Abstract
Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. The metabolic requirements of osteoblast differentiation and mineralization, both essential for regular bone formation, however, remain incompletely understood. Here we identify the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ as key regulator of osteoblast metabolism. Induction of PPARδ was essential for the metabolic adaption and increased rate in mitochondrial respiration necessary for the differentiation and mineralization of osteoblasts. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass. These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover.
Highlights
Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process
The glycolytic activity slightly increased as well, this metabolic adaption resulted in an increase in the ratio between oxygen consumption rate (OCR, an indicator for mitochondrial respiration) and the extracellular acidification rate (ECAR, an indicator for glycolysis), suggestive of a robust metabolic rewiring of differentiating osteoblasts
Nuclear receptors including the members of the peroxisome proliferatoractivated receptor (PPAR) family control pleotropic processes throughout the body, including control of fatty acid and glucose metabolism in liver, adipose tissue and muscle[16]
Summary
Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover. Osteogenic differentiation of mesenchymal stem cells (MSCs) was reported to be paralleled by an increased mitochondrial respiration, where levels of ATP derived from oxidative phosphorylation peak in association with the accumulation of mitochondria that can directly support differentiation of osteoblasts[10,11] These findings show that especially differentiating and mineralizing osteoblasts utilize both aerobic glycolysis and oxidative phosphorylation, indicating that these cells need to adjust their bioenergetic machinery in order to adapt to transient metabolic challenges such as low and high oxygen and varying nutrient supply. The signals that control the induction of mitochondrial respiration dominating during later stages of osteoblast differentiation and mineralization, in turn, have remained elusive
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