Deficiency of Lipocalin-2 Promotes Proliferation and Differentiation of Osteoclast Precursors via Regulation of c-Fms Expression and Nuclear Factor-kappa B Activation

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 (IkappaBalpha) 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.

C-Fms kinase and its small molecule inhibitors: Research advances / 国际药学研究杂志

c-Fms, encoded by the c-fms proto-oncogene, is a member of the platelet derived growth factor receptor (PDGFR) family of receptor tyrosine kinases(RTK). The interaction of c-Fms and the receptor, macrophage colony stimulating factor (M-CSF) can regulate proliferation, differentiation and survival of the mononuclear phagocyte cells. Abnormal expression of c-Fms is associated with a significant number of human pathologies, especially a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms kinase can be considered as a novel choice for treating cancers and other diseases. This review describes the recent progress of c-Fms kinase and its small molecule inhibitors. © 2006 Editorial office of Foreign Medical Sciences.

Macrophage colony-stimulating factor receptor and its inhibitors: Research advances / 国际药学研究杂志

Macrophage colony-stimulating factor receptor(c-Fms),encoded by the c-fms proto-oncogene,is a member of type III receptor tyrosine kinase family. c-Fms activation by binding with its ligand plays important roles in the survival, proliferation and differentiation of the monocyte-macrophage lineage and the development of embryo. Over expression of c-Fms and its ligand result in abnormalities of intracellular signaling pathways mediated by c-Fms, which is associated with tumorigenesis and inflammation. The inhibitors targeting c-Fms block intracellular signaling pathways by inhibiting c-Fms receptor tyrosine kinase are potential drugs for tumor and arthritis therapeutics.