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Paresis of a Bone Morphogenetic Protein-Antagonist Response in a Genetic Disorder of Heterotopic Skeletogenesis

Investigation performed at the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Jaimo Ahn, PhD
Lourdes Serrano de la Peña, PhD
Eileen M. Shore, PhD
Departments of Orthopaedic Surgery (J.A., L.S. de la P., and E.M.S.) and Genetics (E.M.S.), University of Pennsylvania School of Medicine, 424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104

Frederick S. Kaplan, MD
Department of Orthopaedic Surgery, Silverstein-2, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104-5283. E-mail address: frederick.kaplan{at}uphs.upenn.edu

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from National Institutes of Health Grant 2-RO1-AR41916, the International Fibrodysplasia Ossificans Progressiva Association, the Roemex Foundation, the Ian Cali FOP Research Fund, the Betty Laue FOP Resource Center, and the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated. Wyeth Research (Cambridge, Massachusetts) provided the rhBMP-4.

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.

Clinical Relevance: Our findings suggest the potential usefulness of BMP-antagonist-based strategies in the therapy for patients with fibrodysplasia ossificans progressiva and other disorders of excessive bone formation. Furthermore, our studies suggest the importance of modulating endogenous BMP-antagonist activity in therapeutic applications of BMP-induced osteogenesis.

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