Nrf2 mediates gender specific mechanisms on bone accrual and maintenance

PELLEGRINI GG; CREGOR M; MCANDREWS K; DELGADO-CALLE J; SATO AY; DAVIS HM; PLOTKIN L; BELLIDO T

Congreso; American Society for Bone and Mineral Research; 2015

Mice lacking the transcription factor nuclear factor erythroid 2-relatedfactor2 (Nrf2) are prone to develop diseases associated with elevated oxidativestress, suggesting its critical role in endogenous antioxidant responses. However,conflicting results have been published regarding the skeletal phenotype of thesemice likely due to differences in genetic background, age, or gender among thestudies. Here, we performed a longitudinal analysis of bone mineral density(BMD) and circulating markers of bone remodeling in a cohort of littermatesNrf2+/+ (WT) and Nrf2-/-(KO) mice (10 males and 10females per genotype) between 2 and 15 months of age. KO mice were generated byinjection of targeted 129X1/SvJ-derived JM-1 embryonic stem cells intoblastocysts, followed by breeding to C57BL6 mice. Similar to WT littermates, male and female KO mice reached adult peak BMD at ~5 months of age. However,female KO mice attained lower BMD whereas male KO mice reached higher BMD thanWT littermates, particularly in the spine (-6.62 for female and +5.33% for malemice). After 5 months of age, both male and female WT mice began to losespinal BMD (-19.57 and ?18.69%, for male and female WT mice, respectively,between 5 and 15 months of age). However, KO mice lost much less BMD (-9.69 and ?5.04%, for male and female KO mice,respectively). The higher adult peak BMD in KO male mice was accompanied by highercirculating P1NP at 2 and 5 months of age, suggesting that increased bone accrualwas a consequence of elevated bone formation. Further, collagen1 expression wasincreased ~300% vs WT in 15 month old male KO mice, without changes in otherosteoblast or osteoclast markers. In contrast, osteoblast (collagen1, osterix,Runx2, and osteocalcin) as well as osteoclast (cathepsin K and TRAPase) markerswere markedly reduced to ~10% of WT littermates in 15 month old female KO mice,potentially reflecting a reduction in both osteoblasts and osteoclasts. Theseresults suggest that bone maintenance with aging in male KO mice results fromincreased collagen accumulation whereas in female KO mice is due to decreasedbone remodeling rate. We conclude that Nrf2 is required for full bone acquisitionin the female skeleton and has the opposite effect on the male skeleton.Further, the absence of Nrf2 similarly protects both male and female skeletonsfrom bone loss with aging, although by different mechanisms. Thus, Nrf2regulates bone accrual and maintenance by gender specific mechanisms.