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

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.