The Novel Role of PGC1α in Bone Metabolism

Abstract

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

Keywords: bone metabolism; metabolic regulations; mitochondria.

Figure 1

PGC1α deletion affects bone. (A) Representative images of micro-CT-generated sections of the tibia midshaft of PGC1α+/+ and PGC1α−/− mice show a reduction in cortical thickness (Ct. Th) in the absence of PGC1α. Adapted from [12]. (B) Schematic representation of the effect of PGC1α deletion in osteoblasts consisting of the reduction of Ocn and Col1a1 levels.

Figure 2

PGC1α deletion affects marrow adipose tissue (MAT). (A) Photomicrographs of hematoxylin and eosin-stained sections of MAT from PGC1α +/+ and PGC1α −/− (magnification: 20×) show an increased number of adipocytes in the absence of PGC1α (unpublished data). (B) Schematic representation of the effect of PGC1α deletion in bone marrow adipocytes consisting of the increase of C/EBPα expression.