RRC ID 58150
Author 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 LF, Honda H, Shinohara M, Nagao M, Ogata T, Harada I, Sawada Y.
Title Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-κB activity.
Journal Sci Adv
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-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.
Volume 5(9)
Pages eaau7802
Published 2019-9-1
DOI 10.1126/sciadv.aau7802
PII aau7802
PMID 31579816
PMC PMC6760935
MeSH Animals Biomarkers Bone Resorption Bone and Bones / diagnostic imaging Bone and Bones / metabolism* Crk-Associated Substrate Protein / genetics Crk-Associated Substrate Protein / metabolism* Gene Expression Homeostasis* Mice Mice, Knockout NF-kappa B / metabolism* Osteoclasts / metabolism Osteocytes / metabolism RANK Ligand / genetics RANK Ligand / metabolism Signal Transduction* Stress, Mechanical* X-Ray Microtomography
IF 13.117
Times Cited 4
Mice RBRC02338