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Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-?B 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.

SUBMITTER: Miyazaki T

PROVIDER: S-EPMC6760935 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

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

Science advances 20190925 9

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 modul ...[more]

PMID: 31579816

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Project description:BackgroundSkeletal unloading usually induces severe disuse osteoporosis (DOP), which often occurs in patients subjected to prolonged immobility or in spaceflight astronauts. Increasing evidence suggests that exosomes are important mediators in maintaining the balance between bone formation and resorption. We hypothesized that exosomes play an important role in the maintenance of bone homeostasis through intercellular communication between bone marrow mesenchymal stem cells (BMSCs) and osteoclasts under mechanical loading.MethodsCells were divided into cyclic mechanical stretch (CMS)-treated BMSCs and normal static-cultured BMSCs, and exosomes were extracted by ultracentrifugation. After incubation with CMS-treated BMSC-derived exosomes (CMS_Exos) or static-cultured BMSC-derived exosomes (static_Exos), the apoptosis rates of bone marrow macrophages (BMMs) were determined by flow cytometry, and cell viability was detected with a Cell Counting Kit-8 (CCK-8) assay. Osteoclast differentiation was determined with an in vitro osteoclastogenesis assay. Signaling pathway activation was evaluated by western blotting and immunofluorescence staining. Hindlimb unloading (HU)-induced DOP mouse models were prepared to evaluate the function of exosomes in DOP.ResultsBoth CMS_Exos and static_Exos could be internalized by BMMs, and CMS_Exos did not affect BMM viability or increase apoptosis. The CMS_Exos effectively suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis and F-actin ring formation. Further molecular investigation demonstrated that CMS_Exos impaired osteoclast differentiation via inhibition of the RANKL-induced nuclear factor kappa-B (NF-κB) signaling pathway. Both CMS_Exos and static_Exos partly rescued the osteoporosis caused by mechanical unloading; however, the CMS_Exo group showed more obvious rescue. Treatment with CMS_Exos significantly decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts. Exosomes derived from CMS-treated BMSCs strongly inhibited osteoclast differentiation by attenuating the NF-κB signaling pathway in vitro and rescued osteoporosis caused by mechanical unloading in an HU mouse model in vivo.ConclusionsIn this research, we demonstrated that Exosomes derived from CMS-treated BMSCs inhibited osteoclastogenesis by attenuating NF-κB signaling pathway activity in vitro and ameliorated bone loss caused by mechanical unloading in an HU mouse model, providing new insights into intercellular communication between osteoblasts and osteoclasts under mechanical loading.

Dataset Information

Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-?B activity.

Publications

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

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