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Deletion of the Transcription Factor PGC-1α in Mice Negatively Regulates Bone Mass

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Abstract

Peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) is a transcription coactivator that interacts with a broad range of transcription factors involved in several biological responses. Here, we show that PGC1α plays a role in skeletal homeostasis since aged PGC1α-deficient mice (PGC1α−/−) display impaired bone structure. Micro-CT of the tibial mid-shaft showed a marked decrease of cortical thickness in PGC1α−/− (− 11.9%, p < 0.05) mice compared to wild-type littermate. Trabecular bone was also impaired in knock out mice which displayed lower trabecular thickness (Tb.Th) (− 5.9% vs PGC1α+/+, p < 0.05), whereas trabecular number (Tb.N) was higher than wild-type mice (+ 72% vs PGC1α+/+, p < 0.05), thus resulting in increased (+ 31.7% vs PGC1α+/+, p < 0.05) degree of anisotropy (DA), despite unchanged bone volume fraction (BV/TV). Notably, these impairments of cortical and trabecular bone led to a dramatic ~ 48.4% decrease in bending strength (p < 0.01). These changes in PGC1α−/− mice were paralleled by a significant increase in osteoclast number at the cortical bone surface and in serum level of the bone resorption marker, namely, C-terminal cross-linked telopeptides of type I collagen (CTX-I). We also found that in cortical bone, there was lower expression of mRNA codifying for the key bone-building protein Osteocalcin (Ocn). Interestingly, Collagen I mRNA expression was reduced in mesenchymal stem cells from bone marrow of PGC1α−/−, thus indicating that differentiation of osteoblast lineage is downregulated. Overall, results presented herein suggest that PGC1α may play a key role in bone metabolism.

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Acknowledgements

We thank Dr. Antonio Moschetta (Department of Interdisciplinary Medicine, “Aldo Moro” University of Bari, 70124 Bari, Italy) for the generous gift of PGC1α heterozygous mice to generate the colony. This work was supported in part by MIUR Grant ex60% (to M.G.), by SIOMMMS Grant (to G.C.) and by ERISTO (ESA) Grant (to M.G.).

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Author notes

  1. Graziana Colaianni, and Luciana Lippo have contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy

    Graziana Colaianni, Luciana Lippo, Lorenzo Sanesi & Maria Grano

  2. Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari, Bari, Italy

    Giacomina Brunetti, Nunzio Cirulli & Silvia Colucci

  3. Department of Orthopedics and Traumatology, Tor Vergata University of Rome, Rome, Italy

    Monica Celi & Umberto Tarantino

  4. Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy

    Giovanni Passeri

  5. Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Oslo, Norway

    Janne Reseland

  6. Departments of Medicine and Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA

    Ernestina Schipani

  7. Department of Biomedical Science and Human Oncology, Pediatric Unit, University of Bari, Bari, Italy

    Maria Felicia Faienza

  8. PhD School in Tissue and Organ Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, School of Medicine-University of Bari, Bari, Italy

    Luciana Lippo

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Contributions

GC, LL, UT, SC, MG designed research; LL, LS, MC, NC performed research; GC, LL, GB, GP, JR, ES, MFF, UT, SC, MG analyzed, interpreted and discussed the data; and GC, LL, MG wrote the paper.

Corresponding author

Correspondence to Maria Grano.

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Conflict of interest

Graziana Colaianni, Luciana Lippo, Lorenzo Sanesi, Giacomina Brunetti, Monica Celi, Nunzio Cirulli, Giovanni Passeri, Janne Reseland, Ernestina Schipani, Maria Felicia Faienza, Umberto Tarantino, Silvia Colucci, and Maria Grano declare that there is no conflict of interest regarding the publication of this paper.

Human and Animal Rights and Informed Consent

This study is in accordance with the European Law Implementation of Directive 2010/63/EU and all experimental protocols were reviewed and approved by the Veterinary Department of the Italian Ministry of Health (Project 522-2016PR). Experimental procedures have been carried out following the standard biosecurity and the institutional safety procedures. For this type of study formal consent is not required.

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223_2018_459_MOESM1_ESM.docx

Supplementary Table 1: Effect of PGC1α whole body deletion on cortical and trabecular bone of 3-months old mice. MicroCT analysis of tibia and femurs harvested from 3 months old PGC1α+/+ and PGC1α-/- male (♂) and female (♀) mice. Cortical bone parameters included cortical thickness (Ct.Th), polar moment of inertia (pMOI) and bone mineral density (BMD). Trabecular bone parameters included bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), degree of Anisotropy (DA), connectivity density (Conn. Density) and bone mineral density (BMD). Data are presented as mean ± SEM. n = 3–4 mice per group. *p < 0.05 versus PGC1α+/+ (DOCX 16 KB)

223_2018_459_MOESM2_ESM.docx

Supplementary Table 2: Sequence, accession number (NM_) and product length for each primer. Primer sequences, accession number (NM_) and the product length for each primer. All primers span an exon-exon junction. Three housekeeping genes (Glyceraldehyde 3-phosphate dehydrogenase, &#x03B2;2-microglobulin and &#x03B2;-actin) were chosen because they are normally stably expressed in bone and adipose tissues (DOCX 16 KB)

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Colaianni, G., Lippo, L., Sanesi, L. et al. Deletion of the Transcription Factor PGC-1α in Mice Negatively Regulates Bone Mass. Calcif Tissue Int 103, 638–652 (2018). https://doi.org/10.1007/s00223-018-0459-4

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