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Lipocalin-2 upregulation in hypoxic murine osteocytes enhances RANKL-induced osteoclastogenesis
Kohei Narita1, Fumitoshi Ohori1, Aseel Marahleh1,2
1Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
Scientific Reports
|January 6, 2026
Summary
Hypoxia upregulates lipocalin-2 (Lcn2) in osteocytes, promoting bone resorption by increasing RANKL. This discovery offers a new therapeutic target for bone metabolic diseases.
Area of Science:
- Bone Biology
- Cellular Signaling
- Molecular Mechanisms
Background:
- Osteocytes are key regulators of bone remodeling.
- Hypoxia is implicated in bone diseases and orthodontic tooth movement (OTM), increasing osteoclastogenesis.
- The molecular mechanisms linking hypoxia to osteoclastogenesis are not fully understood.
Purpose of the Study:
- Identify hypoxia-responsive genes in osteocytes.
- Investigate the role of these genes in osteoclastogenesis.
Main Methods:
- Transcriptome analysis of MLO-Y4 osteocytes under hypoxia.
- Real-time RT-PCR and Western blot analysis.
- Co-culture experiments and immunohistochemistry in OTM models.
Main Results:
- Lipocalin-2 (Lcn2) was the most significantly upregulated gene in hypoxic osteocytes.
- Lcn2 enhanced osteoclastogenesis indirectly via osteocytes by increasing RANKL expression.
- LCN2 activated the MAPK signaling pathway in osteocytes.
- Increased LCN2 expression was observed in hypoxic osteocytes on the compression side of OTM.
Conclusions:
- Hypoxia upregulates Lcn2 in osteocytes, promoting osteoclastogenesis and bone resorption.
- Lcn2 acts through osteocytes to increase RANKL expression.
- Lcn2 is a potential therapeutic target for hypoxic bone metabolic diseases.
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