Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Regan, Jenna N.; Lim, Joohyun; Shi, Yu; Joeng, Kyu Sang; Arbeit, Jeffrey M.; Shohet, Ralph V.; Long, Fanxin

doi:10.1073/pnas.1324290111

Cited by 126 publications

(107 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By P22, GFP + cells were not only present in osteoblasts and osteocytes of both cortical and trabecular bone, but were also abundant at the chondroosseous junction, which is known to be enriched for osteoblast precursors ( Fig. 1D-D″) (Regan et al, 2014). Thus, Dmp1-Cre targets osteoblast lineage cells at an earlier stage than previously reported.…”

Section: Resultsmentioning

confidence: 56%

Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse

et al. 2015

Self Cite

View full text Add to dashboard Cite

Exogenous bone morphogenetic proteins (Bmp) are well known to induce ectopic bone formation, but the physiological effect of Bmp signaling on normal bone is not completely understood. By deleting the receptor Bmpr1a in osteoblast lineage cells with Dmp1-Cre, we observed a dramatic increase in trabecular bone mass in postnatal mice, which was due to a marked increase in osteoblast number that was likely to be driven by hyperproliferation of Sp7 + preosteoblasts. Similarly, inducible deletion of Bmpr1a in Sp7 + cells specifically in postnatal mice increased trabecular bone mass. However, deletion of Smad4 by the same approaches had only a minor effect, indicating that Bmpr1a signaling suppresses trabecular bone formation through effectors beyond Smad4. Besides increasing osteoblast number in the trabecular bone, deletion of Bmpr1a by Dmp1-Cre also notably reduced osteoblast activity, resulting in attenuation of periosteal bone growth. The impairment in osteoblast activity correlated with reduced mTORC1 signaling in vivo, whereas inhibition of mTORC1 activity abolished the induction of protein anabolism genes by BMP2 treatment in vitro. Thus, physiological Bmpr1a signaling in bone exerts a dual function in both restricting preosteoblast proliferation and promoting osteoblast activity.

show abstract

Section: Resultsmentioning

confidence: 56%

Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The repercussions of enhanced signaling by HIF-1α versus HIF-2α were recently studied in models of Osx-Cre:GFP-driven overexpression of the respective HIFs (38), confirming and extending earlier studies indicating that the genes regulated by HIF-1α and HIF-2α in osteoblasts are overlapping but nonidentical. While HIF-1α appears to be primarily responsible for meditating the metabolic switch to glycolysis, VEGF upregulation in osteogenic cells is controlled by both HIF-1α and HIF-2α (10,21,38). Additionally, HIF-2α has been shown to be the main regulator for EPO production by osteoblasts (12) and to regulate OPG, the factor that inhibits osteoclastogenesis by counteracting RANKL (38).…”

Section: Discussionmentioning

confidence: 99%

“…Recent in vivo work using genetically modified mouse models has been actively investigating this topic, and revealed a prominent role for glucose metabolism during osteoblast differentiation (18,19). Moreover, aerobic glycolysis has been implicated as an important driver of bone formation and shown to be regulated by osteoanabolic pathways involving Wnt-LRP5 signaling, parathyroid hormone, and HIF (20)(21)(22)(23).…”

Section: Inactivation Of Vhl In Osteoprogenitors Leads To An Expandedmentioning

confidence: 99%

Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

Dirckx

Tower

Mercken

et al. 2018

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

“…Guntur and colleagues (59) also showed that glycolysis was essential for terminal differentiation of osteoblasts and that oxidative phosphorylation was more important early in the differentiation scheme. More recently, Regan and colleagues, (60) of the Long Fig. 1.…”

Section: Skeletal Control Of Metabolic Balancementioning

confidence: 99%

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

Lecka‐Czernik

Rosen

2015

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Skeletal complications have recently been recognized as another of the several comorbidities associated with diabetes. Clinical studies suggest that disordered glucose and lipid metabolism have a profound effect on bone. Diabetes-related changes in skeletal homeostasis result in a significant increased risk of fractures, although the pathophysiology may differ from postmenopausal osteoporosis. Efforts to understand the underlying mechanisms of diabetic bone disease have focused on the direct interaction of adipose tissue with skeletal remodeling and the potential influence of glucose utilization and energy uptake on these processes. One aspect that has emerged recently is the major role of the central nervous system in whole-body metabolism, bone turnover, adipose tissue remodeling, and beta cell secretion of insulin. Importantly, the skeleton contributes to the metabolic balance inherent in physiologic states. New animal models have provided the insights necessary to begin to dissect the effects of obesity and insulin resistance on the acquisition and maintenance of bone mass. In this Perspective, we focus on potential mechanisms that underlie the complex interactions between adipose tissue and skeletal turnover by focusing on the clinical evidence and on preclinical studies indicating that glucose intolerance may have a significant impact on the skeleton. In addition, we raise fundamental questions that need to be addressed in future studies to resolve the conundrum associated with glucose intolerance, obesity, and osteoporosis. © 2015 American Society for Bone and Mineral Research. KEY WORDS: BONE-FAT INTERACTIONS; SYSTEMS BIOLOGY; BONE INTERACTORS; CELL/TISSUE SIGNALING; TRANSCRIPTION FACTORS; DISEASES AND DISORDERS OF/RELATED TO BONE Clinical Insight Into the Effect of Disordered Glucose and Lipids Homeostasis on BoneD iabetes mellitus (DM) can be considered a disease of intracellular glucose starvation in muscle and fat, due to either lack of insulin (Type 1 [T1D]) or impaired insulin action (Type 2 [T2D]). Both types of DM are associated with an increase in fractures; however, the skeletal phenotype is very different. T1D patients have reduced bone mineral density (BMD), due to insulin and amylin deficiency, whereas T2D patients have either normal or high BMD. T2D is a disease of disordered energy storage as well as glucose intolerance and altered bone strength. Its prevalence is high and not abating. In the United States, 29.1 million people-9.3% of the population-have diabetes; among them, nearly 60% are characterized as obese (http://www.cdc.gov). Insulin resistance is a characteristic feature of T2D in liver, muscle, and fat, leading to glucose intolerance, elevated cardiometabolic risk factors (eg, low-density lipoprotein [LDL] cholesterol), and excess hepatic glucose output. Visceral adipocytes, in particular, are large and surrounded by fibrous and inflammatory elements.In clinical medicine a major paradox is the relationship of obesity to the skeleton. Obese individuals tend to have higher...

show abstract

Up-regulation of glycolytic metabolism is required for HIF1α-driven bone formation

Cited by 126 publications

References 34 publications

Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse

Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse

Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

Contact Info

Product

Resources

About