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J Biol Chem. 2015 Jul 3;290(27):16744-58. doi: 10.1074/jbc.M114.628313. Epub 2015 May 7.

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

Author information

1
From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, Harvard-MIT Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
2
From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
3
NorthWest Academic Centre, The University of Melbourne, St. Albans, Victoria 3065, Australia, and.
4
Harvard-MIT Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Bioengineering Department, Institut Quimic de Sarria, Ramon Llull University, 08017 Barcelona, Spain.
5
Amgen Inc., Thousand Oaks, California 91320.
6
From the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, pdivieti@bu.edu.

Abstract

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.

KEYWORDS:

Wnt pathway; bone; cell biology; cell line; cell sorting; mechanical unloading; osteocyte; sclerostin; shear stress

PMID:
25953900
PMCID:
PMC4505423
DOI:
10.1074/jbc.M114.628313
[Indexed for MEDLINE]
Free PMC Article

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