The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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SPA0355 prevents ovariectomy-induced bone loss in mice

  • Kim, Sang Hoon (Department of Surgery, Chonbuk National University Medical School) ;
  • Zhang, Zhongkai (Department of Orthopaedic Surgery, Chonbuk National University Medical School) ;
  • Moon, Young Jae (Department of Biochemistry, Chonbuk National University Medical School) ;
  • Park, Il Woon (Department of Cognitive Science, Case Western Reserve University) ;
  • Cho, Yong Gon (Department of Laboratory Medicine, Chonbuk National University Medical School) ;
  • Jeon, Raok (College of Pharmacy, Sookmyung Women's University) ;
  • Park, Byung-Hyun (Department of Biochemistry, Chonbuk National University Medical School)
  • Received : 2018.07.24
  • Accepted : 2018.11.15
  • Published : 2019.01.01
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Abstract

Estrogen withdrawal in post-menopausal women leads to overactivation of osteoclasts, which contributes to the development of osteoporosis. Inflammatory cytokines are known as one of mechanisms of osteoclast activation after estrogen deficiency. SPA0355 is a thiourea derivative that has been investigated for its antioxidant and anti-inflammatory activities. However, its efficacy in bone resorption has not been previously investigated. The aim of this study was to investigate the impact of SPA0355 on the development of osteoporosis and to explore its mode of action. In vitro experiments showed that SPA0355 inhibited receptor activator of $NF-{\kappa}B$ ligand (RANKL)-induced osteoclastogenesis in primary bone marrow-derived macrophages. This effect appears to be independent of estrogen receptor activation as ICI 180,782 failed to abrogate its effects on osteoclasts. Further signaling studies revealed that SPA0355 suppressed activation of the MAPKs, Akt, and $NF-{\kappa}B$ pathways. SPA0355 also increased osteoblastic differentiation, as evidenced by its effects on alkaline phosphatase activity and mineralization nodule formation. Intraperitoneal administration of SPA0355 to ovariectomized mice prevented bone loss, as verified by three-dimensional images and bone morphometric parameters derived from ${\mu}CT$ analysis. Noticeably, SPA0355 did not show hepatotoxicity and nephrotoxicity and also had little effect on hematological parameters. Taken together, the results indicate that SPA0355 may protect against bone loss in ovariectomized mice by stimulation of osteoblast differentiation and by inhibition of osteoclast resorption. Therefore, SPA0355 is a safe and potential candidate for management of postmenopausal osteoporosis.

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