Abstract
Members of the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors have been identified in a wide variety of organisms, ranging from invertebrates to mammals. Bone morphogenetic proteins (BMPs) constitute a subgroup of proteins belonging to the TGF-beta superfamily. BMPs were initially identified by their ability to induce endochondral bone formation at ectopic sites, suggesting a critical role for this family in development and regeneration of the skeleton. They are also expressed at a variety of nonskeletal sites during development, suggesting possible extraskeletal roles for these proteins. We cloned a novel member of the BMP family that is expressed at high levels in the placenta and the prostate and that we have designated as prostate-derived factor (PDF). Based on cDNA sequence analysis, the predicted PDF protein contains two cysteines in addition to the seven conserved cysteines that are the hallmark of the members of the TGF-beta superfamily. In addition, Northern blot hybridization to poly(A)+ RNA showed low levels of expression in the kidney and pancreas. We further characterized the expression of this member of the BMP family by in situ hybridization and immunohistochemistry. These results show high expression in the terminal villae of the placenta. The expression of the protein as visualized by immunohistochemistry shows an expression pattern identical to that of the message in the terminal villae of the placenta. In day 18 rat embryos, protein expression was also seen in the skin and in the cartilaginous tissue of developing skeleton. Orchidectomy and dihydrotestosterone treatment of rats revealed that PDF expression is regulated by androgens in the prostate. In addition, subcutaneous implantation of recombinant PDF induced cartilage formation and the early stages of endochondral bone formation. These data indicate that PDF has a functional relationship to the BMPs.
Highlights
Morphogenetic proteins have been identified that play critical roles in regulating tissue differentiation and maintenance during embryogenesis and in the adult organism
Called the transforming growth factor- (TGF-)1 superfamily. This superfamily includes bone morphogenetic proteins (BMPs), cartilage-derived morphogenetic proteins (CDMPs), Mullerrian inhibiting substance, activins, inhibins, TGF-, growth and differentiation factors, and the Drosophila decapentaplegic gene complex (DPP) [1,2,3]. These morphogenetic proteins are synthesized as large precursor molecules that are cleaved at a dibasic cleavage site (RXXR) to release carboxylterminal domains containing a characteristic motif of seven conserved cysteines
Multiple recombinant BMPs and CDMPs are capable of inducing endochondral bone formation at ectopic sites [1, 3]
Summary
Morphogenetic proteins have been identified that play critical roles in regulating tissue differentiation and maintenance during embryogenesis and in the adult organism. This superfamily includes bone morphogenetic proteins (BMPs), cartilage-derived morphogenetic proteins (CDMPs), Mullerrian inhibiting substance, activins, inhibins, TGF-, growth and differentiation factors, and the Drosophila decapentaplegic gene complex (DPP) [1,2,3] These morphogenetic proteins are synthesized as large precursor molecules that are cleaved at a dibasic cleavage site (RXXR) to release carboxylterminal domains containing a characteristic motif of seven conserved cysteines. Mutations in CDMP-1 in humans and growth and differentiation factor-5, the murine homologue of CDMP-1, leads to specific morphological abnormalities in limbs and joints [9, 10] Members of this family have specific activities in addition to the pluripotent functions each member might share with the rest of the family. These receptors belong to a family of Ser/Thr kinase receptors and have been designated as either type I or type II based on their molecular weights
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