Research ArticleMechanotransduction

Microtubules tune mechanotransduction through NOX2 and TRPV4 to decrease sclerostin abundance in osteocytes

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Science Signaling  21 Nov 2017:
Vol. 10, Issue 506, eaan5748
DOI: 10.1126/scisignal.aan5748

Microtubule stability determines mechanosensitivity

In response to increased mechanical load, osteocytes promote bone formation by reducing the abundance of sclerostin, an inhibitor of the cells that build bone. Lyons et al. found that mechanical stress activated reactive oxygen species production and Ca2+ influx to decrease sclerostin abundance in cultured osteocytes. The sensitivity of this pathway to mechanical stress correlated with the extent of a particular posttranslational modification called detyrosination, which stabilizes the microtubule network. Thus, pharmacological manipulations that alter microtubule detyrosination in osteocytes could be an effective strategy to counteract conditions characterized by low bone density.


The adaptation of the skeleton to its mechanical environment is orchestrated by mechanosensitive osteocytes, largely by regulating the abundance of sclerostin, a secreted inhibitor of bone formation. We defined a microtubule-dependent mechanotransduction pathway that linked fluid shear stress to reactive oxygen species (ROS) and calcium (Ca2+) signals that led to a reduction in sclerostin abundance in cultured osteocytes. We demonstrated that microtubules stabilized by detyrosination, a reversible posttranslational modification of polymerized α-tubulin, determined the stiffness of the cytoskeleton, which set the mechanoresponsive range of cultured osteocytes to fluid shear stress. We showed that fluid shear stress through the microtubule network activated NADPH oxidase 2 (NOX2)–generated ROS that target the Ca2+ channel TRPV4 to elicit Ca2+ influx. Furthermore, tuning the abundance of detyrosinated tubulin affected cytoskeletal stiffness to define the mechanoresponsive range of cultured osteocytes to fluid shear stress. Finally, we demonstrated that NOX2-ROS elicited Ca2+ signals that activated the kinase CaMKII to decrease the abundance of sclerostin protein. Together, these discoveries may identify potentially druggable targets for regulating osteocyte mechanotransduction to affect bone quality.

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