CDDO-Me, Sulforaphane and tBHQ attenuate the RANKL-induced osteoclast differentiation via activating the NRF2-mediated antioxidant response

Abstract

Metabolic bone diseases are global public health concerns and are primarily caused by uncontrolled osteoclast (OC) formation and activation. During OC differentiation, intracellular reactive oxygen species (ROS) stimulated by receptor activator of nuclear factor kappa-B ligand (RANKL) can serve as the signaling molecules to promote osteoclastic genes expression. Nuclear factor erythroid-2 related factor 2 (NRF2), a master mediator of cellular antioxidant response, also plays a critical role in OC differentiation through the regulation of redox homeostasis. In this study, we investigated the effects of three NRF2 inducers on osteoclastogenesis, including Bardoxolone methyl (CDDO-Me), Sulforaphane (SFN), and tert-butylhydroquinone (tBHQ). By treating RAW cells with three compounds, we found that NRF2 was activated and its downstream antioxidant genes were upregulated, and the RANKL-induced intracellular ROS production and osteoclastogenesis were impaired. Additionally, the expression of nuclear factor of activated T cells c1 (NFATC1), C-FOS and tumor necrosis factor alpha (TNFα) were inhibited after acute exposures (6 hours) to the three compounds. Furthermore, suppressed expression of osteoclast differentiation associated genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), matrix metalloproteinase-9 (MMP-9) and dendritic cell specific transmembrane protein (DC-STAMP) were observed after prolonged exposures (5 days) to the compounds. Taken together, these results suggest that CDDO-Me, SFN and tBHQ attenuate RANKL-induced osteoclastogenesis via activation of NRF2-mediated antioxidant response. Among these compounds, relatively low concentrations of CDDO-Me showed stronger active and inhibitory effects on antioxidant response and osteoclastogenesis, respectively.

Baitouweng Decoction Ameliorates Ulcerative Colitis in Mice Partially Attributed to Regulating Th17/Treg Balance and Restoring Intestinal Epithelial Barrier

“…However, TBHQ as an activator of ERK did not aggravate DSS-induced colitis. It may be that TBHQ can also activate nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant response, which may partially neutralize the colonic damage caused by the activation of the ERK pathway ( Xue et al, 2019 ). In vitro , BTW also inhibited the activity of NF-κB/ERK in LPS-activated RAW 264.7 cells.…”

Sulforaphane Inhibits Osteoclastogenesis via Suppression of the Autophagic Pathway

“…Recently, it was reported that SFN could also be used to treat diseases associated with pathological bone resorption, such as bone metastasis in breast cancer, osteoporosis, and osteoarthritis [ 25 , 26 , 27 ]. In addition, Tomohiro Takagi et al suggested that SFN plays a negative role in RANKL-induced osteoclastogenesis, but the underlying mechanisms need to be further investigated [ 10 , 28 ]. Autophagy is required during osteoclastogenesis and could be modulated by SFN.…”

Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo

“…In the case of matrix metalloproteinases-2/-9, primary effects of triterpenoids on their activity, as far as we know, have not been yet published, however, recently, Preciado et al reported that betulinic, oleanolic and ursolic acids can bind to catalytic site of snake venom metalloproteinases, being similar to those in human matrix metalloproteinases, and significantly inhibit their enzymatic and biological activities [ 93 , 94 ]. Furthermore, CDDO-Me and its analog RTA408 were found to decrease expression of MMP-9 in various models, including tumor necrosis factor α- (TNF-α-), receptor activator of nuclear factor kappa-B ligand- (RANKL-) and interleukin 1β- (IL-1β)-stimulated chronic myelogenous leukemia KBM-5 cells, RAW264.7 macrophages and rat brain astrocytes [ 72 , 95 , 96 ], respectively, as well as primary mammary tumor cells, isolated from polyoma middle T mice [ 97 ], which is consistent with revealed ability of SM to inhibit expression of MMP-9 in metastatic foci in lungs of B16 melanoma-bearing mice ( Figure 8 E). It should be emphasized, however, that prediction of JNK1 and MMP-2/-9 as EMT-associated protein targets of SM was carried out using computer modeling approach and, therefore, these findings only hypothesize about probable molecular mechanism of inhibitory effect of SM on EMT.…”