- Email: [email protected]
Interactions between bone tissue and energy metabolism
Joint Bone Spine 77 (2010) 287–289
Editorial
Interactions between bone tissue and energy metabolism
Keywords: Osteocalcin Energy metabolism Leptin Serotonin ATF4
1. Introduction The classic functions of bone consist in a metabolic effect that maintains phosphate and calcium homeostasis and in a structural effect that enables locomotion and protects vital organs, such as the brain and spinal cord. Using transgenic mice, Karsenty and co-workers recently identified a novel endocrine function of bone that consists in regulating the energy metabolism. The hypothesis that bone was an endocrine organ came from the clinical observation that testicular or ovarian insufficiency invariably causes bone loss, whereas obesity protects against osteoporosis. This observation suggested that bone, energy metabolism, and fertility may all depend on the same endocrine system. To investigate this hypothesis, researchers looked for factors linking bone, reproduction, and appetite. Results generated by studies of leptin constituted a powerful driving force for delineating the endocrine functions of bone. 2. Impact of energy metabolism on bone mass Leptin released by adipocytes is a hormone that controls appetite and reproduction via a relay point in the brain. During evolution, leptin appeared simultaneously with bone remodeling and not with appetite. Mice lacking leptin (ob/ob) are obese and infertile. Thus they investigate whether these (ob/ob) mice have a bone phenotype. Histomorphometric evaluation of the lumbar spine (L3-L4) of (ob/ob) leptin-deficient mice showed an increase in bone mass (bone volume/total volume) related to increased bone formation [1]. As leptin receptor is expressed in the hypothalamus and brainstem, leptin was infused by intracerebroventricular injections (ICV) in dosages that did not cross the blood-brain barrier to (ob/ob) leptin-deficient mice. Leptin ICV corrected the bone phenotype, whereas saline did not, indicating that leptin acted indirectly on bone via a cerebral relay point. This was the first experiment to demonstrate that bone mass was under cerebral control. However, the results did not determine whether the control was mediated by neuronal or hormonal pathways. Reflex sympathetic dystrophy syndrome (RSDS) is a clinical situation of which several features suggest scientific hypotheses. The
typical feature is abrupt onset of regional bone loss that spares the joint spaces and typically produces a patchy appearance. In addition, vasomotor disturbances and increased sweating are present, suggesting sympathetic overactivity. There have been reports of improvements obtained with nonselective beta-blockers, such as propranolol [2,3]. Furthermore, several vast epidemiological studies investigated the association between beta-blocker therapy and the fracture risk. The results showed that beta-blocker therapy significantly decreased the hip fracture risk, by about one-fourth, with odds ratios ranging from 0.68 to 0.76 [4–6]. These clinical data are consistent with the high bone mass and low sympathetic activity that characterize leptin-deficient mice. They suggested to Karsenty and co-workers that the central control of bone mass was mediated by a neuronal pathway that involved the sympathetic system. To investigate this hypothesis, pairs of (ob/ob) leptin-deficient mice were connected by a surgically created shared circulation (parabiosis). Intracerebroventricular injection of leptin to one of the mice in each pair corrected the bone mass in the injected animals but not in the partners, demonstrating that leptin acted via a neuronal pathway [7]. The level of sympathetic activity in (ob/ob) mice was corrected by administering the beta-adrenergic receptor agonist isoproterenol. Isoproterenol abolished neither the excessive appetite nor the obesity but corrected the bone phenotype, demonstrating a role for the sympathetic nervous system [7]. In sum, leptin has been proven to inhibit bone formation via a cerebral relay point and the sympathetic nervous system. Thus, fat mass controls bone mass, i.e., energy metabolism controls bone mass. In general, when one endocrine system acts on another, there is always a counter-regulation mechanism that balances the activities of the two systems. The next question, therefore, was whether bone acts on energy metabolism.
3. The skeleton is an endocrine organ affecting energy metabolism The research strategy consisted in identifying osteoblastspecific genes for which knock-out mice could be generated, in order to study the metabolic phenotype of these animals. One of the candidate genes is Esp, which encodes the tyrosine phosphatase receptor OST-PTP and is expressed in osteoblasts, embryonic stem cells, and Sertoli cells but not in fat or pancreatic tissue. Mice lacking the Esp gene (Esp−/− ) were generated and their energy metabolism studied. Unexpectedly, Esp−/− mice had a high mortality rate at birth that was related, not to skeletal abnormalities, but to severe hypoglycemia. Subsequently, their blood glucose levels were significantly decreased compared to wild-type mice. Glucose tolerance
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.04.013
288
Editorial / Joint Bone Spine 77 (2010) 287–289
tests showed that Esp−/− mice had significantly better glycemia control than wild-type mice and returned faster to their baseline blood glucose level. Esp−/− mice had significantly higher serum insulin levels compared to wild-type mice and a stronger insulin response to glucose load. Histologically, the pancreatic  cells were larger and more numerous than in wild-type mice. Esp−/− mice also exhibited improved peripheral sensitivity to insulin. This increased insulin sensitivity was related to increased circulating levels of adiponectin produced by adipocytes. Esp−/− mice had lower serum triglyceride levels and smaller amounts of visceral fat. Thus, their phenotype suggested protection against diabetes. Importantly, this protective phenotype is found not only in mice with whole-body Esp deficiency but also in mice that lack Esp only in their osteoblasts. Conversely, Esp overexpression in osteoblasts of wild-type mice is associated with impaired glucose tolerance due to a combination of decreased serum insulin levels, decreased insulin secretion and increased insulin resistance [8]. In sum, osteoblast-specific deletion in rodents of a phosphatase can improve the handling of glucose and decrease the fat mass. Esp encodes a tyrosine phosphatase receptor and therefore cannot act directly on the target tissues of energy metabolism. Cocultures of wild-type osteoblasts and pancreatic cells separated by a filter showed increased insulin expression by the pancreatic cells. This effect was replicated by culturing pancreatic cells with osteoblast-conditioned media. Similarly, co-culturing osteoblasts and adipocytes led to adiponectin expression by the adipocytes. These experimental results indicate that the osteoblasts secrete a soluble factor acting on both adipocytes and pancreatic cells. Thus, the skeleton can be viewed as an endocrine organ affecting energy metabolism.
4. Noncarboxylated osteocalcin: a bone hormone with effects on energy metabolism The profile of the candidate hormone must meet the following three criteria: specific production by osteoblasts, secretion, and amenability to regulation. Osteocalcin is found in all vertebrates and is considered a differentiation marker for mature osteoblasts. Osteocalcin is secreted into the bone matrix and bloodstream. Carboxylation of the glutamate residues of osteocalcin offers one opportunity for regulation. In addition, genetic linkage studies have shown that the osteocalcin gene is located in a diabetes susceptibility region. Osteocalcin-deficient mice exhibit moderate and delayed abnormalities in the bone phenotype [9] but become overweight at a young age despite a normal diet. Studies of the metabolic phenotype of osteocalcin-deficient mice showed a significant increase in blood glucose compared to wildtype mice. This hyperglycemia was accompanied with impaired glucose-load tolerance related to decreased circulating insulin levels and increased insulin resistance and visceral fat. This profile suggestive of diabetes is the mirror image of the phenotype seen in Esp−/− mice [8]. Complementary in vitro studies have confirmed that noncarboxylated osteocalcin stimulates insulin production by the pancreas and adiponectin production by the adipocytes. To test the therapeutic potential of noncarboxylated osteocalcin, adult wild-type mice were treated with various doses for four weeks by continuous infusion via an implanted pump. At treatment completion, glucose tolerance test showed improved glucose handling with a smaller glycemia peak and faster return to the baseline value. Treated mice had dose-dependently higher serum insulin levels, greater peripheral sensitivity to insulin, and less visceral fat. In animals given a high-calorie high-fat diet, noncarboxylated osteocalcin slowed the development of obesity and diabetes [10].
5. Recent advances Three transcription factors are specific of osteoblasts. Osx and Runx2 are involved in mesenchymatous cell differentiation and osteoblastogenesis. ATF4 belongs to the CREB family and is involved more selectively in regulating osteoblast functions, such as bone mineralization and bone formation. ATF4, which is under sympathetic system regulation, enhances Esp and Osteocalcin gene expression, thereby diminishing the active form of osteocalcin. This effect of ATF4 explains that mice lacking Atf4 have increased amounts of active noncarboxylated osteocalcin and a protective metabolic phenotype [11]. FoxO1 is a transcription factor targeted
Fig. 1. Diagram of osteoblast signaling pathways involved in energy metabolism regulation. Effects of insulin and the sympathetic nervous system (SNS) on osteocalcin (OCN) and its carboxylation via OST-PTP. Insulin receptor (IRS).
Fig. 2. Interactions between bone tissue and energy metabolism. Leptin receptor (ObRb), ventromedial hypothalamus (VMH), arcuate nucleus (NA), sympathetic nervous system (SNS), active noncarboxylated osteocalcin (unOCN), carboxylated osteocalcin (OCNcarb).
Editorial / Joint Bone Spine 77 (2010) 287–289
by insulin and is expressed in many tissues involved in energy metabolism [12]. Specific FoxO1 deletion in osteoblasts produces a protective metabolic phenotype by diminishing Esp expression and increasing Osteocalcin expression [13] (Fig. 1). Another recent advance is the identification of the first neuronal circuits that control bone mass. The leptin receptor ObRb is expressed in the brainstem. Using a dual genetic and histological approach, researchers have established that the brainstem serotoninergic neurons express the leptin receptor ObRb. Axonal tracing experiments have shown that these serotoninergic neurons project to the hypothalamus at the arcuate nucleus, where they inhibit appetite, and at the ventromedial hypothalamus, where they control the sympathetic nervous system and bone mass [14] (Fig. 2). The identification of these interactions invites further studies of interactions between bone tissue and other tissues involved in energy metabolism. This new field of bone endocrinology is already opening up new treatment perspectives for type 2 diabetes and osteoporosis. Also, other endocrine functions of the skeleton may remain to be discovered. Conflict of interest statement The authors have no conflicts of interest to declare. Acknowledgements
289
[3] Visitsunthorn U, Prete P. Reflex sympathetic dystrophy of the lower extremity: a complication of herpes zoster with dramatic response to propranolol. West J Med 1981;135:62–6. [4] Pasco JA, Henry MJ, Sanders KM, et al. Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: geelong Osteoporosis Study. J Bone Miner Res 2004;19:19–24. [5] Reid IR, Gamble GD, Grey AB, et al. Beta-blocker use BMD, and fractures in the study of osteoporotic fractures. J Bone Miner Res 2005;20:613–8. [6] Schlienger RG, Kraenzlin ME, Jick SS, et al. Use of beta-blockers and risk of fractures. JAMA 2004;292:1326–32. [7] Takeda S, Elefteriou F, Levasseur R, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002;111:305–17. [8] Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007;130:456–69. [9] Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcindeficient mice. Nature 1996;382:448–52. [10] Ferron M, Hinoi E, Karsenty G, et al. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 2008;105:5266–70. [11] Yoshizawa T, Hinoi E, Jung DY, et al. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest 2009;119:2807–17. [12] Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabolism. Oncogene 2008;27:2320–36. [13] Rached MT, Kode A, Silva BC, et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest 2010;120:357–68. [14] Yadav VK, Oury F, Suda N, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009;138:976–89.
Cyrille B. Confavreux a,∗,b Inserm U831–Université de Lyon, Service de rhumatologie, Pavillon F, Hôpital Edouard Herriot, 5, place d’Arsonval, 69003 Lyon, France b Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, 10032, USA a
We thank Professor Gérard Karsenty and Doctor Patricia Ducy for their teaching and fruitful discussion during the preparation of this manuscript. This work was supported by the young researcher award from the Fondation Bettencourt and by grants from the Société franc¸aise de rhumatologie (SFR) and Philippe Foundation Inc. References [1] Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100: 197–207. [2] Simson G. Letter: Propranolol for causalgia and Sudeck’s atrophy. JAMA 1974;227:327.
∗ Tel.:
+33 4 72 11 74 55, Fax: +33 4 72 11 74 83. E-mail address: [email protected] 10 March 2010 Available online 4 June 2010
Editorial
Interactions between bone tissue and energy metabolism
Keywords: Osteocalcin Energy metabolism Leptin Serotonin ATF4
1. Introduction The classic functions of bone consist in a metabolic effect that maintains phosphate and calcium homeostasis and in a structural effect that enables locomotion and protects vital organs, such as the brain and spinal cord. Using transgenic mice, Karsenty and co-workers recently identified a novel endocrine function of bone that consists in regulating the energy metabolism. The hypothesis that bone was an endocrine organ came from the clinical observation that testicular or ovarian insufficiency invariably causes bone loss, whereas obesity protects against osteoporosis. This observation suggested that bone, energy metabolism, and fertility may all depend on the same endocrine system. To investigate this hypothesis, researchers looked for factors linking bone, reproduction, and appetite. Results generated by studies of leptin constituted a powerful driving force for delineating the endocrine functions of bone. 2. Impact of energy metabolism on bone mass Leptin released by adipocytes is a hormone that controls appetite and reproduction via a relay point in the brain. During evolution, leptin appeared simultaneously with bone remodeling and not with appetite. Mice lacking leptin (ob/ob) are obese and infertile. Thus they investigate whether these (ob/ob) mice have a bone phenotype. Histomorphometric evaluation of the lumbar spine (L3-L4) of (ob/ob) leptin-deficient mice showed an increase in bone mass (bone volume/total volume) related to increased bone formation [1]. As leptin receptor is expressed in the hypothalamus and brainstem, leptin was infused by intracerebroventricular injections (ICV) in dosages that did not cross the blood-brain barrier to (ob/ob) leptin-deficient mice. Leptin ICV corrected the bone phenotype, whereas saline did not, indicating that leptin acted indirectly on bone via a cerebral relay point. This was the first experiment to demonstrate that bone mass was under cerebral control. However, the results did not determine whether the control was mediated by neuronal or hormonal pathways. Reflex sympathetic dystrophy syndrome (RSDS) is a clinical situation of which several features suggest scientific hypotheses. The
typical feature is abrupt onset of regional bone loss that spares the joint spaces and typically produces a patchy appearance. In addition, vasomotor disturbances and increased sweating are present, suggesting sympathetic overactivity. There have been reports of improvements obtained with nonselective beta-blockers, such as propranolol [2,3]. Furthermore, several vast epidemiological studies investigated the association between beta-blocker therapy and the fracture risk. The results showed that beta-blocker therapy significantly decreased the hip fracture risk, by about one-fourth, with odds ratios ranging from 0.68 to 0.76 [4–6]. These clinical data are consistent with the high bone mass and low sympathetic activity that characterize leptin-deficient mice. They suggested to Karsenty and co-workers that the central control of bone mass was mediated by a neuronal pathway that involved the sympathetic system. To investigate this hypothesis, pairs of (ob/ob) leptin-deficient mice were connected by a surgically created shared circulation (parabiosis). Intracerebroventricular injection of leptin to one of the mice in each pair corrected the bone mass in the injected animals but not in the partners, demonstrating that leptin acted via a neuronal pathway [7]. The level of sympathetic activity in (ob/ob) mice was corrected by administering the beta-adrenergic receptor agonist isoproterenol. Isoproterenol abolished neither the excessive appetite nor the obesity but corrected the bone phenotype, demonstrating a role for the sympathetic nervous system [7]. In sum, leptin has been proven to inhibit bone formation via a cerebral relay point and the sympathetic nervous system. Thus, fat mass controls bone mass, i.e., energy metabolism controls bone mass. In general, when one endocrine system acts on another, there is always a counter-regulation mechanism that balances the activities of the two systems. The next question, therefore, was whether bone acts on energy metabolism.
3. The skeleton is an endocrine organ affecting energy metabolism The research strategy consisted in identifying osteoblastspecific genes for which knock-out mice could be generated, in order to study the metabolic phenotype of these animals. One of the candidate genes is Esp, which encodes the tyrosine phosphatase receptor OST-PTP and is expressed in osteoblasts, embryonic stem cells, and Sertoli cells but not in fat or pancreatic tissue. Mice lacking the Esp gene (Esp−/− ) were generated and their energy metabolism studied. Unexpectedly, Esp−/− mice had a high mortality rate at birth that was related, not to skeletal abnormalities, but to severe hypoglycemia. Subsequently, their blood glucose levels were significantly decreased compared to wild-type mice. Glucose tolerance
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.04.013
288
Editorial / Joint Bone Spine 77 (2010) 287–289
tests showed that Esp−/− mice had significantly better glycemia control than wild-type mice and returned faster to their baseline blood glucose level. Esp−/− mice had significantly higher serum insulin levels compared to wild-type mice and a stronger insulin response to glucose load. Histologically, the pancreatic  cells were larger and more numerous than in wild-type mice. Esp−/− mice also exhibited improved peripheral sensitivity to insulin. This increased insulin sensitivity was related to increased circulating levels of adiponectin produced by adipocytes. Esp−/− mice had lower serum triglyceride levels and smaller amounts of visceral fat. Thus, their phenotype suggested protection against diabetes. Importantly, this protective phenotype is found not only in mice with whole-body Esp deficiency but also in mice that lack Esp only in their osteoblasts. Conversely, Esp overexpression in osteoblasts of wild-type mice is associated with impaired glucose tolerance due to a combination of decreased serum insulin levels, decreased insulin secretion and increased insulin resistance [8]. In sum, osteoblast-specific deletion in rodents of a phosphatase can improve the handling of glucose and decrease the fat mass. Esp encodes a tyrosine phosphatase receptor and therefore cannot act directly on the target tissues of energy metabolism. Cocultures of wild-type osteoblasts and pancreatic cells separated by a filter showed increased insulin expression by the pancreatic cells. This effect was replicated by culturing pancreatic cells with osteoblast-conditioned media. Similarly, co-culturing osteoblasts and adipocytes led to adiponectin expression by the adipocytes. These experimental results indicate that the osteoblasts secrete a soluble factor acting on both adipocytes and pancreatic cells. Thus, the skeleton can be viewed as an endocrine organ affecting energy metabolism.
4. Noncarboxylated osteocalcin: a bone hormone with effects on energy metabolism The profile of the candidate hormone must meet the following three criteria: specific production by osteoblasts, secretion, and amenability to regulation. Osteocalcin is found in all vertebrates and is considered a differentiation marker for mature osteoblasts. Osteocalcin is secreted into the bone matrix and bloodstream. Carboxylation of the glutamate residues of osteocalcin offers one opportunity for regulation. In addition, genetic linkage studies have shown that the osteocalcin gene is located in a diabetes susceptibility region. Osteocalcin-deficient mice exhibit moderate and delayed abnormalities in the bone phenotype [9] but become overweight at a young age despite a normal diet. Studies of the metabolic phenotype of osteocalcin-deficient mice showed a significant increase in blood glucose compared to wildtype mice. This hyperglycemia was accompanied with impaired glucose-load tolerance related to decreased circulating insulin levels and increased insulin resistance and visceral fat. This profile suggestive of diabetes is the mirror image of the phenotype seen in Esp−/− mice [8]. Complementary in vitro studies have confirmed that noncarboxylated osteocalcin stimulates insulin production by the pancreas and adiponectin production by the adipocytes. To test the therapeutic potential of noncarboxylated osteocalcin, adult wild-type mice were treated with various doses for four weeks by continuous infusion via an implanted pump. At treatment completion, glucose tolerance test showed improved glucose handling with a smaller glycemia peak and faster return to the baseline value. Treated mice had dose-dependently higher serum insulin levels, greater peripheral sensitivity to insulin, and less visceral fat. In animals given a high-calorie high-fat diet, noncarboxylated osteocalcin slowed the development of obesity and diabetes [10].
5. Recent advances Three transcription factors are specific of osteoblasts. Osx and Runx2 are involved in mesenchymatous cell differentiation and osteoblastogenesis. ATF4 belongs to the CREB family and is involved more selectively in regulating osteoblast functions, such as bone mineralization and bone formation. ATF4, which is under sympathetic system regulation, enhances Esp and Osteocalcin gene expression, thereby diminishing the active form of osteocalcin. This effect of ATF4 explains that mice lacking Atf4 have increased amounts of active noncarboxylated osteocalcin and a protective metabolic phenotype [11]. FoxO1 is a transcription factor targeted
Fig. 1. Diagram of osteoblast signaling pathways involved in energy metabolism regulation. Effects of insulin and the sympathetic nervous system (SNS) on osteocalcin (OCN) and its carboxylation via OST-PTP. Insulin receptor (IRS).
Fig. 2. Interactions between bone tissue and energy metabolism. Leptin receptor (ObRb), ventromedial hypothalamus (VMH), arcuate nucleus (NA), sympathetic nervous system (SNS), active noncarboxylated osteocalcin (unOCN), carboxylated osteocalcin (OCNcarb).
Editorial / Joint Bone Spine 77 (2010) 287–289
by insulin and is expressed in many tissues involved in energy metabolism [12]. Specific FoxO1 deletion in osteoblasts produces a protective metabolic phenotype by diminishing Esp expression and increasing Osteocalcin expression [13] (Fig. 1). Another recent advance is the identification of the first neuronal circuits that control bone mass. The leptin receptor ObRb is expressed in the brainstem. Using a dual genetic and histological approach, researchers have established that the brainstem serotoninergic neurons express the leptin receptor ObRb. Axonal tracing experiments have shown that these serotoninergic neurons project to the hypothalamus at the arcuate nucleus, where they inhibit appetite, and at the ventromedial hypothalamus, where they control the sympathetic nervous system and bone mass [14] (Fig. 2). The identification of these interactions invites further studies of interactions between bone tissue and other tissues involved in energy metabolism. This new field of bone endocrinology is already opening up new treatment perspectives for type 2 diabetes and osteoporosis. Also, other endocrine functions of the skeleton may remain to be discovered. Conflict of interest statement The authors have no conflicts of interest to declare. Acknowledgements
289
[3] Visitsunthorn U, Prete P. Reflex sympathetic dystrophy of the lower extremity: a complication of herpes zoster with dramatic response to propranolol. West J Med 1981;135:62–6. [4] Pasco JA, Henry MJ, Sanders KM, et al. Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: geelong Osteoporosis Study. J Bone Miner Res 2004;19:19–24. [5] Reid IR, Gamble GD, Grey AB, et al. Beta-blocker use BMD, and fractures in the study of osteoporotic fractures. J Bone Miner Res 2005;20:613–8. [6] Schlienger RG, Kraenzlin ME, Jick SS, et al. Use of beta-blockers and risk of fractures. JAMA 2004;292:1326–32. [7] Takeda S, Elefteriou F, Levasseur R, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell 2002;111:305–17. [8] Lee NK, Sowa H, Hinoi E, et al. Endocrine regulation of energy metabolism by the skeleton. Cell 2007;130:456–69. [9] Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcindeficient mice. Nature 1996;382:448–52. [10] Ferron M, Hinoi E, Karsenty G, et al. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A 2008;105:5266–70. [11] Yoshizawa T, Hinoi E, Jung DY, et al. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest 2009;119:2807–17. [12] Gross DN, van den Heuvel AP, Birnbaum MJ. The role of FoxO in the regulation of metabolism. Oncogene 2008;27:2320–36. [13] Rached MT, Kode A, Silva BC, et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J Clin Invest 2010;120:357–68. [14] Yadav VK, Oury F, Suda N, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009;138:976–89.
Cyrille B. Confavreux a,∗,b Inserm U831–Université de Lyon, Service de rhumatologie, Pavillon F, Hôpital Edouard Herriot, 5, place d’Arsonval, 69003 Lyon, France b Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, 10032, USA a
We thank Professor Gérard Karsenty and Doctor Patricia Ducy for their teaching and fruitful discussion during the preparation of this manuscript. This work was supported by the young researcher award from the Fondation Bettencourt and by grants from the Société franc¸aise de rhumatologie (SFR) and Philippe Foundation Inc. References [1] Ducy P, Amling M, Takeda S, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100: 197–207. [2] Simson G. Letter: Propranolol for causalgia and Sudeck’s atrophy. JAMA 1974;227:327.
∗ Tel.:
+33 4 72 11 74 55, Fax: +33 4 72 11 74 83. E-mail address: [email protected] 10 March 2010 Available online 4 June 2010