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.
Ahn
Jaimo
J
Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA.
Feldman
George
G
Terry
Leota
L
Shore
Eileen M
EM
Kaplan
Frederick S
FS
D000483:Alleles; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D009221:Myositis Ossificans / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D010375:Pedigree; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019485:Bone Morphogenetic Proteins; D016328:NF-kappa B; D012313:RNA