Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility.
The
interaction of nanoparticles (NPs) with pulmonary surfactant
is important for understanding the potential adverse effects of inhaled
engineered and incidental nanomaterials. The effects of a low concentration
(0.001 wt %) of charged, hydrophilic silica NPs of hydrodynamic diameter
of ∼20 nm on the phase behavior and lateral structure of lipid-only
and naturally derived surfactant monolayers were investigated at the
air/water interface using surface pressure–area isotherms and
Brewster angle microscopy, respectively. Atomic force microscopy was
used to image the morphology of films transferred onto mica substrate
with nanometer resolution. We show that the silica NPs can significantly
alter the condensed domain size and shape even in the absence of apparent
differences in the monolayer compression isotherms. The cationic particles
notably induce structural and morphological progressions in a binary
model containing anionic phosphoglycerol that are similar to
those observed for the natural surfactant film that contains cationic
proteins. These findings specifically highlight the impact of the
NP charge on the phase transformations in pulmonary surfactant, with
implications for the engineering of nanomaterials for commercial use
and bioapplications.
Highlights
Machine learning approaches allow for the simultaneous analysis to an entire microCT dataset to minimize bias and demonstrated that collective microarchitectural changes.
K-Means clusters and Support Vector Machine classification visualization provide intuitive interpretations of the differences in bone structure and microarchitecture between groups.
These techniques are complimentary to common statistical testing and provide additional ways of showing differences between microCT outcomes.
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