Skeletal effects of nongenomic thyroid hormone receptor beta signaling.

ABSTRACT: Thyroid hormone (TH) levels increase rapidly during the prepubertal growth period in mice, and this change is necessary for endochondral ossification of the epiphyses. This effect of TH on epiphyseal chondrocyte hypertrophy is mediated via TR?1. In addition to its traditional genomic signaling role as a transcription factor, TR?1 can also exert nongenomic effects by interacting with other signaling molecules such as PI3K. To investigate the role of nongenomic TR?1 signaling in endochondral ossification, we evaluated the skeletal phenotype of TR?147F mutant mice which exhibit a normal genomic response of TR?1 to TH, but the nongenomic response through the PI3K pathway is impaired. Using microCT, we found that 13-week-old TR?147F mice had significantly less trabecular bone mass at three sites. Histomorphometric analyses revealed that mineralizing surface to bone surface and BFR/BS were reduced in the mutant mice. Mechanistically, we found that activation of TR? increased Alp and Osx expression in control but not TR?147F osteoblasts. Since canonical ?-catenin signaling has been implicated in mediating nongenomic TR?-PI3K signaling, we evaluated the effect of TR?1 activation on ?-catenin target gene expression in MC3T3-E1 pre-osteoblasts. We found that ?-catenin target genes were increased, suggesting that nongenomic TR?1-PI3K pathway modulation of ?-catenin signaling may mediate TR?1 effects on osteoblast differentiation. Together, these results suggest that TH acting through TR?1 regulates endochondral ossification in part via nongenomic signaling in mice. Further investigation of this nongenomic mechanism of TR?1 signaling could lead to novel therapeutic targets for treatment and prevention of osteoporosis.

SUBMITTER: Lindsey RC 

PROVIDER: S-EPMC6685746 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature