Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function

Abstract

Excessive osteoclast activity can lead to an imbalance between the synthesis and breakdown of bone, with pathologic consequences that include osteoporosis and periodontitis. Thus, controlling osteoclast differentiation and function has significant therapeutic implications. In this study, we investigated the effects of dehydrocostus lactone (DL) on osteoclast differentiation and activation and elucidated the possible mechanisms underlying these processes. DL suppressed osteoclast differentiation by reducing the expression of the nuclear factor of activated T‐cells, cytoplasmic 1. When used to challenge differentiated osteoclasts, DL also effectively inhibited their enlargement and resorption activity, and biochemical approaches revealed that DL attenuates osteoclast activation by inhibiting the migration and lysosome biogenesis and secretion via the down‐regulation of integrin β3, PKC‐β, and autophagy related 5 expression. Furthermore, DL prevented bone destruction in inflammation‐ and ovariectomy‐induced osteolytic mouse models. These results indicate that DL has therapeutic potential to treat bone diseases caused by excessive or hyperactive osteoclasts.—Lee, H. I., Lee, J., Hwang, D., Lee, G.‐R., Kim, N., Kwon, M., Lee, H., Piao, D., Kim, H. J., Kim, N. Y., Kim, H. S., Seo, E. K., Kang, D., Jeong, W. Dehydrocostus lactone suppresses osteoclast differentiation by regulating NFATc1 and inhibits osteoclast activation through modulating migration and lysosome function. FASEB J. 33, 9685–9694 (2019). http://www.fasebj.org

Protective Effects of Punicalagin on Osteoporosis by Inhibiting Osteoclastogenesis and Inflammation via the NF-κB and MAPK Pathways

“…Osteoclasts are unique cells that play a critical role in maintaining bone homeostasis and normal bone density. It has also been demonstrated that osteoclasts are crucial in osteoporosis (Jacome-Galarza et al, 2019;Lee et al, 2019). Excessive osteoclastogenesis and bone resorption result in changes in trabecular bone mass and microstructure, leading to the potential risk of fracture (Tella and Gallagher, 2014;Lin et al, 2016).…”

“…Then, nuclear factor of activated T cells cytoplasmic 1 (NFATc1), the main transcription factor that regulates osteoclast differentiation, will be triggered to stimulate preosteoclast maturation (Jiang et al, 2019;Zhao K. et al, 2019). Maturational osteoclasts, which are characterized by tartrate-resistant acid phosphatase (TRAP) expression, can generate actin-bound sealing zones for attaching to the surface of bone, and osteoclasts then release proteolytic enzymes, such as cathepsin K (CTSK), which promote resorption pit formation (Lee et al, 2019;Zhao X. et al, 2019). Excessive osteoclastogenesis and bone resorption result in changes in trabecular bone mass and microstructure, leading to the potential risk of fracture; this indicates the need to find therapeutic approaches to prevent osteoporosis (Eriksen et al, 2014;Chen et al, 2019;Jacome-Galarza et al, 2019).…”

Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK, and Nrf2, thereby attenuating osteoclastogenesis

“…In a recent study, it was reported that DL inhibits RANKLinduced osteoclastogenesis by negatively regulating NFATc1 (16). In order to investigate the DL-mediated inhibition of NFATc1, the effect of DL on NF-B that plays an essential role http://bmbreports.org BMB Reports in NFATc1 expression was explored.…”

“…Dehydrocostus lactone (DL) has been reported to possess antioxidant activity (14) and protect osteoblast cell line MC3T3-E1 against oxidative stress and dysfunction (15). Recently, we reported that DL inhibits osteoclast differentiation by regulating NFATc1, and attenuates osteoclast activation by modulating migration and lysosome function (16). However, the mechanism of DL-mediated regulation of RANKL-induced NFATc1 activation has yet to be elucidated.…”

Pathogenic Mechanisms of Myeloma Bone Disease and Possible Roles for NRF2

“…These data suggested that NRF2 is crucial to OC activity, but the underlying mechanism of NRF2 in regulating OC activity remains unclear [123]. Increased p38 MAP kinase activity but not the NF-kB pathway was associated to ROS elevation in NFR2 knockout mice [124][125][126][127]. Moreover, NRF2 also represses OC activity via regulating the activity of NFATc1, which is the master transcription factor for osteoclastogenesis [124,128].…”