PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ
Authors: Peng Deng
Xianghang Luo
John Szymanski
Yunsong Liu
Christine Hong
Jiong Li
Bo Yu
Cun-Yu Wang
Jiandie Lin
Lihong Huo
Journal: Cell stem cell (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: PGC-1α; TAZ; aging; bone; fat
Affiliations: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: ., Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA., Department of Prosthodontics, School of Stomatology, Peking University, Beijing 100081, China., Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, People's Republic of China., Division of Growth and Development, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA., Life Sciences Institute, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA., Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, Broad Stem Cell Research Center and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: .

Abstract:  Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Here, we identify peroxisome-proliferator-activated receptor γ coactivator 1-α (PGC-1α) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs. Loss of PGC-1α promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Conversely, induction of PGC-1α attenuated osteoporotic bone loss and MAT accumulation. Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ. Our results suggest that PGC-1α is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging. 

Retracted: No

PubPeer comments:
 Photographs of staining in Fig.4D, S4O and S5D are the same, just rotated. # **Fig.4** ![file] # **Fig.S4** ![file] # **Fig.S5** ![file] , 
 Improper cutting of WB pictures in Fig.7A, with no relation to the corresponding loading controls. Even in the figure legend stated:  The YAP image was cropped from two parts of the same blot, with two irrelevant lanes removed . So, obviously the gel loading control, tubulin, was stained on a membrane from the different gel. # **Fig.7** ![file] , 
 I, too, have some issues with this publication. I question, that PGC1a expression in bone MSCs (not SSC as wrongly called in this paper) is responsible for the phenotype observed. RNA measurements are shown in relative values to control - it would be nice to know the real ct-values. Looking into several microarray and RNAseq datasets of bone marrow stromal cell populations (incl the one used here), no PGC1a expression can be found. The authors also do not provide any data that show that adipose tissues (white and brown) as well as muscle tissue are unaffected. Specifically the effects seen in whole-body knockouts, but also LepR- and Prx1-Cre animals could be simply due to peripheral changes that have secondary effects on bone structure. I completely agree with the previous comments and would like to add the following: The alpha-tubulin blot (as shown in post above) has an unnormal background and shows no traces of running bands. Please also take a look at Figure 5A (see attached image, overexposed by me) particularly, as bands of PGC1a+ vs PGC1a- of each tissue look unbelievably similar, as if they were the same sample. Further, the last band has a clear smear but not the slightest sign of a band no matter how much overexposed![file] (is this possible?). , 
 Western Blot re-used from earlier paper for tubulin: Current paper Fig. 7A ![file] Previous paper Fig.5E  Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-u03baB https: www.nature.com articles nm.3586.pdf ![file] , 
 We sincerely thank the readers to detect the errors in our paper, and we deeply apologize for any confusion it might cause. We are currently working with the journal editors to issue a correction to rectify these unintentional errors. We will update the forum once the correction is published, and relevant raw data will also be made accessible. We still maintain conditional Pgc-1a knockout mouse strains and are happy to provide them to other investigators who wish to repeat our results. , 
 I noticed that a new version of the online manuscript has been recently posted on the Cell Stem Cell website. All of the figure duplication issues mentioned above by others have been u201ccorrectedu201d through figure replacement. However, no explanation is provided anywhere and there is no longer any link to the original published version. There is only a postdated addendum to the publication history which says  corrected online: September 10, 2018u201d. For the sake of transparency, the authors should provide a link to the original version and some kind of explanation. , 
 To summarize, the major issues mentioned by others above were the following: 1) A rotated half of an image from Fig 4D was used also in Fig S4O. 2) A rotated other half of the same image from Fig 4D was used also in Fig S5D. 3) A select single well image from Fig 4D was used also in Fig S5D and placed adjacent to another single well image along with the above rotated half image mentioned in (2). 4) An alpha-tubulin western blot panel from a previous paper from four years back was reused in Fig 7A as a loading control. What could be an explanation for all of these issues if they are unintentional errors? , 
 After evaluating our raw data, the journal will publish a correction with inclusion of the originally published figures (available online on Sept 20). In the meantime, the online version of the article has now been corrected to avoid further confusion of the readers. Here is the link for the raw data related to the above mentioned figures: http: dx.doi.org 10.17632 v2rpgbvhfr.2 , 
 After correcting all the concerns mentioned above, could the authors take a look at Figure 1L, please? The 18M old Pgc1a+ + mouse panel appears to show an overlap with the 18M old Pgc1a- - mouse panel. Shown with red boxes. ![file] , 
 And while the authors go through their IHC photos, could they also please check Figures 2G and 6I? Some panels appear to show more areas of overlap, as shown here with pink and yellow boxes. ![file] , 
 Hard-to-find erratum, October 2018, here: https: www.cell.com cell-stem-cell fulltext S1934-5909(18)30438-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1934590918304387%3Fshowall%3Dtrue Our colleagues alerted us to some errors in our paper via comments on PubPeer . We immediately investigated and realized that we had inadvertently replaced some of our images while assembling the figures for the final revision of our manuscript. In Figure 7A, we mistakenly replaced the loading control for the TAZ western blot with an image from another folder. The correct loading control blots for both TAZ and YAP are displayed now. In Figures S4O and S5D, the ALP staining images were mistakenly duplicated from Figure 4D, and are now replaced with the correct images. Furthermore, in Figures 4B, S4G, and S4P, we made a mistake in our calculations for ARS quantification and have also replaced the bar graphs in these panels with the corrected ones. In the interest of further transparency, we have placed the raw data files associated with all corrected figures on Mendeley data at https: doi.org 10.17632 v2rpgbvhfr.2. These changes do not affect our original conclusions. We deeply apologize for any inconvenience caused by these errors. Can the authors please comment on the duplications found in comments #11 and #12 above? Will these also be addressed with a correction, or is there a point where readers should lose faith in this paper? ,