PT  - JOURNAL ARTICLE
AU  - Neha S. Dole
AU  - Cristal S. Yee
AU  - Courtney M. Mazur
AU  - Claire Acevedo
AU  - Tamara Alliston
TI  - TGFβ regulation of perilacunar/canalicular remodeling is sexually dimorphic
AID  - 10.1101/737395
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 737395
4099  - http://biorxiv.org/content/early/2019/08/16/737395.short
4100  - http://biorxiv.org/content/early/2019/08/16/737395.full
AB  - Bone fragility is the product of defects in bone mass and bone quality, both of which show sex-specific differences. Despite this, the cellular and molecular mechanisms underpinning the sexually dimorphic control of bone quality remain unclear, limiting our ability to effectively prevent fractures, especially in postmenopausal osteoporosis. Recently, using male mice, we found that systemic or osteocyte-intrinsic inhibition of TGFβ signaling, achieved using the 9.6-kb DMP1 promoter-driven Cre recombinase (TβRIIocy−/− mice), suppresses osteocyte perilacunar/canalicular remodeling (PLR) and compromises bone quality. Since systemic TGFβ inhibition more robustly increases bone mass in female than male mice, we postulated that sex-specific differences in bone quality could likewise result, in part, from dimorphic regulation of PLR by TGFβ. Moreover, since lactation induces PLR, we examined the effect of TGFβ inhibition on the female skeleton during lactation. In contrast to males, female mice that possess an osteocyte-intrinsic defect in TGFβ signaling were protected from TGFβ-dependent defects in PLR and bone quality. The expression of requisite PLR enzymes, the lacuno-canalicular network, and the flexural strength of female TβRIIocy−/− bone was intact. With lactation, however, bone loss, and induction in PLR and osteocytic parathyroid hormone type I receptor (PTHR1) expression, were suppressed in TβRIIocy−/− bone, relative to wild-type. Indeed, differential control of PTHR1 expression, by TGFβ and other factors, may contribute to dimorphism in PLR regulation in male and female TβRIIocy−/− mice. These findings provide key insights into the sex-based differences in osteocyte PLR that underlie bone quality and highlight TGFβ signaling as a crucial regulator of lactation-induced PLR.