TY - JOUR
T1 - Effects of age and estrogen on skeletal gene expression in humans as assessed by RNA sequencing
AU - Farr, Joshua N.
AU - Roforth, Matthew M.
AU - Fujita, Koji
AU - Nicks, Kristy M.
AU - Cunningham, Julie M.
AU - Atkinson, Elizabeth J.
AU - Therneau, Terry M.
AU - McCready, Louise K.
AU - Peterson, James M.
AU - Drake, Matthew T.
AU - Monroe, David G.
AU - Khosla, Sundeep
N1 - Funding Information:
We thank the women for their participation in this study. This work was orted in part by an investigator initiated grant from Merck and by P01 AG004875 from the National Institute of Aging (NIA). It was also made possible by the Mayo Clinical Center for Clinical and Translational Science (CCaTS), Grant Number UL1 TR000135 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no other relevant declarations. Dr. Farr is orted by a career development award from the Robert and Arlene Kogod Center on Aging (Mayo Clinic). Dr. Khosla had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information:
This study was supported, in part, by an investigator-initiated grant from Merck. There are no other relevant declarations. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
Publisher Copyright:
© 2015 Farr et al.
PY - 2015/9/24
Y1 - 2015/9/24
N2 - Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining prespecified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome. Here we present an RNAseq analysis of human bone samples, obtained from iliac crest needle biopsies, to yield the first in vivo interrogation of all genes and pathways that may be altered in bone with aging and E therapy in humans. 58 healthy women were studied, including 19 young women (mean age ± SD, 30.3 ± 5.4 years), 19 old women (73.1 ± 6.6 years), and 20 old women treated with 3 weeks of E therapy (70.5 ± 5.2 years). Using generally accepted criteria (false discovery rate [q] < 0.10), aging altered a total of 678 genes and 12 pathways, including a subset known to regulate bone metabolism (e.g., Notch). Interestingly, the LEF1 transcription factor, which is a classical downstream target of the Wnt/β-catenin signaling pathway, was significantly downregulated in the bones from the old versus young women; consistent with this, LEF1 binding sites were significantly enriched in the promoter regions of the differentially expressed genes in the old versus young women, suggesting that aging was associated with alterations in Wnt signaling in bone. Further, of the 21 unique genes altered in bone by E therapy, the expression of INHBB (encoding for the inhibin, beta B polypeptide), which decreased with aging (by 0.6-fold), was restored to young adult levels in response to E therapy. In conclusion, our data demonstrate that aging alters a substantial portion of the skeletal transcriptome, whereas E therapy appears to have significant, albeit less wide-ranging effects. These data provide a valuable resource for the potential identification of novel biomarkers associated with age-related bone loss and also highlight potential pathways that could be targeted to treat osteoporosis.
AB - Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining prespecified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome. Here we present an RNAseq analysis of human bone samples, obtained from iliac crest needle biopsies, to yield the first in vivo interrogation of all genes and pathways that may be altered in bone with aging and E therapy in humans. 58 healthy women were studied, including 19 young women (mean age ± SD, 30.3 ± 5.4 years), 19 old women (73.1 ± 6.6 years), and 20 old women treated with 3 weeks of E therapy (70.5 ± 5.2 years). Using generally accepted criteria (false discovery rate [q] < 0.10), aging altered a total of 678 genes and 12 pathways, including a subset known to regulate bone metabolism (e.g., Notch). Interestingly, the LEF1 transcription factor, which is a classical downstream target of the Wnt/β-catenin signaling pathway, was significantly downregulated in the bones from the old versus young women; consistent with this, LEF1 binding sites were significantly enriched in the promoter regions of the differentially expressed genes in the old versus young women, suggesting that aging was associated with alterations in Wnt signaling in bone. Further, of the 21 unique genes altered in bone by E therapy, the expression of INHBB (encoding for the inhibin, beta B polypeptide), which decreased with aging (by 0.6-fold), was restored to young adult levels in response to E therapy. In conclusion, our data demonstrate that aging alters a substantial portion of the skeletal transcriptome, whereas E therapy appears to have significant, albeit less wide-ranging effects. These data provide a valuable resource for the potential identification of novel biomarkers associated with age-related bone loss and also highlight potential pathways that could be targeted to treat osteoporosis.
UR - http://www.scopus.com/inward/record.url?scp=84946944635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946944635&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0138347
DO - 10.1371/journal.pone.0138347
M3 - Article
C2 - 26402159
AN - SCOPUS:84946944635
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 9
M1 - e0138347
ER -