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.Harada, I.Sawada, Y.2020-02-042020-02-042019-09Miyazaki, T., Zhao, Z., Ichihara, Y., Yoshino, D., Imamura, T., Sawada, K., … Sawada, Y. (2019). Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-κB activity. Science advances, 5(9), eaau7802. doi:10.1126/sciadv.aau7802https://hdl.handle.net/1805/21979Mechanical 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-κB activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-κB activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-κB-mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-κB activity. Collectively, fluid shear stress-dependent Cas-mediated alleviation of NF-κB activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-κB together with systemic distribution of interstitial fluid, the Cas-NF-κB interplay may also underpin regulatory mechanisms in other tissues and organs.en-USAttribution-NonCommercial 4.0 InternationalMechanical regulation of bone homeostasisp130Cas-mediated alleviationNF-κB activityMechanical loadingArticle