OR29-04 TGFβ Regulates Bone Perilacunar/Canalicular Remodeling in a Sexually Dimorphic Manner

Sexual dimorphism in the material properties of bone extracellular matrix (ECM) and geometry, which are parameters of bone quality have been recognized (Alswat, 2017; Nieves et al., 2005). However, the molecular mechanisms responsible for dimorphic bone quality remain unclear, limiting our ability to therapeutically target fragility, which is determined by bone quality. Recently, using male mice, we found that systemic or osteocyte-intrinsic inhibition of TGFβ signaling (TβRII(ocy-/-)), suppresses perilacunar/canalicular remodeling (PLR) and compromises bone quality (Dole et al., 2017). Since we previously demonstrated that female bone mass is more sensitive to TGFβ (Mohammad et al., 2009), we hypothesized that loss of osteocytic TGFβ in females will lead to more severe deterioration of PLR and bone quality. Analysis of female bones, however, surprisingly revealed sexual dimorphism in the TGFβ regulation of osteocyte function. While the male TβRII(ocy-/-) mice demonstrated reduced trabecular bone mass and repression in expression of requisite PLR genes, including matrix metalloproteinases (Mmp2, Mmp13, and Mmp14), cathepsin K (Ctsk), and tartrate-resistant acid phosphatase (Acp5/TRAP) (Qing et al., 2012), the female TβRII(ocy-/-) bones were intact. With absence of osteocytic TGFβ signaling, the canaliculi of male TβRII(ocy-/-) osteocytes were truncated and a severe deterioration of lacuno-canalicular network (LCN) was observed. Unlike the male TβRII(ocy-/-) mice that exhibited poor bone quality, female TβRII(ocy-/-) bones were completely protected from bone quality defects and macromechanical bone fragility. Thus, TGFβ-dependent regulation PLR and bone quality is sexually dimorphic. Since, lactation is a potent PLR agonist, we also evaluated the lactation-induced PLR response of TβRII(ocy-/-) female mice. Compared to WT, lactation-induced bone loss and upregulation of PLR genes was significantly attenuated in the TβRII(ocy-/-) female mice. Lactation-mediated increases in osteocyte lacunar volume were suppressed in TβRII(ocy-/-) bones as well. This mitigation in PLR of lactating TβRII(ocy-/-) mice was analogous to that observed in mice with osteocyte-specific ablation of parathyroid hormone type I receptor (PTHR1) (Qing et al., 2012). Remarkably, lactation-inducible PTHR1 expression was also diminished in TβRII(ocy-/-) osteocytes. Therefore, osteocyte-intrinsic TGFβ signaling is critical for the maximal induction of PLR during lactation, and TGFβ is an upstream regulator of PTHR1-dependent activation of osteocytic PLR. Indeed, we also found sexual dimorphism in the regulation of osteocytic PTHR1 expression by TGFβ, such that male, but not female, TβRII(ocy-/-) mice had reduced PTHR1 compared to WT. In summary, we identify a novel PTH-dependent mechanism that protects female bone against the severe bone fragility that results from suppressed TGFβ signaling in osteocytes.