Endocrine Regulation of Energy Metabolism by the Skeleton

Lee, Na Kyung; Sowa, Hideaki; Hinoi, Eiichi; Ferron, Mathieu; Ahn, Jae S.; Confavreux, Cyrille; Dacquin, Romain; Mee, P. Joseph; McKee, Marc D.; Jung, Dae Young; Zhang, Zhiyou; Kim, Jason K.; Mauvais-Jarvis, Franck; Ducy, Patricia; Karsenty, Gérard

doi:10.1016/j.cell.2007.05.047

Cited by 2,228 publications

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“…It has been established that mice lacking the osteocalcin gene had a phenotype that was obese, hyperglycemic, insulin-resistant, and glucose-intolerant. (16,17) Another study done in wild-type mice also observed the importance of osteocalcin in the regulation of glucose metabolism and fat mass. (18) At its simplest level, this relationship offers a plausible link between the established inverse relationship between body size, osteoporosis, and fracture risk.…”

Section: Introductionmentioning

confidence: 96%

“…Targeted deletion of the osteocalcin gene results in a high BMD phenotype. (15) More recently, in a seminal paper by Lee and colleagues, (16) an additional role for OC as a hormone integral to the regulation of energy metabolism also has been identified. It has been established that mice lacking the osteocalcin gene had a phenotype that was obese, hyperglycemic, insulin-resistant, and glucose-intolerant.…”

Section: Introductionmentioning

confidence: 99%

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Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification

McGuigan

Kumar

Ivaska

et al. 2010

Journal of Bone and Mineral Research

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Osteoporosis is a major health problem affecting more than 75 million people throughout Europe, the United States, and Japan. Epidemiologic studies have determined that both genetic and environmental factors contribute to the pathogenesis of osteoporosis. We have investigated the association between polymorphisms at the osteocalcin locus and variables linked to bone health. Osteocalcin provides a link between bone and energy metabolism, hence its potential importance as an osteoporosis candidate gene. In this study, we included a total of 996 women (all aged 75 years) from the Osteoporosis Prospective Risk Assessment (OPRA) cohort. We sequenced the osteocalcin gene along with flanking regions to search for novel coding polymorphisms. We also analyzed four polymorphisms selected from within and flanking regions of the osteocalcin gene to study their association with serum total osteocalcin levels (STotalOC), total-body (TB) bone mineral density (BMD), fracture, TB fat mass, and body mass index (BMI). The promoter polymorphism rs1800247 was significantly associated with S-TotalOC ( p ¼ .012) after controlling for BMI and TB BMD. The polymorphism rs1543297 was significantly associated with prospectively occurring fractures ( p ¼ .008). In a model taking into account rs1543297 and rs1800247, along with TB BMD, BMI, smoking, and S-TotalOC, the polymorphisms together were able to identify an additional 6% of women who sustained a fracture ( p ¼ .02). We found no association between the polymorphisms and TB BMD, BMI, or TB fat mass. In conclusion, polymorphisms in and around the osteocalcin locus are significantly associated with S-TotalOC and fracture. Genotyping at the osteocalcin locus could add valuable information in the identification of women at risk of osteoporosis. ß

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification

McGuigan

Kumar

Ivaska

et al. 2010

Journal of Bone and Mineral Research

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“…RUNX2 has been identified as a ‘master gene’ in the differentiation of osteoblasts, serving as a key transcription factor that regulates extracellular matrix (ECM) gene products (e.g., osteocalcin, OCN) (Lee et al ., 2000; Tu et al ., 2008). OCN is secreted by osteoblasts, it is believed to play a role in the body's metabolic regulation, and it is pro‐osteoblastic (bone building; Lee et al ., 2007). OCN is therefore often used as a marker of bone formation.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

2016

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SummaryFibrotic aortic valve disease (FAVD) is an important cause of aortic stenosis, yet currently there is no effective treatment for FAVD due to its unknown etiology. The purpose of this study was to investigate whether deficiency in the anti‐aging Klotho gene (KL) promotes high‐fat‐diet‐induced FAVD and to explore the underlying molecular mechanism. Heterozygous Klotho‐deficient (KL +/−) mice and WT littermates were fed with a high‐fat diet (HFD) or normal diet for 13 weeks, followed by treatment with the AMPKα activator (AICAR) for an additional 2 weeks. A HFD caused a greater increase in collagen levels in the aortic valves of KL +/− mice than of WT mice, indicating that Klotho deficiency promotes HFD‐induced aortic valve fibrosis (AVF). AMPKα activity (pAMPKα) was decreased, while protein expression of collagen I and RUNX2 was increased in the aortic valves of KL +/− mice fed with a HFD. Treatment with AICAR markedly attenuated HFD‐induced AVF in KL +/− mice. AICAR not only abolished the downregulation of pAMPKα but also eliminated the upregulation of collagen I and RUNX2 in the aortic valves of KL +/− mice fed with HFD. In cultured porcine aortic valve interstitial cells, Klotho‐deficient serum plus cholesterol increased RUNX2 and collagen I protein expression, which were attenuated by activation of AMPKα by AICAR. Interestingly, silencing of RUNX2 abolished the stimulatory effect of Klotho deficiency on cholesterol‐induced upregulation of matrix proteins, including collagen I and osteocalcin. In conclusion, Klotho gene deficiency promotes HFD‐induced fibrosis in aortic valves, likely through the AMPKα–RUNX2 pathway.

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“…It is a small protein of 100 amino acids, and is secreted solely by osteoblasts. Functionally, osteocalcin is pro-osteoblastic and bone building by influencing mineralization (Lee et al, 2007). Osteocalcin can be modified post-translationally by carboxylation through the activity of a vitamin-K dependent carboxylase.…”

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confidence: 99%