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Int J Mol Sci. 2019 Mar 22;20(6). pii: E1467. doi: 10.3390/ijms20061467.

Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis.

Author information

1
Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea. hjoonkim@pusan.ac.kr.
2
Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea. ya120010@naver.com.
3
Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea. celinechoi@pusan.ac.kr.
4
Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea. mkbae@pusan.ac.kr.
5
Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea. dshwang@pusan.ac.kr.
6
Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea. dshwang@pusan.ac.kr.
7
Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea. ssh8080@pusan.ac.kr.
8
Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea. ssh8080@pusan.ac.kr.
9
Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea. omsljy@pusan.ac.kr.
10
Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea. omsljy@pusan.ac.kr.

Abstract

Bisphosphonates are one of the most widely used synthetic pyrophosphate analogues for the treatment of bone resorbing diseases such as osteoporosis, multiple myeloma, and bone metastases. Although the therapeutic usefulness of bisphosphonates mainly depends on their anti-osteoclastogenic effect, a severe side-effect of bisphosphonates called bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be explained by the anti-osteoclastogenic effect of bisphosphonates. In the present study, we have evaluated the changes in osteoclastogenesis- or osteoblastogenesis-supporting activities of osteocytes induced by bisphosphonates. Zoledronate, a nitrogen-containing bisphosphonate, markedly increased both the receptor activator of nuclear factor kB ligand (RANKL) as well as sclerostin in osteocyte-like MLO-Y4 cells, which were functionally revalidated by osteoclast/osteoblast generating activities of the conditioned medium obtained from zoledronate-treated MLO-Y4 cells. Of note, the zoledronate treatment-induced upregulation of the RANKL expression was mediated by autocrine interleukin-6 (IL-6) and subsequent activation of the signal transducer and activator of transcription 3 (STAT3) pathway. These results were evidenced by the blunted RANKL expression in the presence of a Janus activated kinase (JAK2)/STAT3 inhibitor, AG490. Also, the osteoclastogenesis-supporting activity was significantly decreased in zoledronate-treated MLO-Y4 cells in the presence of IL-6 neutralizing IgG compared to that of the control IgG. Thus, our results show previously unanticipated effects of anti-bone resorptive bisphosphonate and suggest a potential clinical importance of osteocytes in BRONJ development.

KEYWORDS:

RANKL; bisphosphonate; interleukin-6; osteoclast; osteocyte

PMID:
30909508
PMCID:
PMC6471260
DOI:
10.3390/ijms20061467
[Indexed for MEDLINE]
Free PMC Article

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