Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-␤ superfamily of growth factors and are used clinically to induce new bone formation. The purpose of this study was to evaluate receptor utilization by BMP-2, BMP-4, BMP-6, and BMP-7 in primary human mesenchymal stem cells (hMSC), a physiologically relevant cell type that probably mediates the in vivo effects of BMPs. RNA interference-mediated gene knockdown revealed that osteoinductive BMP activities in hMSC are elicited through the type I receptors ACVR1A and BMPR1A and the type II receptors ACVR2A and BMPR2. BMPR1B and ACVR2B were expressed at low levels and were not found to play a significant role in signaling by any of the BMPs evaluated in this study. Type II receptor utilization differed significantly between BMP-2/4 and BMP-6/7. A greater reliance on BMPR2 was observed for BMP-2/4 relative to BMP-6/7, whereas ACVR2A was more critical to signaling by BMP-6/7 than BMP-2/4. Significant differences were also observed for the type I receptors. Although BMP-2/4 used predominantly BMPR1A for signaling, ACVR1A was the preferred type I receptor for BMP-6/7. Signaling by both BMP-2/4 and BMP-6/7 was mediated by homodimers of ACVR1A or BMPR1A. A portion of BMP-2/4 signaling also required concurrent BMPR1A and ACVR1A expression, suggesting that BMP-2/4 signal in part through ACVR1A/BMPR1A heterodimers. The capacity of ACVR1A and BMPR1A to form homodimers and heterodimers was confirmed by bioluminescence resonance energy transfer analyses. These results suggest different mechanisms for BMP-2/4-and BMP-6/7-induced osteoblastic differentiation in primary hMSC. Bone morphogenetic proteins (BMPs)2 are members of the transforming growth factor-␤ superfamily of growth factors. BMPs are key regulators of cellular growth and differentiation and regulate tissue formation in both developing and mature organisms. To date, ϳ20 unique BMP ligands have been identified and categorized into numerous subclasses based on amino acid sequence similarity (1, 2). BMP-7 (osteogenic protein-1) and BMP-2 are well studied members of this family of growth factors and are now being used clinically to induce new bone formation in spine fusions and long bone nonunion fractures (3, 4). BMP-2 and BMP-7 belong to two closely related BMP subclasses, namely the BMP-2/4 subclass and the BMP-5/6/7 subclass (1). The capacity of ligands from both BMP subclasses to induce osteoblastic differentiation has been rigorously demonstrated (5). However, a thorough understanding of the mechanism through which distinct BMP ligands affect target cells is lacking. Such information is central to realizing the potential of individual BMPs as therapeutic agents and for the rational targeting of a specific BMP to the appropriate clinical indication.BMP activities are mediated by tetramers of serine/threonine kinase receptors, consisting of two type I and two type II receptors. Three type I receptors (BMPR1A (ALK-3), BMPR1B (ALK-6), and ACVR1A (ALK-2)) and three type II receptors (BMPR2, ACV...

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