Paresis of a bone morphogenetic protein-antagonist response in a genetic disorder of heterotopic skeletogenesis.
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.
Ahn
Jaimo
J
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Serrano de la Pena
Lourdes
L
Shore
Eileen M
EM
Kaplan
Frederick S
FS
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D002352:Carrier Proteins; D002460:Cell Line; D025461:Feedback, Physiological / Q000235:genetics* / Q000502:physiology; D038681:Follistatin / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009221:Myositis Ossificans / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D009999:Ossification, Heterotopic / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D038681:Follistatin; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D000099176:Noggin Protein; C525809:BMP4 protein, human; C486399:GREM1 protein, human; C054234:chordin