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

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-?B activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-?B activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-?B–mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-?B activity. Collectively, fluid shear stress–dependent Cas-mediated alleviation of NF-?B activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-?B together with systemic distribution of interstitial fluid, the Cas–NF-?B interplay may also underpin regulatory mechanisms in other tissues and organs. Copyright © 2019 The Authors.