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

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.

The Novel Role of PGC1α in Bone Metabolism

“…This result suggested that the elevated Receptor activator of nuclear factor kappa-Β ligand (RANKL) levels observed in bone marrow of knock-out mice could be the indirect mechanism through which osteoblasts increase osteoclast formation and activity in vivo. Moreover, in agreement with Lin and colleagues' study of 2004 [19], PGC1α knockout mice had 30% lower weight than control mice, lower ratio of inguinal white adipose tissue (iWAT)/body weight and strong decrease (~75%) in adipocyte area [12]. Colaianni and colleagues also evaluated, in iWAT, the uncoupling protein 1 (Ucp1) expression, considering its importance as a master gene involved in the trans-differentiation program from white adipocytes to adipocytes with a brown adipose tissue (BAT)-like phenotype [20].…”

“…Increases Osteocalcin expression together with Nuclear related receptor-1 [8] Enhances Osteocalcin promoter activity interacting with Estrogen-related receptor alpha [9] Restores the inhibition of osteogenic differentiation and mitochondrial activity Sirtuin 3 knockdown-induced [10] Upregulates many key factors involved in osteoblast and osteocyte differentiation [11] PGC1α deletion causes a reduction in cortical thickness and in osteocalcin and collagen type I α 1 levels [12] PGC1α/β deficiency results in cortical and trabecular parameter reduction [11] PGC1α absence induces marrow adipose tissue accumulation [13] PGC1α activation in leptin receptor-deficient diabetic mice increases osteoblastic gene expression and inhibits atrogene transcription [14] In this review, we aim to summarize the current knowledge of the role of PGC1α as an anabolic factor in bone metabolism in both physiological condition and bone related pathologies, with the focus on paving the way for further studies in the future.…”

“…Global deletion of PGC1α has a pronounced impact on bone phenotype, particularly in adulthood. PGC1α deficient mice aged 12 months showed lower bone mass and strength than wild-type littermates [ 12 ]. PGC1α loss compromised long bones, especially the tibia, causing a reduction in cortical bone mass and strength [ 12 ].…”

“…Th) decreased in PGC1α knock-out mice, trabecular number (Tb. N) increased compared to wild-type mice, thus enhancing anisotropy degree [ 12 ]. The anisotropy, notably in bone tissue, is a parameter also used in humans to detect the degree of material organization, thus defining the relationship between architectural structure and mechanical properties of bone [ 15 ].…”

Osteoclast-derived IGF1 is required for pagetic lesion formation in vivo

“…Structural parameters were ana-lyzed in reconstructed 3-dimensional images using evaluation software (μCT v1.6, Scanco Medical) according to the recommended guideline (18). The regions of interest were defined using previously described methods (37,38). The cancellous bone and marrow compartments of the L5 vertebral body were examined between the cranial and caudal growth plates.…”