The Antioxidant Endogenous Response in Bone is Regulated by Nrf2 in a Gender Specific Manner

PELLEGRINI GG; CREGOR, M; MORALES CC; MCANDREWS, K; PLOTKIN L; BURR D; WEAVE C; BELLIDO T

Congreso; American Society for Bone and Mineral Research Annual Meeting; 2016

ASBMR

Earlier studies showed that the transcription factor Nrf2, which activates antioxidant defense mechanisms, regulates bone accrual by gender specific mechanisms, as it is required in the female skeleton but dispensable, and even detrimental, in the male skeleton. Here, we examined the antioxidant endogenous response and its relationship with bone volume and architecture in female (F) and male (M), young (3 month) and old (15 month) mice expressing (WT) or lacking (KO) Nrf2. Young and old KO mice of either gender exhibited the expected reduction in Nrf2 mRNA expression compared with WT littermates. Nrf2 deletion did not lead to compensatory increase in Nrf1 and Nrf3, other members of this transcription factor family. Loss of Nrf2 decreased Nrf1 expression in F and M bones; it did not alter Nrf3 expression in F bones but decreased it in young M bones. In addition, the expression of Nrf1 and 3 are dependent on Nrf2 in young M bones but only Nrf1 expression depends on Nrf2 in F bones. We next examined in bone the expression of phase II antioxidant enzymes known to be regulated by Nrf2 in other tissues. NAD(P)H quinone dehydrogenase 1 (NQO1), heme oxygenase 1 (HMOX1), ferritin light chain 1 (FTL1) and glutathione S-transferase pi 1 (GSTP) were downregulated in KO, young and old, F mice and young M mice. In addition, WT old M mice exhibited Nrf2 expression as low as KO old M mice and the expression of NQO1, HMOX1, FTL1 and GSTP were also low and not further decreased by Nrf2 deletion. In contrast, the expression of TXNRD1 (thioredoxin reductase 1) and superoxide dismutase 1 (SOD1) was lower in F KO mice but no different in M KO mice of either age compared to the respective littermate WT. Thus, all phase II antioxidant enzymes were dependent on Nrf2 in F, whereas in males TXNRD1 and SOD1 were controlled by alternative mechanisms. Moreover, Nrf2 deficiency affected bone acquisition also depending on the gender. Thus, M KO mice (young and old) exhibited higher bone volume and trabecular thickness compared to WT littermates. In contrast, bone volume was lower in young F KO mice, and trabecular number was also decreased and trabecular spacing was higher in both young and old F KO mice. These findings demonstrate that Nrf2 regulates the antioxidant endogenous response and bone accrual differentially depending on the gender, and suggest that Nrf2-independent mechanisms mediated by TXNRD1 and SOD1 protect the M skeleton against the detrimental effect of oxidative stress.