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Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva.

Abstract

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.

Authors+Show Affiliations

Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12579020

Citation

Ahn, Jaimo, et al. "Exoneration of NF-kappaB Dysregulation in Fibrodysplasia Ossificans Progressiva." Clinical Orthopaedics and Related Research, 2003, pp. 205-13.
Ahn J, Feldman G, Terry L, et al. Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva. Clin Orthop Relat Res. 2003.
Ahn, J., Feldman, G., Terry, L., Shore, E. M., & Kaplan, F. S. (2003). Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva. Clinical Orthopaedics and Related Research, (406), 205-13.
Ahn J, et al. Exoneration of NF-kappaB Dysregulation in Fibrodysplasia Ossificans Progressiva. Clin Orthop Relat Res. 2003;(406)205-13. PubMed PMID: 12579020.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exoneration of NF-kappaB dysregulation in fibrodysplasia ossificans progressiva. AU - Ahn,Jaimo, AU - Feldman,George, AU - Terry,Leota, AU - Shore,Eileen M, AU - Kaplan,Frederick S, PY - 2003/2/13/pubmed PY - 2003/3/6/medline PY - 2003/2/13/entrez SP - 205 EP - 13 JF - Clinical orthopaedics and related research JO - Clin. Orthop. Relat. Res. IS - 406 N2 - 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. SN - 0009-921X UR - https://www.unboundmedicine.com/medline/citation/12579020/Exoneration_of_NF_kappaB_dysregulation_in_fibrodysplasia_ossificans_progressiva_ L2 - http://Insights.ovid.com/pubmed?pmid=12579020 DB - PRIME DP - Unbound Medicine ER -