PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ

Abstract

Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Here, we identify peroxisome-proliferator-activated receptor γ coactivator 1-α (PGC-1α) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs. Loss of PGC-1α promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Conversely, induction of PGC-1α attenuated osteoporotic bone loss and MAT accumulation. Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ. Our results suggest that PGC-1α is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging.

Dendrobium officinale polysaccharides regulate age‐related lineage commitment between osteogenic and adipogenic differentiation

“…Yu et al recently showed PGC-1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal ageing. 14 In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group. Furthermore, it was clear that H 2 O 2 -induced oxidative stress promoted adipogenesis of BMSCs at the expense of osteogenesis, tified that the deficiency of NRF2 antioxidant pathway was a driver mechanism in premature ageing disorder Hutchinson-Gilford progeria syndrome (HGPS), and the impairment of NRF2 transcriptional activity would cause oxidative stress and related progeroid phenotypes including bone loss.…”

“…Extensive researches suggested that oxidative stress accumulation was responsible for lineage commitment of BMSCs and the bone‐fat imbalance. Yu et al recently showed PGC‐1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone‐fat balance in osteoporosis and skeletal ageing . In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group.…”

Dendrobium officinale polysaccharides regulate age‐related lineage commitment between osteogenic and adipogenic differentiation

“…Yu et al recently showed PGC-1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal ageing. 14 In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group. Furthermore, it was clear that H 2 O 2 -induced oxidative stress promoted adipogenesis of BMSCs at the expense of osteogenesis, tified that the deficiency of NRF2 antioxidant pathway was a driver mechanism in premature ageing disorder Hutchinson-Gilford progeria syndrome (HGPS), and the impairment of NRF2 transcriptional activity would cause oxidative stress and related progeroid phenotypes including bone loss.…”

“…Extensive researches suggested that oxidative stress accumulation was responsible for lineage commitment of BMSCs and the bone‐fat imbalance. Yu et al recently showed PGC‐1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone‐fat balance in osteoporosis and skeletal ageing . In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group.…”

Tauroursodeoxycholic Acid Mitigates Oxidative Stress and Promotes Differentiation in High Salt-Stimulated Osteoblasts via NOX1 Mediated by PGC-1α

“…In agreement with these findings, the declined PGC-1α expression and augmented NOX1 expression in NaCl-challenged MC3T3-E1 cells were both reversed by TUDCA. PGC-1α is an important regulator of mitochondrial biosynthesis that has been supported to facilitate bone formation and hamper bone resorption [14,17]. Further studies in this study also proved that PGC-1α deletion partially abolished the impacts of TUDCA on PGC-1α and NOX1, viability, differentiation, and oxidative stress in NaCl-treated osteoblasts.…”

Ubiquinol supplementation modulates energy metabolism and bone turnover during high intensity exercise

“…41–43 In relation to its effect on bone turnover, it has been observed that its loss in the mesenchymal cells results in an increased bone loss, due to a decrease in the formation processes and increased adipogenesis in the bone marrow, 41 having a positive effect on the bone due to its effect on oxidative stress and inflammation. 44 As we have commented, in the current study, the expression of PGC-1α increased after exercise and especially with ubiquinol supplementation, which could have substantial beneficial effects on improving glucose transport, fatty acid oxidation and the mitochondrial function of skeletal muscle, 41,45 representing an ergogenic effect on the skeletal muscle. In addition, the increase in noradrenaline recorded after the exercise tests in the ubiquinol group indicates a stimulation of glucose uptake and clearance, enhancing the ability to shift to higher levels of muscular carbohydrate use, 37 representing also a metabolic advantage for the myofibres, because the post-exercise hyperglycemia induced by noradrenaline is necessary for muscle glycogen repletion.…”

Dendrobium officinale polysaccharides regulate age‐related lineage commitment between osteogenic and adipogenic differentiation

“…Yu et al recently showed PGC-1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal ageing. 14 In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group. Furthermore, it was clear that H 2 O 2 -induced oxidative stress promoted adipogenesis of BMSCs at the expense of osteogenesis, tified that the deficiency of NRF2 antioxidant pathway was a driver mechanism in premature ageing disorder Hutchinson-Gilford progeria syndrome (HGPS), and the impairment of NRF2 transcriptional activity would cause oxidative stress and related progeroid phenotypes including bone loss.…”

“…Extensive researches suggested that oxidative stress accumulation was responsible for lineage commitment of BMSCs and the bone‐fat imbalance. Yu et al recently showed PGC‐1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone‐fat balance in osteoporosis and skeletal ageing . In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group.…”

Tauroursodeoxycholic Acid Mitigates Oxidative Stress and Promotes Differentiation in High Salt-Stimulated Osteoblasts via NOX1 Mediated by PGC-1α

“…In agreement with these findings, the declined PGC-1α expression and augmented NOX1 expression in NaCl-challenged MC3T3-E1 cells were both reversed by TUDCA. PGC-1α is an important regulator of mitochondrial biosynthesis that has been supported to facilitate bone formation and hamper bone resorption [14,17]. Further studies in this study also proved that PGC-1α deletion partially abolished the impacts of TUDCA on PGC-1α and NOX1, viability, differentiation, and oxidative stress in NaCl-treated osteoblasts.…”

Ubiquinol supplementation modulates energy metabolism and bone turnover during high intensity exercise

“…41–43 In relation to its effect on bone turnover, it has been observed that its loss in the mesenchymal cells results in an increased bone loss, due to a decrease in the formation processes and increased adipogenesis in the bone marrow, 41 having a positive effect on the bone due to its effect on oxidative stress and inflammation. 44 As we have commented, in the current study, the expression of PGC-1α increased after exercise and especially with ubiquinol supplementation, which could have substantial beneficial effects on improving glucose transport, fatty acid oxidation and the mitochondrial function of skeletal muscle, 41,45 representing an ergogenic effect on the skeletal muscle. In addition, the increase in noradrenaline recorded after the exercise tests in the ubiquinol group indicates a stimulation of glucose uptake and clearance, enhancing the ability to shift to higher levels of muscular carbohydrate use, 37 representing also a metabolic advantage for the myofibres, because the post-exercise hyperglycemia induced by noradrenaline is necessary for muscle glycogen repletion.…”

Dendrobium officinale polysaccharides regulate age‐related lineage commitment between osteogenic and adipogenic differentiation

“…Yu et al recently showed PGC-1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone-fat balance in osteoporosis and skeletal ageing. 14 In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group. Furthermore, it was clear that H 2 O 2 -induced oxidative stress promoted adipogenesis of BMSCs at the expense of osteogenesis, tified that the deficiency of NRF2 antioxidant pathway was a driver mechanism in premature ageing disorder Hutchinson-Gilford progeria syndrome (HGPS), and the impairment of NRF2 transcriptional activity would cause oxidative stress and related progeroid phenotypes including bone loss.…”

“…Extensive researches suggested that oxidative stress accumulation was responsible for lineage commitment of BMSCs and the bone‐fat imbalance. Yu et al recently showed PGC‐1a, a master regulator of oxidative metabolism, controlled skeletal stem cell fate and bone‐fat balance in osteoporosis and skeletal ageing . In accordance with previous studies, our results showed a higher level of oxidative stress and lower level of antioxidant activity in aged group compared to young group.…”

Tauroursodeoxycholic Acid Mitigates Oxidative Stress and Promotes Differentiation in High Salt-Stimulated Osteoblasts via NOX1 Mediated by PGC-1α

“…In agreement with these findings, the declined PGC-1α expression and augmented NOX1 expression in NaCl-challenged MC3T3-E1 cells were both reversed by TUDCA. PGC-1α is an important regulator of mitochondrial biosynthesis that has been supported to facilitate bone formation and hamper bone resorption [14,17]. Further studies in this study also proved that PGC-1α deletion partially abolished the impacts of TUDCA on PGC-1α and NOX1, viability, differentiation, and oxidative stress in NaCl-treated osteoblasts.…”

Ubiquinol supplementation modulates energy metabolism and bone turnover during high intensity exercise

“…41–43 In relation to its effect on bone turnover, it has been observed that its loss in the mesenchymal cells results in an increased bone loss, due to a decrease in the formation processes and increased adipogenesis in the bone marrow, 41 having a positive effect on the bone due to its effect on oxidative stress and inflammation. 44 As we have commented, in the current study, the expression of PGC-1α increased after exercise and especially with ubiquinol supplementation, which could have substantial beneficial effects on improving glucose transport, fatty acid oxidation and the mitochondrial function of skeletal muscle, 41,45 representing an ergogenic effect on the skeletal muscle. In addition, the increase in noradrenaline recorded after the exercise tests in the ubiquinol group indicates a stimulation of glucose uptake and clearance, enhancing the ability to shift to higher levels of muscular carbohydrate use, 37 representing also a metabolic advantage for the myofibres, because the post-exercise hyperglycemia induced by noradrenaline is necessary for muscle glycogen repletion.…”