Critical Regulation of Bone Morphogenetic Protein-induced Osteoblastic Differentiation by Delta1/Jagged1-activated Notch1 Signaling

Abstract

Functional involvement of the Notch pathway in osteoblastic differentiation has been previously investigated using the truncated intracellular domain, which mimics Notch signaling by interacting with the DNAbinding protein CBF-1. However, it is unclear whether Notch ligands Delta1 and Jagged1 also induce an identical cellular response in osteoblastic differentiation. We have shown that both Delta1 and Jagged1 were expressed concomitantly with Notch1 in maturating osteoblastic cells during bone regeneration and that overexpressed and immobilized recombinant Delta1 and Jagged1 alone did not alter the differentiated state of MC3T3-E1 and C2C12 cells. However, they augmented bone morphogenetic protein-2 (BMP2)-induced alkaline phosphatase activity and the expression of several differentiation markers, except for osteocalcin, and ultimately enhanced calcified nodule and in vivo ectopic bone formation of MC3T3-E1. In addition, both ligands transmitted signal through the CBF-1-dependent pathway and stimulated the expression of HES-1, a direct target of Notch pathway. To test the necessity of Notch signaling in BMP2-induced differentiation, Notch signaling was inhibited by the dominant negative extracellular domain of Notch1, specific inhibitor, or small interference RNA. These treatments decreased alkaline phosphatase activity as well as the expression of other differentiation markers and inhibited the promoter activity of Id-1, a target gene of the BMP pathway. These results indicate the functional redundancy between Delta1 and Jagged1 in osteoblastic differentiation whereby Delta1/Jagged1-activated Notch1 enhances BMP2-induced differentiation through the identical signaling pathway. Furthermore, our data also suggest that functional Notch signaling is essential not only for BMP2-induced osteoblast differentiation but also for BMP signaling itself.

JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women

“…This gene encodes a cell surface protein called JAGGED 1, which belongs to the Delta/Serrate domain (DSL) family. Moreover, in vitro and in vivo assays have shown that JAG1 gene is expressed in osteoblastic cells during bone regeneration and its activation is also associated with increased bone mineral deposition (Nobta et al 2005). Interestingly, a recently published genome-wide association analysis identified that the rs2273061 polymorphism localized in intron 3 of the JAG1 gene was associated with the presence of variations of BMD and osteoporotic fractures in subjects of European descent and in Asian populations.…”

Plasticity in adipogenesis and osteogenesis of human mesenchymal stem cells

“…The reverse regulation pattern of down regulated non-adipogenic gene products (e.g. jagged 1, JAG1 correlated with osteogenesis (Nobta et al, 2005) and angiogenesis (Uyttendaele et al, 2000), CYR61 involved in angiogenesis (Lau and Lam, 1999;Schutze et al, 2005a), muscle-associated tropomyosin 1 (alpha), cysteine and glycine-rich protein 2, CSRP2, myosin heavy polypeptide 11 smooth muscle, and villin 2 A c c e p t e d M a n u s c r i p t -17 -(ezrin), VIL2 (MacLeod and Gooding, 1988;Louis et al, 1997;Babu et al, 2000;Moyen et al, 2004)) and up regulated adipogenesis-related gene products (C/EBPα, LPL and acetyl-CoA carboxylase β (Rosen et al, 2002;Wu et al, 1999;Fried et al, 1993;Spiegelman et al, 1993), and two glucose transporter molecules SLC2A3 and SLC2A14) could contribute to the switch of preosteoblasts into adipocytes during transdifferentiation. Furthermore, the initiation of transdifferentiation could involve other factors and signaling pathways that have not been described in the context of direct differentiation or whose functions have not been revealed so far.…”

Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1

“…In an in vivo breast cancer to bone metastasis model, the presence of BMP-2 in a scaffold increased the metastatic frequency of the breast cancer cell line SUM1315 (Moreau et al, 2007). On the other hand, treatment with BMP-2 in the breast cancer cell line C2C12 resulted in increased expression of Id-1 (Katagiri et al, 1994;Nobta et al, 2005;Raida et al, 2005;Langenfeld et al, 2006), while BMP-2 also positively regulated the expression of Id-1 in certain cell contexts (Locklin et al, 2001;Takeda et al, 2004). Because BMPs have very important roles in the development of bone metastasis in prostate cancer cells (Feeley et al, 2005(Feeley et al, , 2006, it might be possible that BMP-2 in the bone environment promotes metastasis of cancer cells to bone through upregulation of the intrinsic expression of Id-1 in cancer cells.…”