Preprint Article Version 1 NOT YET PEER-REVIEWED

Iguratimod Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss through the Inhibition of RANKL Signaling Pathway

  1. Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
  2. Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
Version 1 : Received: 1 November 2016 / Approved: 2 November 2016 / Online: 2 November 2016 (06:37:01 CET)

How to cite: Wu, Y.; Sun, Y.; Ye, Y.; Zhang, P.; Guo, J.; Huang, J.; Jing, X.; Xiang, W.; Yu, S.; Guo, F. Iguratimod Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss through the Inhibition of RANKL Signaling Pathway. Preprints 2016, 2016110013 (doi: 10.20944/preprints201611.0013.v1). Wu, Y.; Sun, Y.; Ye, Y.; Zhang, P.; Guo, J.; Huang, J.; Jing, X.; Xiang, W.; Yu, S.; Guo, F. Iguratimod Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss through the Inhibition of RANKL Signaling Pathway. Preprints 2016, 2016110013 (doi: 10.20944/preprints201611.0013.v1).

Abstract

Iguratimod is a novel disease-modifying antirheumatic drug which is widely used in China. Recent evidence showed that iguratimod attenuated Walker 256 rat mammary gland carcinoma cells induced bone destruction and osteoclasts formation in vivo. Thus, we presumed that iguratimod may suppress osteoclastogenesis and prevent osteoclast-related diseases including postmenopausal osteoporosis. In this study, ovariectomized (OVX) mice were used to detect the effects of iguratimod in vivo. Bone marrow mononuclear cells (BMMCs) were cultured to detect the effects of iguratimod on receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis in vitro and the molecular mechanisms involved. The results demonstrated that iguratimod prevented ovariectomy-induced bone loss by suppressing osteoclast activity. Consistently, iguratimod suppressed RANKL-induced osteoclastgenesis and bone resorption. Furthermore, iguratimod inhibited RANKL-stimulated tumor necrosis factor receptor-associated factor 6 (TRAF6) - transforming growth factor β-activated kinase-1 (TAK1) complex formation, followed by suppressing the activation of downstream mitogen-activated protein kinase (MAPK), NF-κB and c-fos. Iguratimod subsequently decreased the expression of osteoclast-specific genes via targeting nuclear factor of activated T cells c1 (NFATc1). In conclusion, our results clearly show that iguratimod can inhibit OVX-induced bone loss and osteoclastogenesis through modulating RANKL signaling. Therefore, iguratimod may be used as a novel therapy to mitigate postmenopausal osteoporosis.

Subject Areas

iguratimod; postmenopausal osteoporosis; ovariectomy; osteoclast; RANKL; MAPK pathway; NF-κB pathway; TRAF6; TAK1

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