Year: 2020
Type: article
Abstract: 1. Abstract 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 (TβRII ocy−/− 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 TβRII ocy−/− bone was intact. With lactation, however, bone loss, and induction in PLR and osteocytic parathyroid hormone type I receptor (PTHR1) expression, were suppressed in TβRII ocy−/− 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 TβRII ocy−/− 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.
DOI: 10.1002/jbmr.4023
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: National Science Foundation, U.S. Department of Defense, U.S. Department of Energy, National Institutes of Health, Office of Science, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, Office of Research on Women's Health, Basic Energy Sciences, Lawrence Berkeley National Laboratory
Awards: G1079818582, G1143651532, G1148965125, G1286236842, G1286251239, G1337523522, The mechanobiology of TGF-beta signaling in chondrocytes, G1863003419, G2141279964, The mechanistic control of bone quality and joint crosstalk by osteocytes, G2618837358, G2795275917, G30714459, G3083819904, G382641700, G419881185, G42916606, G4501827968, G498139845, G5175575554, G6295457011, G650090426, G6652958823, G6998434892, G7015462466, G7354628648, UCSF Core Center for Musculoskeletal Biology and Medicine, G9000213115, Core Center for Musculoskeletal Biology and Medicine, G969889393, Mechanoregulation of Growth Factor Receptor Assembly and Signaling
OpenAlex ID: W3015586784