Molecular Biology of Bone Formation

Identification of BMP-9 as the most osteogenic BMP in vitro and in vivo. Although several BMPs (mostly BMP-2 and BMP-7) have been shown to induce bone formation, it is unclear whether the ones currently used represent the most osteogenic BMPs. Through a comprehensive analysis of the 14 types of human BMPs, the He, Haydon, and Luu lab previously demonstrated that BMP-2, BMP-6, and BMP-9 are the most potent osteogenic BMPs in osteoblastic progenitor cells in vitro, which was published in the Journal of Bone and Joint Surgery with over 500 citations so far. They have concluded several rounds of in vivo studies and found that BMP-2, BMP-6 and BMP9 are the most potent osteogenic BMPs at inducing orthotopic bone formation in athymic mice (Gene Theraoy  11: 1312-1320; J Orthop Res 25: 665-677; and Front Biosci  13: 2001-2021). Interestingly, they have also found that osteogenic BMPs can induce adipogenic differentiation of mesenchymal stem cells (Stem Cells and Development 18: 545-559). They have demonstrated that TGFbeta/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells (J Biol Chem. 285(38): 29588-98.).

To identify potentially important mediators of BMP-induced osteogenic signaling, Drs. He, Haydon and Luu determined the transcriptional differences between three osteogenic BMPs (i.e., BMP2, 6, and 9) and two inhibitory/non-osteogenic BMPs (i.e., BMP3 and 12).  Through the microarray analysis in pre-osteoblast progenitor cells, they found that expression level of 203 genes (105 up-regulated and 98 down-regulated) was altered >2-fold upon osteogenic BMP stimulation. Gene ontology analysis revealed that osteogenic BMPs, but not inhibitory/non-osteogenic BMPs, activate genes involved in the proliferation of pre-osteoblast progenitor cells towards osteoblastic differentiation, and simultaneously inhibit myoblast-specific gene expression. Their findings are consistent with the notion that osteogenesis and myogenesis are two divergent processes (Journal of Cellular Biochemistry 90: 1149-1165). The Molecular Oncology Lab identified several potentially signaling mediators of BMP-induced osteogenesis. Several such downstream targets are the Inhibitors of DNA binding/Differentiation helix-loop-helix (a.k.a., Id proteins), Connective Tissue Growth Factor (a.k.a., CTGF), Hey1, and growth hormone. Their studies thus far have demonstrated that both Ids, CTGF, Hey1, and growth hormone play an important role in BMP-9 induced osteogenic signaling (Journal of Biological Chemistry  279: 32941-32949; Journal of Biological Chemistry 279: 55958-55968;  Journal of Biological Chemistry 284: 649-659; and J Bone Miner Res. 2012, 27(7):1566-75).

Role of Wnt/b-catenin signaling in osteogenic differentiation of mesenchymal stem cells: The He, Haydon and Luu group previously demonstrated that Wnt/beta-catenin signaling is de-regulated in over 70% of human osteosarcomas. He, Haydon, and Luu lab have demonstrated that normal Wnt/b-catenin signaling is required for BMP9 signaling in MSCs (Journal of Cellular and Molecular Medicine 13:2448-2464). They have completed a microarray analysis on the genes regulated by Wnt3A in mesenchymal stem cells, and found that CTGF is also highly regulated by Wnt. They have recently finished a study, in which they demonstrate that CTGF is a mutual target of Wnt and BMP-9 and play an important role in regulating osteogenic differentiation (Journal of Biological Chemistry  279: 55958-55968; Molecular and Cellular Biology 26: 2955–2964. Furthermore, Drs. He, Haydon and Luu have recently investigated the potential synergistic effect of other factors on BMP9-mediated osteogenic differentiation and bone formation. Such factors include retinoid receptors and IGFs (PLoS ONE 5: e11917 and Journal of Bone and Mineral Research  25:2447-59).