Abstract
ABSTRACTBone relies on mechanical cues to build and maintain tissue composition and architecture. Our understanding of bone cell mechanotransduction continues to evolve, with a few key signaling pathways emerging as vital. Wnt/β‐catenin, for example, is essential for proper anabolic response to mechanical stimulation. One key complex that regulates β‐catenin activity is the mammalian target of rapamycin complex 2 (mTORc2). mTORc2 is critical for actin cytoskeletal reorganization, an indispensable component in mechanotransduction in certain cell types. In this study, we probed the impact of the mTORc2 signaling pathway in osteocyte mechanotransduction by conditionally deleting the mTORc2 subunit Rictor in Dmp1‐expressing cells of C57BL/6 mice. Conditional deletion of the Rictor was achieved using the Dmp1–Cre driver to recombine Rictor floxed alleles. Rictor mutants exhibited a decrease in skeletal properties, as measured by DXA, μCT, and mechanical testing, compared with Cre‐negative floxed littermate controls. in vivo axial tibia loading conducted in adult mice revealed a deficiency in the osteogenic response to loading among Rictor mutants. Histological measurements of osteocyte morphology indicated fewer, shorter cell processes in Rictor mutants, which might explain the compromised response to mechanical stimulation. In summary, inhibition of the mTORc2 pathway in late osteoblasts/osteocytes leads to decreased bone mass and mechanically induced bone formation. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Mechanical stimulation of bone tissue is a major determinant of skeletal mass, distribution, and strength.[1]
Despite the paucity of data on mammalian target of rapamycin complex 2 (mTORc2) biology, prior work demonstrates a critical role for mTORc2 in mechanically induced activation of β-catenin, a crucial node in bone cell mechanotransduction.[13]. We found that mechanical stimulation of mesenchymal stem progenitor cells (MSPCs) recruits mTORc2 to focal adhesions where it orchestrates cytoskeletal reorganization, subsequent protein kinase B (AKT) activation, Gsk3β phosphorylation, and β-catenin survival and nuclear translocation.[14,15] Inhibition of the mTORc2 component Rictor disrupts mechanically induced cytoskeletal reorganization, AKT activation, and promotes β-catenin degradation
Our goal in this study was to investigate whether the mTORc2 complex plays a significant role in bone homeostasis and in the anabolic response to mechanical loading, when manipulated very late in the mesenchymal lineage
Summary
Mechanical stimulation of bone tissue is a major determinant of skeletal mass, distribution, and strength.[1]. Stimulated osteocytes transduce physical stimuli into biochemical signals that reach the bone surface, where the effector cell populations (osteoblasts and osteoclasts) or their progenitors can be accessed and directed for appropriate spatiotemporal activity. The integrity of this intercellular transduction process relies on the fidelity of a multitude of complex signaling cascades within the osteocyte. Our results suggest that the mTORc2 complex in the osteocyte population is crucial for achieving peak bone mass, strength, and responsiveness to mechanical inputs
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