The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensin...

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Published in:The Journal of biological chemistry 2015-07, Vol.290 (27), p.16744-16758
Main Authors: Spatz, Jordan M., Wein, Marc N., Gooi, Jonathan H., Qu, Yili, Garr, Jenna L., Liu, Shawn, Barry, Kevin J., Uda, Yuhei, Lai, Forest, Dedic, Christopher, Balcells-Camps, Mercedes, Kronenberg, Henry M., Babij, Philip, Pajevic, Paola Divieti
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing
Animals
Biomechanical Phenomena
bone
Cell Biology
Cell Line
cell sorting
Glycoproteins - genetics
Glycoproteins - metabolism
Gravitation
Intercellular Signaling Peptides and Proteins
mechanical unloading
Mice
osteocyte
Osteocytes - chemistry
Osteocytes - metabolism
RANK Ligand - genetics
RANK Ligand - metabolism
sclerostin
shear stress
Up-Regulation
Wnt pathway
Wnt Proteins - genetics
Wnt Proteins - metabolism
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Summary:Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensing stresses and strains in bone. Sclerostin, a product of the SOST gene, is produced postnatally primarily by osteocytes and is a negative regulator of bone formation. Recent studies show that SOST is mechanically regulated at both the mRNA and protein levels. During prolonged bed rest and immobilization, circulating sclerostin increases both in humans and in animal models, and its increase is associated with a decrease in parathyroid hormone. To investigate whether SOST/sclerostin up-regulation in mechanical unloading is a cell-autonomous response or a hormonal response to decreased parathyroid hormone levels, we subjected osteocytes to an in vitro unloading environment achieved by the NASA rotating wall vessel system. To perform these studies, we generated a novel osteocytic cell line (Ocy454) that produces high levels of SOST/sclerostin at early time points and in the absence of differentiation factors. Importantly, these osteocytes recapitulated the in vivo response to mechanical unloading with increased expression of SOST (3.4 ± 1.9-fold, p < 0.001), sclerostin (4.7 ± 0.1-fold, p < 0.001), and the receptor activator of nuclear factor κΒ ligand (RANKL)/osteoprotegerin (OPG) (2.5 ± 0.7-fold, p < 0.001) ratio. These data demonstrate for the first time a cell-autonomous increase in SOST/sclerostin and RANKL/OPG ratio in the setting of unloading. Thus, targeted osteocyte therapies could hold promise as novel osteoporosis and disuse-induced bone loss treatments by directly modulating the mechanosensing cells in bone. Background: Recent studies have suggested osteocytes as key players in mechanosensation and skeletal metabolism. Results: Simulated microgravity induces an autonomous up-regulation of SOST/sclerostin and RANKL/OPG in a novel osteocytic cell line, Ocy454. Conclusion: Mechanical loading regulates intrinsic osteocyte responses in concert with hormonal and cytokine inputs. Significance: Learning how osteocytes sense mechanical loads would enable novel interventions to prevent disuse-induced bone loss.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.628313