While bisphosphonates are generally well-tolerated drugs clinically, several adverse effects, such as gastroesophageal irritation and osteonecrosis of the jaw, have been reported ( Kennel and Drake, 2009). In addition, bisphosphonates directly inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-stimulated osteoclast differentiation and fusion in RAW264.7 cells ( Abe et al., 2012). Bisphosphonates, a class of chemicals that are most commonly used to treat osteoporosis, are adsorbed onto bone surfaces and taken up by osteoclasts to induce apoptosis and promote bone formation ( Drake et al., 2008 Rogers et al., 2011). The pharmacological treatment of osteoporosis is to inhibit osteoclast activities or decrease the number of osteoclasts present to promote bone formation. The imbalance of bone resorption and formation caused by malnutrition, lack of exercise, and reductions in estrogen and testosterone leads to decreased bone density and osteoporosis ( Karsenty and Wagner, 2002 Boyle et al., 2003 Suzuki and Yoshida, 2010). Bone homeostasis is maintained through a balance between osteoclast bone resorption and formation. Fractures are a typical symptom, with a higher prevalence in women than men and an estimated 200 million patients affected worldwide ( Svedbom et al., 2013). Osteoporosis is a progressive metabolic disease in which the bone structure deteriorates due to a decrease in bone density associated with aging and lifestyle factors. This is the first study, to our knowledge, that has found that 10-gingerol in GHE could suppress osteoclastic activity in both in vitro and in vivo conditions. In addition, 10-gingerol inhibited CTSK activity under cell-free conditions. Interestingly, nuclear factor of activated T-cells cytoplasmic 1, a master transcription regulator of osteoclast differentiation upstream of the osteoclastic activators, was downregulated in zebrafish scales but showed no alteration in RAW264.7 cells. Gene expression analysis revealed that 10-gingerol suppressed osteoclast markers in RAW264.7 cells and zebrafish scales. In zebrafish, GHE and 10-gingerol suppressed osteoclastogenesis in prednisolone-induced osteoporosis regenerated scales to promote normal regeneration. We identified that the fractions containing 10-gingerol suppressed osteoclastogenesis in RAW264.7 cells detected by tartrate-resistant acid phosphatase (TRAP) staining. In this study, we separated GHE into several fractions using silica gel column chromatography and evaluated their effects on osteoclastogenesis using a RAW264.7 cell osteoclast differentiation assay ( in vitro) and the zebrafish scale model of osteoporosis ( in vivo). However, the anti-osteoclastic components in GHE have not yet been identified. We previously reported that the hexane extract of ginger rhizome could suppress receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells. Osteoporosis is the most common aging-associated bone disease and is caused by hyperactivation of osteoclastic activity. 7Department of Bioinformatics, Advanced Science Research Promotion Center, Mie University, Tsu, Japan.6Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Japan.5Department of Life Sciences, Graduate School of Bioresources, Mie University, Tsu, Japan.4Tsuji Oil Mills Co., Ltd., Matsusaka, Japan.3Tsuji Health & Beauty Science Laboratory, Mie University, Tsu, Japan. ![]() 2Zebrafish Drug Screening Center, Mie University, Tsu, Japan.1Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan.Liqing Zang 1,2†, Kazuhiro Kagotani 1,3,4†, Hiroko Nakayama 1,2, Jacky Bhagat 1,2, Yuki Fujimoto 4, Akihito Hayashi 4, Ryoji Sono 4, Hirotaka Katsuzaki 5, Norihiro Nishimura 1,2 and Yasuhito Shimada 2,6,7*
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