Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-ҡB activity

T. Miyazaki, Z. Zhao, Y. Ichihara, D. Yoshino, T. Imamura, K. Sawada, S. Hayano, H. Kamioka, S. Mori, H. Hirata, K. Araki, K. Kawauchi, K. Shigemoto, S. Tanaka, L. F. Bonewald, H. Honda, M. Shinohara, M. Nagao, T. Ogata, I. HaradaY. Sawada

Research output: Contribution to journalArticle

Abstract

Mechanical loading plays an important role in bone homeostasis. However, molecular mechanisms behind the mechanical regulation of bone homeostasis are poorly understood. We previously reported p130Cas (Cas) as a key molecule in cellular mechanosensing at focal adhesions. Here, we demonstrate that Cas is distributed in the nucleus and supports mechanical loading–mediated bone homeostasis by alleviating NF-ҡB activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-ҡB activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-ҡB–mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-ҡB activity. Collectively, fluid shear stress–dependent Cas-mediated alleviation of NF-ҡB activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-ҡB together with systemic distribution of interstitial fluid, the Cas–NF-ҡB interplay may also underpin regulatory mechanisms in other tissues and organs.

Original languageEnglish
Article numbereaau7802
JournalScience Advances
Volume5
Issue number9
DOIs
Publication statusPublished - Sep 25 2019

ASJC Scopus subject areas

  • Physics and Astronomy (miscellaneous)
  • General

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    Miyazaki, T., Zhao, Z., Ichihara, Y., Yoshino, D., Imamura, T., Sawada, K., Hayano, S., Kamioka, H., Mori, S., Hirata, H., Araki, K., Kawauchi, K., Shigemoto, K., Tanaka, S., Bonewald, L. F., Honda, H., Shinohara, M., Nagao, M., Ogata, T., ... Sawada, Y. (2019). Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-ҡB activity. Science Advances, 5(9), [eaau7802]. https://doi.org/10.1126/sciadv.aau7802