Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism

Ferron, Mathieu; Wei, Jianwen; Yoshizawa, Tatsuya; Fattore, Andrea Del; DePinho, Ronald A.; Teti, Anna; Ducy, Patricia; Karsenty, Gérard

doi:10.1016/j.cell.2010.06.003

Cited by 998 publications

(1,142 citation statements)

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“…We found that the answers to these two questions were tightly linked. (3,8) The insulin receptor is receptor tyrosine kinase (RTK), and a classic mechanism to downregulate the activities of RTKs is through the action of an intracellular tyrosine phosphatase. Indeed, insulin signaling in myoblasts and hepatocytes is negatively regulated by a protein tyrosine phosphatase called PTP-1B.…”

Section: Novel Findings Novel Questionsmentioning

confidence: 99%

“…This hypothesis turned out to be correct. One of us (GK) showed that osteoblasts secrete osteocalcin, (3) one of the most abundant proteins of the bone extracellular matrix. (4) Osteocalcin is made only by osteoblasts and is subject to posttranslational carboxylation on three or four glutamic residues, depending on the species, that provides the molecule high affinity for hydroxyappatite.…”

Section: Introductionmentioning

confidence: 99%

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The osteoblast: An insulin target cell controlling glucose homeostasis

Clemens

Karsenty

2010

Journal of Bone and Mineral Research

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The past five years have witnessed the emergence and discovery of unexpected functions played by the skeleton in whole-organism physiology. Among these newly described tasks is the role of bone in the control of energy metabolism, which is achieved through the secretion of osteocalcin, an osteoblasts-derived hormone regulating insulin secretion, insulin sensitivity, and energy expenditure. These initial findings raised several fundamental questions on the nature of insulin action in bone. Discoveries made independently by our two groups have provided answers recently to some of these questions. Through the analysis of mice lacking insulin receptor (InsR) only in osteoblasts, we found that insulin signaling in these cells favors whole-body glucose homeostasis. Importantly, this function of insulin signaling in osteoblasts was achieved through the negative regulation of osteocalcin carboxylation and bioavailability. Our studies also established that insulin signaling in osteoblasts was a positive regulator not only of postnatal bone acquisition but also of bone resorption. Interestingly, it appears that insulin signaling in osteoblasts induced osteocalcin activation by stimulating osteoclast activity. Indeed, the low pH generated during bone resorption is a sufficient means to decarboxylate osteocalcin. Our findings establish that the osteoblast is an important target used by insulin to control whole-body glucose homeostasis and identify bone resorption as the mechanism regulating osteocalcin activation. ß

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Section: Novel Findings Novel Questionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The osteoblast: An insulin target cell controlling glucose homeostasis

Clemens

Karsenty

2010

Journal of Bone and Mineral Research

Self Cite

246

179

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“…(48,49) Thus, in osteoblasts, insulin signaling regulates expression of Runx2 and production of osteocalcin. In addition, insulin increases support for osteoclastogenesis by decreasing expression of osteoprotegerin (OPG), a decoy receptor for RANKL.…”

Section: Skeletal Control Of Metabolic Balancementioning

confidence: 99%

“…The genetic absence of Esp1 in mice results in significant hypoglycemia, due to excess undercarboxylated osteocalcin. (48,51) On the other hand, FoxO1 upregulates Esp1 expression, thereby impairing glucose tolerance. (52) Thus, in mice there is a complex interaction between glucose homeostasis and skeletal remodeling.…”

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confidence: 99%

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

Lecka‐Czernik

Rosen

2015

Journal of Bone and Mineral Research

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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...

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“…The osteoblast is thought to be the main actor, affecting multiple organs, such as the BM, the pancreas, and the testis. It regulates hematopoiesis directly as a hematopoietic stem cell (HSC) niche (1,2), as well as energy metabolism and male fertility by producing osteocalcin (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Osteocytes and Homeostasis of Remote Organs

Sato

Katayama

2015

Curr Osteoporos Rep

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The study of bones has attracted researchers from many medical fields. To understand bone-organ interactions, hematologists were challenged to investigate bone marrow (BM), the core of bone where hematopoiesis takes place. Through studies of the hematopoietic stem cells niche, hematologists contributed to the discovery of unexpected functions of bone-forming osteoblasts and bone-buried osteocytes.Especially, the recent findings about osteocytes, as the regulatory system of lympho-hematopoiesis and fat metabolism, highlighted the central role of skeletal tissue in inter-organ communication. The cross-cutting consideration including hematology and many other fields will expand the bone research.

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Insulin Signaling in Osteoblasts Integrates Bone Remodeling and Energy Metabolism

Cited by 998 publications

References 48 publications

The osteoblast: An insulin target cell controlling glucose homeostasis

The osteoblast: An insulin target cell controlling glucose homeostasis

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

Osteocytes and Homeostasis of Remote Organs

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