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

Peroxisome proliferator-activated receptor-gamma coactivator (PGC1) is a transcription coactivator that interacts with a broad range of transcription factors involved in several biological responses. Here, we show that PGC1 plays a role in skeletal homeostasis since aged PGC1-deficient mice (PGC1(-/-)) display impaired bone structure. Micro-CT of the tibial mid-shaft showed a marked decrease of cortical thickness in PGC1(-/-) (-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 PGC1(+/+), p<0.05), whereas trabecular number (Tb.N) was higher than wild-type mice (+72% vs PGC1(+/+), p<0.05), thus resulting in increased (+31.7% vs PGC1(+/+), 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 similar to 48.4% decrease in bending strength (p<0.01). These changes in PGC1(-/-) 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 PGC1(-/-), thus indicating that differentiation of osteoblast lineage is downregulated. Overall, results presented herein suggest that PGC1 may play a key role in bone metabolism.