Fetuin/alpha 2-HS glycoprotein is a transforming growth factor-beta type II receptor mimic and cytokine antagonist

The serum glycoprotein fetuin is expressed during embryogenesis in multiple tissues including limb buds and has been shown to promote bone remodeling and stimulate cell proliferation in vitro. In this report, we demonstrate that fetuin antagonizes the antiproliferative action of transforming growth factor-beta 1 (TGF-beta 1) in cell cultures. Surface plasmon resonance measurements show that fetuin binds directly to TGF beta 1 and TGF-beta 2 and with greater affinity to the TGF-beta-related bone morphogenetic proteins (BMP-2, BMP-4, and BMP-6). In a competitive enzyme-linked immunosorbent assay, fetuin blocked binding of TGF-beta 1 to the extracellular domain of TGF-beta receptor type II (T beta RII), one of the primary TGF-beta-binding receptors. A comparison of fetuin and T beta RII shows homology in an 18-19-amino acid sequence, which we have designated TGF-beta receptor II homology 1 domain (TRH1). Since the TRH1 sequence is known to form a disulfide loop in fetuin, cyclized TRH1 peptides from both fetuin and T beta RII were chemically synthesized and tested for cytokine binding activity. Cyclized TRH1 peptide from T beta RII bound to TGF-beta 1 with greater affinity than to BMP-2, while the cyclized TRH1 peptide from fetuin bound preferentially to BMP-2. Finally, fetuin or neutralizing anti-TGF-beta antibodies blocked osteogenesis and deposition of calcium-containing matrix in cultures of dexamethasone-treated rat bone marrow cells. In summary, these experiments define the TRH1 peptide loop as a cytokine-binding domain in both T beta RII and fetuin and suggest that fetuin is a natural antagonist of TGF-beta and BMP activities.