OVEREXPRESSION OF AN OSTEOGENIC MORPHOGEN IN FIBRODYSPLASIA OSSIFICANS PROGRESSIVA

Background Fibrodysplasia ossificans progressiva is a heritable disord er of connective tissue characterized by congenital malformation of th e great toes and postnatal formation of ectopic bone, Although the dis order was first described more than 300 years ago, the genetic defect and pathophysiology remain unknown. Bone morphogenetic proteins are po tent bone-inducing morphogens that participate in the developmental or ganization of the skeleton, and increased production of one or more of these proteins has been proposed as the cause of fibrodysplasia ossif icans progressiva. Methods We studied lymphoblastoid cell lines establ ished from peripheral-blood mononuclear cells of patients with fibrody splasia ossificans progressiva and fibroblast-like cell lines derived from lesional and nonlesional tissue. We used Northern blot analysis a nd ribonuclease protection assays to measure the expression of messeng er RNA (mRNA) of bone morphogenetic proteins 1 to 7 and immunohistoche mical analysis to examine protein expression. Results Among the bone m orphogenetic proteins and mRNAs examined, only bone morphogenetic prot ein 4 and its mRNA were present in increased levels in cells derived f rom an early fibroproliferative lesion in a patient with fibrodysplasi a ossificans progressiva, Bone morphogenetic protein 4 mRNA was expres sed in lymphoblastoid cell lines from 26 of 32 patients with fibrodysp lasia 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 p rogressiva 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-i nducing morphogen (bone morphogenetic protein 4) in lymphocytes is ass ociated with the disabling ectopic osteogenesis of fibrodysplasia ossi ficans progressiva. (C) 1996, Massachusetts Medical Society.