FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice

Rached, Marie Therese; Kode, Aruna; Silva, Barbara C.; Jung, Dae Young; Gray, Susan; Ong, Helena; Paik, Ji Hye; DePinho, Ronald A.; Kim, Jason K.; Karsenty, Gérard; Kousteni, Stavroula

doi:10.1172/jci39901

Cited by 199 publications

(187 citation statements)

References 58 publications

(56 reference statements)

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“…Similarly, embryos infected with Foxo1 miRNA did not demonstrate higher apoptosis in comparison with embryos that received control miRNA. This is consistent with a recent study that demonstrated Foxo1 conditional knock-out mice did not show any adverse effect on apoptosis or proliferation (42). Therefore, we conclude that it is possible for Foxo1 to affect skeletogenesis through a direct role in the differentiation of osteoblasts.…”

Section: Discussionsupporting

confidence: 93%

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Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Teixeira

Liu

Thant

et al. 2010

Journal of Biological Chemistry

123

120

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Skeletogenesis depends on the activity of bone-forming cells derived from mesenchymal cells. The pathways that control mesenchymal cell differentiation are not well understood. We propose that Foxo1 is an early molecular regulator during mesenchymal cell differentiation into osteoblasts. In mouse embryos, Foxo1 expression is higher in skeletal tissues, while Foxo1 silencing has a drastic impact on skeletogenesis and craniofacial development, specially affecting pre-maxilla, nasal bone, mandible, tibia, and clavicle. Similarly, Foxo1 activity and expression increase in mouse mesenchymal cells under the influence of osteogenic stimulants. In addition, silencing Foxo1 blocks the expression of osteogenic markers such as Runx2, alkaline phosphatase, and osteocalcin and results in decreased culture calcification even in the presence of strong osteogenic stimulants. Conversely, the expression of these markers increases significantly in response to Foxo1 overexpression. One mechanism through which Foxo1 affects mesenchymal cell differentiation into osteoblasts is through regulation of a key osteogenic transcription factor, Runx2. Indeed, our results show that Foxo1 directly interacts with the promoter of Runx2 and regulates its expression. Using a tibia organ culture model, we confirmed that silencing Foxo1 decreases the expression of Runx2 and impairs bone formation. Furthermore, our data reveals that Runx2 and Foxo1 interact with each other and cooperate in the transcriptional regulation of osteoblast markers. In conclusion, our in vitro, ex vivo, and in vivo results strongly support the notion that Foxo1 is an early molecular regulator in the differentiation of mesenchymal cells into osteoblast.Undifferentiated mesenchymal cells can differentiate into osteoblasts (bone-forming cells), adipocytes (fat cells), chondrocytes (cartilage cells), and myocytes (muscle cells) under the influence of various hormones and growth factors (1). Commitment and differentiation of mesenchymal cells into osteoblasts is crucial during skeletal development and bone growth.Whether mesenchymal cells differentiate along the osteogenic or other pathway depends on the activation of specific transcription factors. The importance of transcription factors in controlling skeletal development can be appreciated in the human skeletal disorder cleidocranial dysplasia. In this condition, deregulation of an important osteogenic transcription factor, Runx2, produces a striking phenotype with anterior fontanelle, hypoplasia or aplasia of the clavicle, wide pubic symphysis, and short stature (2).Although some of the transcription factors that control osteoblast differentiation are well characterized, the role of others remains unclear. One such factor is Foxo1 (forkhead box class O). Foxo1 belongs to the winged helix/forkhead family of transcription factors that is characterized by a 100-amino acid monomeric DNA-binding domain called the FOX domain. Other portions of the forkhead proteins, such as the DNA transactivation or DNA transrepression domains, a...

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Section: Discussionsupporting

confidence: 93%

“…Indeed, recent work (42) showing that osteocalcin promoter has binding sites for both Runx2 and Foxo1 argues in favor of functional interaction between Foxo1 and Runx2. Further functional analysis to clarify the nature of this interaction is necessary.…”

Section: Discussionmentioning

confidence: 99%

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Teixeira

Liu

Thant

et al. 2010

Journal of Biological Chemistry

123

120

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show abstract

“…Three factors-Runx2, Osterix, and ATF4-act sequentially to control differentiation from an osteochondral progenitor to a fully differentiated and functional osteoblast (Ducy et al, 1997;Komori et al, 1997;Nakashima et al, 2002;Yang et al, 2004). In addition, more broadly expressed transcription factors such as members of the AP1 family, CREB and FOXO1, also contribute to osteoblast differentiation and function (Kenner et al, 2004;Bozec et al, 2010;Rached et al, 2010;Kajimura et al, 2011). A second level of regulation is exerted by nuclear proteins such as STAT1, Twist, or Schnurri, among others.…”

Section: Introductionmentioning

confidence: 99%

miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2

Yu¹,

Zheng²,

Zeng³

et al. 2012

J Exp Med

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“…This action is in turn mediated by the adipokine leptin, which inhibits insulin secretion through direct effects on pancreatic ␤-cells (18) and through inhibition of osteocalcin activity (25). The interplay between bone and metabolism has recently been further elucidated by the discovery that the Forkhead family transcription factor FoxO1, a key regulator of insulin handling in multiple tissues, also acts within the osteoblast to control osteocalcin expression and bioactivity (46).…”

mentioning

confidence: 99%

Short-term voluntary exercise in the rat causes bone modeling without initiating a physiological stress response

Rosa¹,

Firth²,

Blair³

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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research has revealed a neuroendocrine connection between the skeleton and metabolism. Exercise alters both bone modeling and energy balance and may be useful in further developing our understanding of this complex interplay. However, research in this field requires an animal model of exercise that does not cause a physiological stress response in the exercised subjects. In this study, we develop a model of short-term voluntary exercise in the female rat that causes bone modeling without causing stress. Rats were randomly assigned to one of three age-matched groups: control, tower climbing, and squat exercise (rising to an erect bipedal stance). Exercise for 21 days resulted in bone modeling as assessed by peripheral quantitative computed tomography. Fecal corticosterone output was used to assess physiological stress at three time points during the study (preexercise, early exercise, and late in the exercise period). There were no differences in fecal corticosterone levels between groups or time points. This model of voluntary exercise in the rat will be useful for future studies of the influence of exercise on the relationship between skeletal and metabolic health and may be appropriate for investigation of the developmental origins of those effects. computed tomography; corticosterone; exercise; metabolism; stress RECENT ADVANCES IN OUR UNDERSTANDING of the dynamic relationship between body structure and metabolism have revealed a neuroendocrine connection between bone remodeling and energy balance, with both bone and fat acting as endocrine organs (14). The osteoblast-specific protein osteocalcin regulates glucose handling through effects on insulin secretion and sensitivity (33). This action is in turn mediated by the adipokine leptin, which inhibits insulin secretion through direct effects on pancreatic ␤-cells (18) and through inhibition of osteocalcin activity (25). The interplay between bone and metabolism has recently been further elucidated by the discovery that the Forkhead family transcription factor FoxO1, a key regulator of insulin handling in multiple tissues, also acts within the osteoblast to control osteocalcin expression and bioactivity (46).Exercise stimulates modeling of the musculoskeletal system (19, 55, 65), alters metabolism (40), and enhances brain function (17), and thus exercise provides an excellent means of exploring the neuroendocrine connection between bone, fat, and energy balance. The rat model of exercise has been used extensively to study the physiological effects of physical activity using such exercise modalities as swimming (24, 32), running (20,29,41,49,52), jumping (57), tower climbing (43), rising to an erect bipedal stance (11, 64), and weight lifting (62). The effects of exercise on bone have been widely characterized in the rat. Ovariectomized rats undergo changes in bone structure that are nearly identical to those seen in human osteoporosis (28,42), and these animals have proven useful for the study of exercise interventions in osteoporosis treatment (36).In examini...

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FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice

Cited by 199 publications

References 58 publications

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

Foxo1, a Novel Regulator of Osteoblast Differentiation and Skeletogenesis

miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2

Short-term voluntary exercise in the rat causes bone modeling without initiating a physiological stress response

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