Pax5 Negatively Regulates Osteoclastogenesis through Downregulation of Blimp1.

Jiyeon Yu,Hyoeun Jeon,Masamichi Takami,Jun Lee,Sumi Kim,Nari Lee,Jaerang Rho

doi:10.3390/ijms22042097

Abstract

Paired box protein 5 (Pax5) is a crucial transcription factor responsible for B-cell lineage specification and commitment. In this study, we identified a negative role of Pax5 in osteoclastogenesis. The expression of Pax5 was time-dependently downregulated by receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) stimulation in osteoclastogenesis. Osteoclast (OC) differentiation and bone resorption were inhibited (68.9% and 48% reductions, respectively) by forced expression of Pax5 in OC lineage cells. Pax5 led to the induction of antiosteoclastogenic factors through downregulation of B lymphocyte-induced maturation protein 1 (Blimp1). To examine the negative role of Pax5 in vivo, we generated Pax5 transgenic (Pax5Tg) mice expressing the human Pax5 transgene under the control of the tartrate-resistant acid phosphatase (TRAP) promoter, which is expressed mainly in OC lineage cells. OC differentiation and bone resorption were inhibited (54.2–76.9% and 24.0–26.2% reductions, respectively) in Pax5Tg mice, thereby contributing to the osteopetrotic-like bone phenotype characterized by increased bone mineral density (13.0–13.6% higher), trabecular bone volume fraction (32.5–38.1% higher), trabecular thickness (8.4–9.0% higher), and trabecular number (25.5–26.7% higher) and decreased trabecular spacing (9.3–10.4% lower) compared to wild-type control mice. Furthermore, the number of OCs was decreased (48.8–65.3% reduction) in Pax5Tg mice. These findings indicate that Pax5 plays a negative role in OC lineage specification and commitment through Blimp1 downregulation. Thus, our data suggest that the Pax5–Blimp1 axis is crucial for the regulation of RANKL-induced osteoclastogenesis.

Highlights

The strength and rigidity of bone are maintained by a proper homeostatic balance between bone-forming osteoblasts and bone-resorbing osteoclasts (OCs) [1,2]
Pax5 Expression Is Downregulated during RANKL-Induced Osteoclastogenesis
We examined whether Pax5 expression was abundantly maintained in bone marrowderived macrophages (BMMs) on day 0 (Figure 1)

Summary

Introduction

The strength and rigidity of bone are maintained by a proper homeostatic balance between bone-forming osteoblasts and bone-resorbing osteoclasts (OCs) [1,2]. As the only cells exhibiting bone resorption activity in vivo, OCs are clinically important; OCs lead to excess bone destruction in bone loss-associated disorders, such as rheumatoid arthritis, periodontitis, metastatic cancer, and osteoporosis [3,4]. Osteoclastogenesis is mediated mainly by the stimulation of receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Upon RANKL stimulation, the cytoplasmic tail of RANK recruits tumor necrosis factor receptor-associated factors, leading to the activation of downstream signaling pathways and thereby activating osteoclastogenic transcription factors, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), and nuclear factor of activated

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Conclusion