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Previous Volume 335:555-561 August 22, 1996 Number 8 Next

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ABSTRACT

Background Fibrodysplasia ossificans progressiva is a heritable disorder of connective tissue characterized by congenital malformation of the great toes and postnatal formation of ectopic bone. Although the disorder was first described more than 300 years ago, the genetic defect and pathophysiology remain unknown. Bone morphogenetic proteins are potent bone-inducing morphogens that participate in the developmental organization of the skeleton, and increased production of one or more of these proteins has been proposed as the cause of fibrodysplasia ossificans progressiva.

Methods We studied lymphoblastoid cell lines established from peripheral-blood mononuclear cells of patients with fibrodysplasia ossificans progressiva and fibroblast-like cell lines derived from lesional and nonlesional tissue. We used Northern blot analysis and ribonuclease protection assays to measure the expression of messenger RNA (mRNA) of bone morphogenetic proteins 1 to 7 and immunohistochemical analysis to examine protein expression.

Results Among the bone morphogenetic proteins and mRNAs examined, only bone morphogenetic protein 4 and its mRNA were present in increased levels in cells derived from an early fibroproliferative lesion in a patient with fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 mRNA was expressed in lymphoblastoid cell lines from 26 of 32 patients with fibrodysplasia ossificans progressiva but from only 1 of 12 normal subjects (P<0.001). Bone morphogenetic protein 4 and its mRNA were detected in the lymphoblastoid cell lines from a man with fibrodysplasia ossificans progressiva and his three affected children (two girls and a boy), but not from the children's unaffected mother. No other bone morphogenetic proteins were detected.

Conclusions Overexpression of a potent bone-inducing morphogen (bone morphogenetic protein 4) in lymphocytes is associated with the disabling ectopic osteogenesis of fibrodysplasia ossificans progressiva.

Source Information

From the Departments of Orthopaedic Surgery (A.B.S., E.M.S., M.A.Z., F.S.K.), Pathology (F.H.G.), Medicine (R.T., F.S.K.), and Genetics (R.T.), University of Pennsylvania School of Medicine; and the Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia (M.M.) — both in Philadelphia.

Address reprint requests to Dr. Kaplan at the Division of Metabolic Bone Diseases and Molecular Orthopaedics, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Silverstein 2, 3400 Spruce St., Philadelphia, PA 19104.

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