Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells

Abstract

Osteoclasts are derived from hematopoietic precursor cells belonging to the monocyte/macrophage lineage. Osteoclast development has been reported to be regulated by several molecules such as macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor (NF)-B ligand (RANKL), and a decoy receptor of RANKL, osteoprotegerin (OPG). Recently, it was demonstrated that the Notch signaling pathway regulates myeloid differentiation and antagonizes cell fate determination, however, the effect of Notch signaling on the osteoclast lineage has not been reported. In this study, we examined the effect of signaling via Notch receptors on the differentiation into osteoclasts by using cells from the bone marrow, spleen, and peritoneal cavity, and a cloned macrophagelike cell line IntroductionThe control of cell fate by Notch signaling was first described for Drosophila melanogaster neural/epidermal precursors as a mechanism involving lateral inhibition. 1,2 At present, 4 Notch receptors, Notch-1, -2, -3, and -4, and their ligands, Delta-1, -3, and -4, and Jagged-1 and -2 have been identified in mammals. [3][4][5][6][7][8][9][10][11] Notch ligands bind to Notch receptors through their extracellular domain, trigger proteolytic processing, and release the Notch intracellular domain (NIC) from the cell membrane. Cleaved NIC interacts with the DNA-binding transcription factor CBF1/RBP-J, and the complex is translocated into the nucleus. 12,13 This complex binds to the Hairy enhancer of split (Hes1) promoter and stimulates the transcription of the Hes1 gene. 14,15 Overexpressed NIC acts as a constitutively active form of Notch receptor. 16 Recently, several studies have reported the roles of Notch signaling in hematopoietic cell development. 17-20 NIC transgenic mice have defective B-cell development. 21 Notch signaling influences the decision of differentiation into ␣␤ versus ␥␦T cells, 22 as well as that of differentiation into CD4 versus CD8 T cells. 23 Delta-1 blocks differentiation into the B-cell lineage, while it promotes the emergence of T/natural killer (NK) cell precursors. 24 In myeloid cell lineages, an immobilized form of the extracellular domain of Delta-1 induces monocytes to undergo apoptosis when treated with macrophage colony-stimulating factor (M-CSF) 25 and inhibits the differentiation of monocytes into mature macrophages when treated with granulocyte/macrophage (GM)-CSF, but permits their differentiation into dendritic cells in the presence of GM-CSF and interleukin-4 (IL-4). 26 Osteoclasts are also included in the myeloid lineage and are derived from hematopoietic precursor cells shared with the macrophage and dendritic cell lineages. 27,28 Osteoclast differentiation is a multistep process that eventually leads to expression of tartrateresistant acid phosphatase (TRAP), multinucleation, and boneresorbing activity. [29][30][31][32][33] Osteoclastogenesis is dependent on stromal cells that support hematopoiesis, [34][35][36] and it has been demonstrated that the critical molecules produced by s...

Systems level analysis of osteoclastogenesis reveals intrinsic and extrinsic regulatory interactions

“…For instance, the entire Notch pathway is expressed at 72 hr. Relatively little information is available on the role of the Notch pathway in osteoclasts (Yamada et al, 2003). Another unanticipated result was the role of cholesterol in osteoclastogenesis.…”

Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells

“…To investigate the effect of ligand-induced cross-linking of Notch on T cell activation, we used recombinant IgG fusion proteins of Dll1, Dll4 and Jagged1 [22,[26][27][28][29] for in vitro stimulation assays. Immobilized ligands were functionally active as shown by induction of luciferase activity from a CBF1-Luc reporter construct in Jurkat T cells (Fig.…”

Giant cell tumor of bone express p63

“…5,6 Further, p63 is also known to induce expression of Jagged1 7 which is involved in Notch signaling and osteoclastogenesis. 8 p63 is a member of the gene family that includes p53 and p73. It can arise from two different transcriptional start sites, encoding proteins either with (TAp63) or without (DNp63) a transactivating domain.…”