized as one of the Intractable Disorders by the Ministry of Health, Labour and Welfare of Japan. The Research Committee on FOP is working on the molecular mechanisms underlying heterotopic bone formation and the development of new treatments for FOP.

Topics: Activin Receptors, Type I; Bone Morphogenetic Proteins; Drug Discovery; Genes, Dominant; Humans; Molecular Targeted Therapy; Mutation; Myositis Ossificans; Pyrazoles; Pyrimidines; Signal Transduction; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic condition that leads to the formation of a second (heterotopic) skeleton, and is the most catastrophic disorder of heterotopic ossification in humans. Throughout childhood and early adult life, FOP progressively immobilizes all of the joints of the normotopic skeleton, rendering movement impossible. At present, there is no effective prevention or treatment. Recently, a recurrent mutation in the glycine-serine activation domain of the activin receptor IA/activin-like kinase-2, a bone morphogenetic protein type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved druggable target in the TGF-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for activin-like kinase-2. Effective therapies for FOP, and possibly for a vast array of more common conditions of heterotopic ossification, will be based on blocking activin-like kinase-2, a critical node in the BMP signaling pathway.

Topics: Activin Receptors, Type I; Animals; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Proteins; Disease Models, Animal; Drug Design; Humans; Mutation; Myositis Ossificans; Ossification, Heterotopic; Protein Kinase Inhibitors; Signal Transduction; Transforming Growth Factor beta

The potential for regeneration and repair of bone is well known. This article conveys the current progress in the realm of bone morphogenetic proteins and their potential for initiating fracture repair cascade. Demineralized bone matrix induces bone formation and has served as a model for the bone repair cascade. A family of bone morphogenetic proteins has been identified, isolated, and cloned from the demineralized bone matrix. Bone morphogenetic proteins are pleiotropic regulators of chemotaxis, mitosis, and differentiation. The bone morphogenetic protein receptors, Types I and II, bind bone morphogenetic proteins and act in collaboration to transduce the phosphorylation of Smad 1 and Smad 5, which enter the nucleus in partnership with Smad 4 to initiate bone morphogenetic protein responses including fracture healing. The accumulated information on bone morphogenetic proteins may aid in accelerating fracture repair and the potential use of bone morphogenetic protein antibodies to inhibit heterotopic bone formation and fibrodysplasia ossificans progressiva.

Topics: Antibodies; Bone Matrix; Bone Morphogenetic Protein 1; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Bone Regeneration; Cell Differentiation; Chemotaxis; DNA-Binding Proteins; Fracture Healing; Humans; Metalloendopeptidases; Mitosis; Myositis Ossificans; Ossification, Heterotopic; Osteogenesis; Phosphoproteins; Phosphorylation; Protein Binding; Signal Transduction; Smad Proteins; Smad1 Protein; Smad4 Protein; Smad5 Protein; Trans-Activators; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva (FOP) is a catastrophic, ultra-rare disease of heterotopic ossification caused by genetic defects in the

Topics: Activin Receptors, Type I; Fibroblasts; Humans; Mutation; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by progressive heterotopic ossification (HO) in soft tissues due to a heterozygous mutation of the ACVR1A gene (FOP-ACVR1A), which erroneously transduces the BMP signal by Activin-A. Although inflammation is known to trigger HO in FOP, the role of FOP-ACVR1A on inflammatory cells remains to be elucidated.. We generated immortalized monocytic cell lines from FOP-iPSCs (FOP-ML) and mutation rescued iPSCs (resFOP-ML). Cell morphology was evaluated during the monocyte induction and after immortalization. Fluorescence-activated cell sorting (FACS) was performed to evaluate the cell surface markers CD14 and CD16 on MLs. MLs were stimulated with lipopolysaccharide or Activin-A and the gene expression was evaluated by quantitative PCR and microarray analysis. Histological analysis was performed for HO tissue obtained from wild type mice and FOP-ACVR1A mice which conditionally express human mutant ACVR1A gene by doxycycline administration. Without any stimulation, FOP-ML showed the pro-inflammatory signature of CD16+ monocytes with an upregulation of INHBA gene, and treatment of resFOP-ML with Activin-A induced an expression profile mimicking that of FOP-ML at baseline. Treatment of FOP-ML with Activin-A further induced the inflammatory profile with an up-regulation of inflammation-associated genes, of which some, but not all, of which were suppressed by corticosteroid. Experiments using an inhibitor for TGFβ or BMP signal demonstrated that Activin-A-induced genes such as CD16 and CCL7, were regulated by both signals, indicating Activin-A transduced dual signals in FOP-ML. A comparison with resFOP-ML identified several down-regulated genes in FOP-ML including LYVE-1, which is known to suppress matrix-formation in vivo. The down-regulation of LYVE-1 in HO tissues was confirmed in FOP model mice, verifying the significance of the in vitro experiments.. These results indicate that FOP-ML faithfully recapitulated the phenotype of primary monocytes of FOP and the combination with resFOP-ML is a useful tool to investigate molecular events at the initial inflammation stage of HO in FOP.

Topics: Activin Receptors, Type I; Activins; Animals; Doxycycline; Humans; Inflammation; Lipopolysaccharides; Mice; Monocytes; Mutation; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; Transforming Growth Factor beta

Acquired heterotopic ossification (HO) is a painful and debilitating disease characterized by extraskeletal bone formation after injury. The exact pathogenesis of HO remains unknown. Here we show that TGF-β initiates and promotes HO in mice. We find that calcified cartilage and newly formed bone resorb osteoclasts after onset of HO, which leads to high levels of active TGF-β that recruit mesenchymal stromal/progenitor cells (MSPCs) in the HO microenvironment. Transgenic expression of active TGF-β in tendon induces spontaneous HO, whereas systemic injection of a TGF-β neutralizing antibody attenuates ectopic bone formation in traumatic and BMP-induced mouse HO models, and in a fibrodysplasia ossificans progressive mouse model. Moreover, inducible knockout of the TGF-β type II receptor in MSPCs inhibits HO progression in HO mouse models. Our study points toward elevated levels of active TGF-β as inducers and promoters of ectopic bone formation, and suggest that TGF-β might be a therapeutic target in HO.

Topics: Achilles Tendon; Adult; Animals; Antibodies, Neutralizing; Becaplermin; Bone Remodeling; Brain Injuries, Traumatic; Cartilage; Case-Control Studies; Disease Models, Animal; Elbow Injuries; Elbow Joint; Female; Fracture Fixation, Internal; Fractures, Bone; Humans; Male; Mesenchymal Stem Cells; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Muscle, Skeletal; Myositis Ossificans; Ossification, Heterotopic; Osteoclasts; Osteogenesis; Receptor, Transforming Growth Factor-beta Type II; Spinal Cord Injuries; Tendon Injuries; Tendons; Transforming Growth Factor beta; Transforming Growth Factor beta1; Young Adult

Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear.. We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-β activated kinase 1 (TAK1), and NF-κB pathways.. FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-β production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages.. Abnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.

Topics: Activin Receptors, Type I; Chemokines; Cytokines; Humans; Inflammation; Macrophages; Monocytes; Myositis Ossificans; NF-kappa B; Ossification, Heterotopic; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high-throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC-based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ENPP2/mTOR axis in FOP pathogenesis.

Topics: Activins; Animals; Cell Differentiation; Chondrocytes; Chondrogenesis; Embryonic Stem Cells; Female; Humans; Induced Pluripotent Stem Cells; Inhibitory Concentration 50; Lysophospholipids; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Myositis Ossificans; Oligonucleotide Array Sequence Analysis; Phosphoric Diester Hydrolases; Point Mutation; Recombinant Proteins; Signal Transduction; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification. FOP patients develop soft tissue lumps as a result of inflammation-induced flare-ups which leads to the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients possess a mutation (c.617G>A; R206H) in the ACVR1-encoding gene which leads to dysregulated BMP signaling. Nonetheless, not all FOP patients with this mutation exhibit equal severity in symptom presentation or disease progression which indicates a strong contribution by environmental factors. Given the pro-inflammatory role of TGFβ, we studied the role of TGFβ in the progression of osteogenic differentiation in primary dermal fibroblasts from five classical FOP patients based on a novel method of platelet lysate-based osteogenic transdifferentiation. During the course of transdifferentiation the osteogenic properties of the cells were evaluated by the mRNA expression of Sp7/Osterix, Runx2, Alp, OC and the presence of mineralization. During transdifferentiation the expression of osteoblast markers Runx2 (p<0.05) and Alp were higher in patient cells compared to healthy controls. All cell lines exhibited increase in mineralisation. FOP fibroblasts also expressed higher baseline Sp7/Osterix levels (p<0.05) confirming their higher osteogenic potential. The pharmacological inhibition of TGFβ signaling during osteogenic transdifferentiation resulted in the attenuation of osteogenic transdifferentiation in all cell lines as shown by the decrease in the expression of Runx2 (p<0.05), Alp and mineralization. We suggest that blocking of TGFβ signaling can decrease the osteogenic transdifferentiation of FOP fibroblasts.

Topics: Activin Receptors, Type I; Adolescent; Adult; Alkaline Phosphatase; Animals; Benzamides; Blood Platelets; Calcification, Physiologic; Cell Transdifferentiation; Cells, Cultured; Female; Fibroblasts; Gene Expression Regulation; Humans; Ki-67 Antigen; Male; Middle Aged; Models, Biological; Myositis Ossificans; Osteogenesis; Pyrazoles; RNA, Messenger; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Young Adult

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor point mutations in ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP). Two mechanisms of mutated ACVR1 (FOP-ACVR1) have been proposed: ligand-independent constitutive activity and ligand-dependent hyperactivity in BMP signaling. Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling. Activin-A enhanced the chondrogenesis of induced mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs) via aberrant activation of BMP signaling in addition to the normal activation of TGF-β signaling in vitro, and induced endochondral ossification of FOP-iMSCs in vivo. These results uncover a novel mechanism of extraskeletal bone formation in FOP and provide a potential new therapeutic strategy for FOP.

Topics: Activin Receptors, Type I; Activins; Bone Morphogenetic Proteins; Calcification, Physiologic; Chondrogenesis; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Myositis Ossificans; Signal Transduction; Transforming Growth Factor beta

Fibrodysplasia ossificans progressiva is characterized by extensive ossification within muscle tissues, and its molecular pathogenesis is responsible for the constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2). In this study, we investigated the effects of implanting ALK2 (R206H)-transfected myoblastic C2C12 cells into nude mice on osteoclast formation during heterotopic ossification in muscle and subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells with BMP-2 in nude mice induced robust heterotopic ossification with an increase in the formation of osteoclasts in muscle tissues but not in subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells in muscle induced heterotopic ossification more effectively than that of empty vector-transfected cells. A co-culture of ALK2 (R206H)-transfected C2C12 cells as well as the conditioned medium from ALK2 (R206H)-transfected C2C12 cells enhanced osteoclast formation in Raw264.7 cells more effectively than those with empty vector-transfected cells. The transfection of ALK2 (R206H) into C2C12 cells elevated the expression of transforming growth factor (TGF)-β, whereas the inhibition of TGF-β signaling suppressed the enhanced formation of osteoclasts in the co-culture with ALK2 (R206H)-transfected C2C12 cells and their conditioned medium. In conclusion, this study demonstrated that the causal mutation transfection of fibrodysplasia ossificans progressiva in myoblasts enhanced the formation of osteoclasts from its precursor through TGF-β in muscle tissues.

Topics: Activin Receptors, Type I; Animals; Bone Morphogenetic Protein 2; Cells, Cultured; Culture Media, Conditioned; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Muscle, Skeletal; Mutation, Missense; Myoblasts; Myositis Ossificans; NIH 3T3 Cells; Ossification, Heterotopic; Osteoclasts; Osteogenesis; Rats; Signal Transduction; Subcutaneous Tissue; Transforming Growth Factor beta

Transforming growth factor-β family members, which include TGF-βs, activins and bone morphogenetic proteins (BMPs), play important roles in development and maintaining tissue homeostasis. The extracellular TGF-β family members signal across the plasmamembrane by activating type I and type II serine/threonine kinase receptors. Pertubation in TGF-β family receptor signaling has been implicated in certain diseases, including musculo-skeletal disorders. Fibrodysplasia ossificans progressiva (FOP) is a rare disorder characterized by progressive formation of ectopic bone and congenital malformations of the great toes. At present no curative therapy is available, therefore prevention of heterotopic ossification is the hallmark of FOP management. FOP has been linked to an autosomal dominant mutation on chromosome 2, to the gene encoding activin receptor-like kinase 2 (ALK2), a BMP type I receptor. This mutation is found in almost all classically affected FOP patients and causes the FOP phenotype. This discovery has paved the way for further investigations into the molecular basis underlying FOP and has recently pointed towards potential strategies to treat this devastating disease.

Topics: Activin Receptors, Type I; Activins; Animals; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Proteins; Humans; Mutation; Myositis Ossificans; Ossification, Heterotopic; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Topics: Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cervical Vertebrae; Dose-Response Relationship, Drug; Female; Humans; Lumbar Vertebrae; Middle Aged; Myositis Ossificans; Recombinant Proteins; Spinal Fusion; Transforming Growth Factor beta

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.

Topics: Animals; Antigens, CD20; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cats; CD3 Complex; Cell Movement; Child, Preschool; Humans; Immunohistochemistry; Leukocyte Common Antigens; Lymphocytes; Male; Myositis Ossificans; Transforming Growth Factor beta

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.

Topics: Animals; Blotting, Northern; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cell Line; Humans; Immunohistochemistry; Mice; Myositis Ossificans; Proto-Oncogene Proteins c-fos; Transforming Growth Factor beta; Transplantation Chimera

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.

Topics: Alkaline Phosphatase; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Collagen; Desmin; Diagnosis, Differential; Fibromatosis, Aggressive; Humans; Myositis Ossificans; Transforming Growth Factor beta; Vimentin

Topics: Bone and Bones; Digoxigenin; DNA Probes; Fluorescent Dyes; Humans; In Situ Hybridization, Fluorescence; Myositis Ossificans; Paraffin; Propidium; RNA, Messenger; Staining and Labeling; Transforming Growth Factor beta