The wonders of BMP9: From mesenchymal stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism to regenerative medicine

Abstract

Although bone morphogenetic proteins (BMPs) initially showed effective induction of ectopic bone growth in muscle, it has since been determined that these proteins, as members of the TGF-β superfamily, play a diverse and critical array of biological roles. These roles include regulating skeletal and bone formation, angiogenesis, and development and homeostasis of multiple organ systems. Disruptions of the members of the TGF-β/BMP superfamily result in severe skeletal and extra-skeletal irregularities, suggesting high therapeutic potential from understanding this family of BMP proteins. Although it was once one of the least characterized BMPs, BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo, with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs. The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants, revealing the great translational promise of BMP9. Furthermore, emerging evidence indicates that, besides its osteogenic activity, BMP9 exerts a broad range of biological functions, including stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism. This review aims to summarize our current understanding of BMP9 across biology and the body.

Keywords: Adipogenesis; BMP9/GDF2; Bone morphogenetic proteins (BMPs); Mesenchymal stem cells (MSCs); Metabolism; Osteogenesis; Regenerative medicine; Tumorigenesis.

Figure 1

BMP9/Smad signaling. BMP ligands bind to and subsequently activate receptor kinases, which eventually phosphorylate and promote heterodimeric formation of Smad proteins. These Smads proteins can then interact with Smad4 for proper nuclear localization, which is necessary for proper BMP9-induced osteogenic differentiation. Experiments have demonstrated that RNAi-mediated knockdown of Smad4 reduced Smad heterodimer formation and nuclear localization; thus decreased osteogenic differentiation of mesenchymal stem cells.

Figure 2

Signaling crosstalk with BMP9. Several major signaling events must take place in the BMP9-induced osteogenic differentiation of mesenchymal stem cells. The action of BMP9 results in a complicated albeit well-coordinated signaling cascade that results in gene transcription at precise steps of osteogenic differentiation. Cross talk between with BMP9 and other pathways such as the Wnt, Notch, and the other pathways shown results in augmentation of BMP9 signaling.

Figure 3

BMP9 signaling in endothelial cells and angiogenesis. The most current evidence supports the theory that a heterodimer formed by BMP9 and BMP10 provides most BMP biological activity in plasma, and acts as a key regulator of blood vessel homeostasis. ENG and ALK1 are necessary mediators of angiogenesis, with evidence suggesting that BMP9 and closely related BMP10 are the key cytokines upstream of ALK1/pSMAD1/5/8 signaling in endothelial cells.

Figure 4

Potential use of BMP9 in regenerative medicine. The numerous pathologies that lead to bone defects can result in complex shapes, loss of bone, and a myriad of other complications. BMP9 expressing stem cells in conjunction with a biodegradable, thermoresponsive scaffold such as Poly (polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) may one day provide a solution to many of the issues encountered in complex bone defects.

Figure 5

A schematic summary of currently known functions of BMP9 signaling.