Abstract

IntroductionOsteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Recently, Notch receptors have been implicated in the development of osteoclasts. However, the responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis.MethodsMouse 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).ResultsBlockade 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.ConclusionsThe differential regulation of osteoclastogenesis by Notch2/Dll1 and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients.

Highlights

  • Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA)

  • The differential regulation of osteoclastogenesis by Notch2/Delta-like 1 (Dll1) and Notch1/Jagged1 axes may be a novel target for amelioration of bone erosion in RA patients

  • Dll1 enhances but Jagged1 suppresses osteoclastogenesis from mouse bone marrow (BM) Since both Notch receptors and ligands were expressed on CD11b+F4/80+ osteoclast precursors during osteoclastogenesis, we examined the role of Notch ligands

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Summary

Introduction

Osteoclastogenesis plays an important role in the bone erosion of rheumatoid arthritis (RA). Notch receptors have been implicated in the development of osteoclasts. The responsible Notch ligands have not been identified yet. This study was undertaken to determine the role of individual Notch receptors and ligands in osteoclastogenesis. Notch signaling pathways play key roles in cell-fate decision and differentiation in many tissues during embryonic and postnatal development [1]. The importance of Notch signaling in osteoclastogenesis has recently been reported [3,4]. Osteoclast differentiation is a multistep process that leads to expression of tartrate-resistant acid phosphatase (TRAP), multinucleation and bone-resorbing activity. It has been demonstrated that receptor activator of nuclear factor-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF) are critical for osteoclast development [6]. Controlling osteoclastogenesis is important for bone homeostasis and an abnormal osteoclastogenesis leads to imbalance of bone remodeling that is related to various diseases such as osteoporosis, rheumatoid arthritis (RA), and multiple myeloma [5]

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