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Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis.
J Bone Joint Surg Am. 2003 Apr; 85(4):667-74.JB

Abstract

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.

Authors+Show Affiliations

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.No 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

12672843

Citation

Ahn, Jaimo, et al. "Paresis of a Bone Morphogenetic Protein-antagonist Response in a Genetic Disorder of Heterotopic Skeletogenesis." The Journal of Bone and Joint Surgery. American Volume, vol. 85, no. 4, 2003, pp. 667-74.
Ahn J, Serrano de la Pena L, Shore EM, et al. Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis. J Bone Joint Surg Am. 2003;85(4):667-74.
Ahn, J., Serrano de la Pena, L., Shore, E. M., & Kaplan, F. S. (2003). Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis. The Journal of Bone and Joint Surgery. American Volume, 85(4), 667-74.
Ahn J, et al. Paresis of a Bone Morphogenetic Protein-antagonist Response in a Genetic Disorder of Heterotopic Skeletogenesis. J Bone Joint Surg Am. 2003;85(4):667-74. PubMed PMID: 12672843.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis. AU - Ahn,Jaimo, AU - Serrano de la Pena,Lourdes, AU - Shore,Eileen M, AU - Kaplan,Frederick S, PY - 2003/4/4/pubmed PY - 2003/5/28/medline PY - 2003/4/4/entrez SP - 667 EP - 74 JF - The Journal of bone and joint surgery. American volume JO - J Bone Joint Surg Am VL - 85 IS - 4 N2 - 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. SN - 0021-9355 UR - https://www.unboundmedicine.com/medline/citation/12672843/Paresis_of_a_bone_morphogenetic_protein_antagonist_response_in_a_genetic_disorder_of_heterotopic_skeletogenesis_ L2 - http://dx.doi.org/10.2106/00004623-200304000-00013 DB - PRIME DP - Unbound Medicine ER -