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Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis

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Abstract

Bisphosphonates have been known to directly inhibit bone resorption and promote apoptosis in mature osteoclasts. Although bisphosphonates have been recognized as the most effective drugs to treat osteoporosis and bone cancer metastasis, the exact effects and mechanism(s) of bisphosphonates on osteoclastogenesis are unclear. The aim of this study was to clarify whether nitrogen-containing bisphosphonates affect recruitment and differentiation in osteoclasts. We examined the effects of zoledronic acid on receptor activator of NF-κB (RANK) expression and cell migration during osteoclastogenesis in two types of osteoclast precursors, RAW264.7 cells and Bone marrow cells (BMCs). Tumor necrosis factor-α (TNF-α) and RANK ligand (RANKL) upregulated RANK expression in RAW264.7 and BMCs in the presence of macrophage colony stimulating factor in a time-dependent manner. Zoledronic acid (30 and 50 μM) had no effect on cell viability in osteoclast precursors after 36 h of cultivation. Zoledronic acid (10 and 30 μM) strongly inhibited TNF-α- and RANKL-induced upregulation of RANK in a dose-dependent manner. The inhibitory effects on RANK expression were likely to be associated with the suppression of the NF-κB pathway, but not other downstream signaling pathways. Zoledronic acid (30 μM) also suppressed the TNF-α- and RANKL-induced migration of precursors by inhibiting the mevalonic acid pathway. Our results suggest that nitrogen-containing bisphosphonates not only inhibit mature osteoclasts but also prevent osteoclast precursors from differentiating and migrating towards inflammatory osteolysis lesions.

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Abbreviations

BRONJ:

Bisphosphonate-related osteonecrosis of the jaw

FDPS:

Farnesyl diphosphate synthase

FOH:

Farnesol

GGOH:

Geranylgeraniol

HMG-coA:

3-hydroxy-3-methylglutary coenzyme A

M-CSF:

Macrophage colony stimulating factor

NFκB:

Nuclear factor kappa B

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

RANK:

Receptor activator of NF-κB

RANKL:

Receptor activator of NF-κB ligand

SCCs:

Squamous cell carcinoma cells

TNF-α:

Tumor necrosis factor-α

TRAP:

Tartrate-resistant acid phosphatase

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Grants

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (no. 21592381 and 20592383) and a Frontier Research Grant.

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All authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Tamura 2-15-1 Sawara-ku, Fukuoka, 8140193, Japan

    Keiichiro Kimachi, Hiroshi Kajiya, Shuji Nakayama & Koji Okabe

  2. Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka, 8140193, Japan

    Keiichiro Kimachi, Shuji Nakayama & Tetsuro Ikebe

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  1. Keiichiro Kimachi
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  2. Hiroshi Kajiya
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Correspondence to Hiroshi Kajiya.

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Kimachi, K., Kajiya, H., Nakayama, S. et al. Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis. Naunyn-Schmied Arch Pharmacol 383, 297–308 (2011). https://doi.org/10.1007/s00210-010-0596-4

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