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Article

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

1
Department of Oral Physiology, BK21 PLUS Project, and Institute of Translational Dental Sciences, School of Dentistry, Pusan National University, Yangsan 50612, Korea
2
Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan 50612, Korea
3
Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1467; https://doi.org/10.3390/ijms20061467
Received: 21 February 2019 / Revised: 15 March 2019 / Accepted: 21 March 2019 / Published: 22 March 2019
(This article belongs to the Special Issue Osteoblasts and Osteocytes)
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. View Full-Text
Keywords: bisphosphonate; osteocyte; osteoclast; RANKL; interleukin-6 bisphosphonate; osteocyte; osteoclast; RANKL; interleukin-6
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MDPI and ACS Style

Kim, H.J.; Kim, H.J.; Choi, Y.; Bae, M.-K.; Hwang, D.S.; Shin, S.-H.; Lee, J.-Y. Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis. Int. J. Mol. Sci. 2019, 20, 1467. https://doi.org/10.3390/ijms20061467

AMA Style

Kim HJ, Kim HJ, Choi Y, Bae M-K, Hwang DS, Shin S-H, Lee J-Y. Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis. International Journal of Molecular Sciences. 2019; 20(6):1467. https://doi.org/10.3390/ijms20061467

Chicago/Turabian Style

Kim, Hyung J., Ha J. Kim, YunJeong Choi, Moon-Kyoung Bae, Dae S. Hwang, Sang-Hun Shin, and Jae-Yeol Lee. 2019. "Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis" International Journal of Molecular Sciences 20, no. 6: 1467. https://doi.org/10.3390/ijms20061467

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