Euphorbia factor L1 inhibits osteoclastogenesis by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast

• Published in: Free radical biology & medicine Vol. 112; pp. 191 - 199
• Main Authors: Hong, Seong-Eun, Lee, Jiae, Seo, Dong-Hyun, In Lee, Hye, Ri Park, Doo, Lee, Gong-Rak, Jo, You-Jin, Kim, Narae, Kwon, Minjung, Shon, Hansem, Kyoung Seo, Eun, Kim, Han-Sung, Young Lee, Soo, Jeong, Woojin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2017
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Bone Resorption; Caspases - genetics; Caspases - metabolism; Cell Differentiation; Diterpenes - pharmacology; Fas Ligand Protein - genetics; Fas Ligand Protein - metabolism; fas Receptor - genetics; fas Receptor - metabolism; Female; Gene Expression Regulation; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Osteoclast; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteogenesis - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Phenylpropionates - pharmacology; Primary Cell Culture; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand - antagonists & inhibitors; RANK Ligand - pharmacology; Reactive oxygen species; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Signal Transduction; Bone resorption; Reactive oxygen species; Osteoclast; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2017.07.030

Excessive bone resorption caused by increased osteoclast number or activity leads to a variety of bone diseases including osteoporosis, rheumatoid arthritis and periodontitis. Thus, the therapeutic strategy for these diseases has been focused primarily on the inhibition of osteoclast formation and function. This study shows that euphorbia factor L1 (EFL1), a diterpenoid isolated from Euphorbia lathyris, inhibited osteoclastogenesis and induced osteoclast apoptosis. EFL1 suppressed osteoclast formation and bone resorption at both initial and terminal differentiation stages. EFL1 inhibited receptor activator of NF-κB ligand (RANKL)-induced NFATc1 induction with attenuated NF-κB activation and c-Fos expression. EFL1 decreased the level of reactive oxygen species by scavenging them or activating Nrf2, and inhibited PGC-1β that regulates mitochondria biogenesis. In addition, EFL1 induced apoptosis in differentiated osteoclasts by increasing Fas ligand expression followed by caspase activation. Moreover, EFL1 inhibited inflammation-induced bone erosion and ovariectomy-induced bone loss in mice. These findings suggest that EFL1 inhibits osteoclast differentiation by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast, and may provide therapeutic potential for preventing or treating bone-related diseases caused by excessive osteoclast. [Display omitted] •EFL1 inhibits osteoclastogenesis by suppressing NF-κB and PGC-1β.•EFL1 reduces cellular ROS level by scavenging them or activating Nrf2.•EFL1 induces Fas-mediated apoptosis in osteoclasts but not in BMMs.•EFL1 inhibits inflammation- and ovariectomy-induced bone loss in mice.•EFL1 could be useful for treating osteoclast-mediated bone diseases.