%0 Journal Article
%T Differential regulation of osteoclastogenesis by Notch2/Delta-like 1 and Notch1/Jagged1 axes
%A Chiyoko Sekine
%A Akemi Koyanagi
%A Noriko Koyama
%A Katsuto Hozumi
%A Shigeru Chiba
%A Hideo Yagita
%J Arthritis Research & Therapy
%D 2012
%I BioMed Central
%R 10.1186/ar3758
%X Mouse bone marrow-derived macrophages or human peripheral blood monocytes were used as osteoclast precursors and cultured with receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) to induce osteoclasts. Osteoclasts were detected by tartrate-resistant acid phosphatase (TRAP) staining. K/BxN serum-induced arthritic mice and ovariectomized mice were treated with anti-mouse Delta-like 1 (Dll1) blocking monoclonal antibody (mAb).Blockade of a Notch ligand Dll1 with mAb inhibited osteoclastogenesis and, conversely, immobilized Dll1-Fc fusion protein enhanced it in both mice and humans. In contrast, blockade of a Notch ligand Jagged1 enhanced osteoclastogenesis and immobilized Jagged1-Fc suppressed it. Enhancement of osteoclastogenesis by agonistic anti-Notch2 mAb suggested that Dll1 promoted osteoclastogenesis via Notch2, while suppression by agonistic anti-Notch1 mAb suggested that Jagged1 suppressed osteoclastogenesis via Notch1. Inhibition of Notch signaling by a gamma-secretase inhibitor suppressed osteoclastogenesis, implying that Notch2/Dll1-mediated enhancement was dominant. Actually, blockade of Dll1 ameliorated arthritis induced by K/BxN serum transfer, reduced the number of osteoclasts in the affected joints and suppressed ovariectomy-induced bone loss.The differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients.Notch signaling pathways play key roles in cell-fate decision and differentiation in many tissues during embryonic and postnatal development [1]. Four mammalian Notch receptors have been identified, designated as Notch1 to Notch4. Interaction of Notch receptors with membrane-bound ligands of the Delta and Jagged families (Delta-like1 (Dll1), Dll4, Jagged1, and Jagged2) induces gamma-secretase-mediated cleavage and translocation of Notch intracellular domain (ICD) into the nucleus, where it interacts with
%U http://arthritis-research.com/content/14/2/R45