In the last 10 years, a large family of secreted signaling molecules has been discovered that appear to mediate many key events in normal growth and development. The family is known as the TGF-p superfamily (Massague 1990), a name taken from the first member of the family to be isolated (transforming growth factor-^l). This name is somewhat misleading, because TGF-p 1 has a large number of effects in different systems (Spom and Roberts 1992). It actually inhibits the proliferation of many different cell lines, and its original "transforming" activity may be due to secondary effects on matrix pro­ duction and synthesis of other growth factors (Moses et al. 1990). The two dozen other members of the TGF-p superfamily have a remarkable range of activities. In Diosophila, a TGF-p-related gene is required for dorsoventral axis formation in early embryos, communication between tissue layers in gut development, and correct proximal distal patterning of adult appendages. In Xenopus, a TGF-p-related gene is expressed specifically at one end of fertilized eggs and may function in early signaling events that lay out the basic body plan. In mammals, TGF-p-related molecules have been found that control sexual development, pituitary hormone production, and the creation of bones and cartilage. The recognition of TGF-p superfamily members in many different organ­ isms and contexts provides one of the major unifying themes in recent molecular studies of animal growth and development. The rough outlines of the TGF-p family were first rec­ ognized in the 1980s. Since that time, a number of ex­ cellent reviews have appeared that summarize the prop­ erties of different family members (Ying 1989; Massague 1990; Lyons et al. 1991; Spom and Roberts 1992). Here, I will focus on four areas that have seen major progress in the last 3 years: structural characterization of the signal­ ing molecule, isolation of new family members, cloning of receptor molecules, and new genetic tests of the func­ tions of these factors in different organisms.

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The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms.

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Bone morphogenetic proteins: multifunctional regulators of vertebrate development.

Biomaterial developments for bone tissue engineering

To address the function of bone morphogenetic protein-2 (BMP2) in mammalian development, mice with a targeted deletion of the Bmp2 mature region were generated using embryonic stem cell technology. This mutation caused embryonic lethality when homozygous. Mutant embryos failed to close the proamniotic canal, which caused the malformation of the amnion/chorion. BMP2-deficient embryos also exhibited a defect in cardiac development, manifested by the abnormal development of the heart in the exocoelomic cavity. These defects are consistent with the expression of Bmp2 in the extraembryonic mesoderm cells and promyocardium. Thus BMP2 is a critical factor for both extraembryonic and embryonic development.

Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development

Skeletal homeostasis is determined by systemic hormones and local factors. Bone morphogenetic proteins (BMP) are unique because they induce the differentiation of mesenchymal cells toward cells of the osteoblastic lineage and also enhance the differentiated function of the osteoblast. However, the activity of BMPs needs to be tempered by intracellular and extracellular antagonists. BMPs bind to specific receptors and signal by phosphorylating the cytoplasmic proteins mothers against decapentaplegic (Smad) 1 and 5, which form heterodimers with Smad 4, and after nuclear translocation regulate transcription. BMP antagonists can be categorized as pseudoreceptors that compete with signaling receptors, inhibitory Smads that block signaling, intracellular binding proteins that bind Smad 1 and 5, and factors that induce ubiquitination and proteolysis of signaling Smads. In addition, a large number of extracellular proteins that bind BMPs and prevent their binding to signaling receptors have emerged. They are the ...

Bone morphogenetic proteins, their antagonists, and the skeleton.

Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro.

W.K. Jones

Papers

Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro.