Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation.

Autor: Robling AG; Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University/Purdue University at Indianapolis, Indianapolis, IN 46202, USA., Kang KS; Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Bullock WA; Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Foster WH; Department of Anatomy, Physiology and Cell Biology, University of California Davis, Davis, CA, USA., Murugesh D; Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA., Loots GG; Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA; Molecular and Cell Biology Unit, School of Natural Sciences, University of California at Merced, Merced, CA, USA., Genetos DC; Department of Anatomy, Physiology and Cell Biology, University of California Davis, Davis, CA, USA. Electronic address: dgenetos@ucdavis.edu.
Jazyk: angličtina
Zdroj: Bone [Bone] 2016 Nov; Vol. 92, pp. 180-188. Date of Electronic Publication: 2016 Sep 04.
DOI: 10.1016/j.bone.2016.09.001
Abstrakt: Sclerostin (Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost -/- mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous hSOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5 -/- mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost -/- mice, which are resistant to disuse-induced bone loss, ECR5 -/- mice lose bone upon unloading to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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