Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1α-Dependent Transcriptional Program

Abstract

Summary Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process that remains poorly defined. Here, we show that restriction in glucose supply promotes the osteocyte transcriptional program while also being associated with increased mitochondrial DNA levels. Glucose deprivation triggered the activation of the AMPK/PGC-1 pathway. AMPK and SIRT1 activators or PGC-1α overexpression are sufficient to enhance osteocyte gene expression in IDG-SW3 cells, murine primary osteoblasts, osteocytes, and organotypic/ ex vivo bone cultures. Conversely, osteoblasts and osteocytes deficient in Ppargc1a and b were refractory to the effects of glucose restriction. Finally, conditional ablation of both genes in osteoblasts and osteocytes generate osteopenia and reduce osteocytic gene expression in mice. Altogether, we uncovered a role for PGC-1 in the regulation of osteocyte gene expression.

Expression of the type 1 lysophosphatidic acid receptor in osteoblastic cell lineage controls both bone mineralization and osteocyte specification

“…Moreover, targeting SOST with romosozumab has recently been validated as a novel therapy for osteoporosis [56]. Nevertheless, our data agree with recent reports showing that despite a drastic decrease of osteocytic markers including Sost, Ppargc1a/b conditional knockout mice osteoblasts and osteocytes exhibit an osteopenic bone phenotype [57] indicating that miss-egulation of multi-gene programs both in osteoblasts and osteocytes, such as in Ppargc1a/b conditional knockout mice or Lpar1Ob mice, may affect wnt inhibitor production but without promoting bone formation.…”

The Novel Role of PGC1α in Bone Metabolism

“…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.…”

“…In a recent study, the role of PGC1α/β and its activators 5’ adenosine monophosphate-activated protein kinase (AMPK) and SIRT1 in osteocyte differentiation and reprogramming was investigated [ 11 ]. Preosteocytic cells (IDG-SW3), differentiated for 14 days in the presence of glucose, and femur-derived bone organotypic cultures, maintained in glucose media, were treated with 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and SRT2104, two chemical factors activating AMPK and SIRT1 pathway, respectively [ 11 ].…”

“…In a recent study, the role of PGC1α/β and its activators 5’ adenosine monophosphate-activated protein kinase (AMPK) and SIRT1 in osteocyte differentiation and reprogramming was investigated [ 11 ]. Preosteocytic cells (IDG-SW3), differentiated for 14 days in the presence of glucose, and femur-derived bone organotypic cultures, maintained in glucose media, were treated with 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and SRT2104, two chemical factors activating AMPK and SIRT1 pathway, respectively [ 11 ]. AMPK activation via AICAR treatment upregulated Runx2 and Osterix in IDG-SW3 cells and the osteocyte genes Dentin matrix acidic phosphoprotein 1 ( Dmp1 ), Fibroblast growth factor 23 ( Fgf23 ), and Sclerostin ( Sost ) in both IDG-SW3 cells and bone organotypic cultures [ 11 ].…”

“…Preosteocytic cells (IDG-SW3), differentiated for 14 days in the presence of glucose, and femur-derived bone organotypic cultures, maintained in glucose media, were treated with 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and SRT2104, two chemical factors activating AMPK and SIRT1 pathway, respectively [ 11 ]. AMPK activation via AICAR treatment upregulated Runx2 and Osterix in IDG-SW3 cells and the osteocyte genes Dentin matrix acidic phosphoprotein 1 ( Dmp1 ), Fibroblast growth factor 23 ( Fgf23 ), and Sclerostin ( Sost ) in both IDG-SW3 cells and bone organotypic cultures [ 11 ]. In parallel, treatment with SRT2104 activating SIRT1 stimulated the expression of late osteocyte markers.…”