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.

In Sickness and in Health: The Oxygen Reactive Species and the Bone

“…Mitochondrial mass and function decreased while mitophagy augmented through the ROS/FOXO1 pathway (Baldelli et al, 2014). The PGC-1α anabolic role in bone has been highlighted by a number of in vitro and in vivo studies, as recently reviewed by Buccoliero et al, (Buccoliero et al, 2021). Sirtuin 3, a mitochondrial (NAD)dependent deacetylase, is a key regulator of osteoblastic differentiation through regulation of mitochondrial function; its absence reduces the expression of superoxide dismutase 2 (Sod2), a mitochondrial molecule with antioxidant activity that permutes superoxide into the less reactive hydrogen peroxide.…”

“…Sirtuin 3, a mitochondrial (NAD)-dependent deacetylase, is a key regulator of osteoblastic differentiation through regulation of mitochondrial function; its absence reduces the expression of superoxide dismutase 2 (Sod2), a mitochondrial molecule with antioxidant activity that permutes superoxide into the less reactive hydrogen peroxide. PGC-1α stimulates Sirtuin 3 activity on osteogenic differentiation ( Buccoliero et al, 2021 ). How different biophysical stimuli may affect mitochondrial metabolism bone was recently reviewed by ( Wang F.-S. et al, 2021 ).…”

Changes in Metabolism and Mitochondrial Bioenergetics during Polyethylene-Induced Osteoclastogenesis

“…Both PCG-1α and PGC-1β are known to promote mitochondrial biogenesis [ 76 , 77 ]. PCG-1α has been studied more in osteoblasts [ 78 , 79 , 80 ], and has been shown to play a role in mitochondrial metabolism. Its over-expression has been found to affect the activity of Sirtuin 3 (a mitochondrial deacetylase), which controls the increase in osteoclast number by preventing osteoblast mitochondria from decreasing its function [ 78 ].…”

The Role of SIRT3 in the Osteoporosis

“…Accumulating evidence has indicated that intervention for SIRT3 could improve osteoporosis, showing its potential as a treatment strategy. Exogenous supplementation or overexpression of SIRT3 could alleviate bone loss and osteoporosis ( 75 , 104 ). For example, the overexpression of SIRT3 by intravenous injection of recombinant adeno-associated virus 9 carrying SIRT3 plasmid (AAV9-SIRT3) could significantly reduce the occurrence of senile osteoporosis in the mouse model ( 75 ).…”