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KMID : 1100120160230010008
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대한골대사학회지
2016 Volume.23 No. 1 p.8 ~ p.15
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Deficiency of Lipocalin-2 Promotes Proliferation and Differentiation of Osteoclast Precursors via Regulation of c-Fms Expression and Nuclear Factor-kappa B Activation
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Kim Hyun-Ju
Ohk Bo-Ram
Kang Woo-Youl
Seong Sook-Jin
Suk Kyoung-Ho
Lim Mi-Sun
Kim Shin-Yoon
Yoon Young-Ran
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Abstract
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Background: Lipocalin-2 (LCN2), a small glycoprotein, has a pivotal role in diverse biological processes such as cellular proliferation and differentiation. We previously reported that LCN2 is implicated in osteoclast formation induced by receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). In the present study, we used a knockout mouse model to further investigate the role of LCN2 in osteoclast development.
Methods: Osteoclastogenesis was assessed using primary bone marrow-derived macrophages. RANKL and M-CSF signaling was determined by immunoblotting, cell proliferation by bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay (ELISA), and apoptosis by cell death detection ELISA. Bone morphometric parameters were determined using a micro-computed tomography system.
Results: Our results showed that LCN2 deficiency increases tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclast formation in vitro, a finding that reflects enhanced proliferation and differentiation of osteoclast lineage cells. LCN2 deficiency promotes M-CSF-induced proliferation of bone marrow macrophages (BMMs), osteoclast precursors, without altering their survival. The accelerated proliferation of LCN2-deficient precursors is associated with enhanced expression and activation of the M-CSF receptor, c-Fms. Furthermore, LCN2 deficiency stimulates the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), key transcription factors for osteoclastogenesis, and promotes RANKL-induced inhibitor of kappa B (IκBα) phosphorylation. Interestingly, LCN2 deficiency does not affect basal osteoclast formation in vivo, suggesting that LCN2 might play a role in the enhanced osteoclast development that occurs under some pathological conditions.
Conclusions: Our study establishes LCN2 as a negative modulator of osteoclast formation, results that are in accordance with our previous findings.
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KEYWORD
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c-Fms, LCN2, NF-κB, Osteoclast
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