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

Here, 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 h SOST 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 unloadingmore » 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.« less
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [4] ;  [5] ;  [3]
  1. Indiana Univ. School of Medicine, Indianapolis, IN (United States); Indiana Univ./Purdue Univ. at Indianapolis, Indianapolis, IN (United States)
  2. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
  3. Univ. of California, Davis, CA (United States)
  4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  5. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California at Merced, Merced, CA (United States)
Publication Date:
Report Number(s):
LLNL-JRNL-691137
Journal ID: ISSN 8756-3282; PII: S8756328216302472
Grant/Contract Number:
AC52-07NA27344
Type:
Accepted Manuscript
Journal Name:
Bone
Additional Journal Information:
Journal Volume: 92; Journal Issue: C; Journal ID: ISSN 8756-3282
Publisher:
Elsevier
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Sost; Sclerostin; Mechanotransduction; ECR5; Enhancer; Skeleton; Disuse
OSTI Identifier:
1377785
Alternate Identifier(s):
OSTI ID: 1396354