Molecular Endocrinology, doi:10.1210/me.2007-0259
Molecular Endocrinology 21 (11): 2605-2614
Copyright © 2007 by The Endocrine Society
Gone with the Wnts: ß-Catenin, T-Cell Factor, Forkhead Box O, and Oxidative Stress in Age-Dependent Diseases of Bone, Lipid, and Glucose Metabolism
Stavros C. Manolagas and
Maria Almeida
Division of Endocrinology and Metabolism and the Center of Osteoporosis and Metabolic Bone Diseases, Department of Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Stavros C. Manolagas, M.D., Ph.D., 4301 West Markham, No. 587, Little Rock, Arkansas 72205-7199. E-mail: manolagasstavros{at}uams.edu.
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ABSTRACT
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The Wnt/ß-catenin signaling pathway affects several biological processes ranging from embryonic development, patterning, and postembryonic stem cell fate, to bone formation and insulin secretion in adulthood. ß-Catenin mediates canonical Wnt signaling by binding to and activating members of the T-cell factor (TCF) transcription factor family. Similar to the Wnt/ß-catenin pathway, oxidative stress influences fundamental cellular processes including stem cell fate and has been linked to aging and the development of age-related diseases. However, the molecular details of the pathogenetic effects of oxidative stress on the homeostasis of many different tissues remain unclear. ß-Catenin has been recently implicated as a pivotal molecule in defense against oxidative stress by serving as a cofactor of the forkhead box O (FOXO) transcription factors. In addition, it has been shown that oxidative stress is a pivotal pathogenetic factor of age-related bone loss and strength in mice, leading to, among other changes, a decrease in osteoblast number and bone formation. These particular cellular changes evidently result from diversion of the limited pool of ß-catenin from TCF- to FOXO-mediated transcription in osteoblastic cells. Fascinatingly, attenuation of Wnt-mediated transcription, resulting from an autosomal-dominant missense mutation in LRP6, a coreceptor for the Wnt-signaling pathway, has been linked recently genetically not only to premature osteoporosis, but also to coronary artery disease as well as several features of the metabolic syndrome including hyperlipidemia, hypertension, and diabetes, but not obesity. In this minireview, we highlight evidence linking the age-associated oxidative stress with FOXOs, Wnt/ß-catenin signaling, osteoblastogenesis, adipogenesis, osteoporosis, and several features of the metabolic syndrome. We hypothesize that antagonism of Wnt signaling by oxidative stress with increasing age may be a common molecular mechanism contributing to the development not only of involutional osteoporosis, but several pathologies such as atherosclerosis, insulin resistance, and hyperlipidemia, all of which become more prevalent with advancing age.
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INTRODUCTION
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WNTS ARE SECRETED lipid-modified proteins that bind to a receptor complex comprising frizzled (fz) and the low-density lipoprotein receptor-related proteins 5 or 6 (LRP5 or LRP6) (1, 2, 3, 4, 5). Activation of this receptor complex by Wnts leads to inactivation of glycogen synthase kinase 3ß (GSK-3ß), which prevents the proteosomal degradation of the transcriptional coactivator ß-catenin and, thereby, promotes its accumulation in the cytoplasm (6, 7). ß-Catenin translocates into the nucleus where it associates with the T-cell factor (TCF) lymphoid-enhancer binding factor (LEF) family of transcription factors and regulates the expression of Wnt target genes (8) (Fig. 1
). In addition to this so-called canonical pathway, Wnts can signal via the protein kinase C, Rho-, or c-Jun N-terminal kinase (JNK) (9). Several moieties serve as antagonists of Wnt signaling: secreted fz-related proteins (SFRPs) act as soluble decoy fz receptors by preventing binding of Wnt to fz. Dickkopfs (Dkks) and sclerostin (Sost) bind to and inactivate signaling from LRP5/LRP6 (10, 11). The scaffolding protein axin, GSK-3ß, and the tumor suppressor, adenomatosis polyposi coli, antagonize Wnt signaling by promoting ß-catenin degradation.
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Fig. 1. The Increase of ROS with Age Antagonizes the Skeletal and Metabolic Effects of Wnt/ß-Catenin by Diverting ß-Catenin from TCF- to FOXO-Mediated Transcription
Activation of FOXO-mediated transcription by ROS via JNK is depicted on the left. The adapter protein p66shc is activated by increased intracellular ROS and also generates ROS in the mitochondria. The Wnt/ß-catenin signaling cascade is depicted on the right. Activation of the LRP5/6-fz receptor complex by Wnts leads to inactivation of GSK-3ß, which prevents the proteosomal degradation of ß-catenin (depicted by the broken ß-catenin symbol) and, thereby, promotes its accumulation in the cytoplasm. Upon its translocation into the nucleus ß-catenin associates with the TCF/LEF family of transcription factors and regulates the expression of Wnt target genes. With increasing age, increased ROS production diverts the limited pool of ß-catenin (depicted by the green oval containing four ß-catenin molecules) from TCF/LEF to FOXO-mediated transcription, thus tilting the balance to the left. This shift of the balance, depicted by the different size of the yellow arrows, may be responsible for the conversion of the beneficial effects of Wnt/ß-catenin on bone, glucose, and lipid metabolism to the adverse effects of oxidative stress on these biological processes, and thereby the development of osteoporosis and some features of the metabolic syndrome. APC, Adenomatosis polyposi coli; ALP, alkaline phosphatase; LDL, low-density lipoprotein; Ob, Osteoblast; Oc, osteoclast; OPG, osteoprotegerin; SOD, superoxide dismutase.
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WNT SIGNALING, ß-CATENIN, AND BONE METABOLISM
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During the last 6 yr, it has been extensively documented that Wnt/LRP5 or LRP6 signaling is a critical determinant of bone mass. Indeed, loss or gain of function mutations in LRP5 leads to osteoporosis-pseudoglioma syndrome (12) or the hereditary high bone mass trait in humans, respectively (13, 14, 15). Likewise, LRP5-deficient mice show decreased bone formation and osteoblast proliferation (16) whereas transgenic mice that express the LRP5 G171V activating mutation in osteoblasts exhibit increased bone formation and high bone mass (17). Consistent with the bone mass phenotype of LRP5 mutations, deletion of the Wnt signaling antagonists SFRP-1, Dkk1, or adenomatosis polyposi coli enhances trabecular bone accrual in adult animals. Bone senses and adapts to meet mechanical needs by means of an extensive mechanotransduction network comprising osteocytes (former osteoblasts entombed individually in lacunae of the mineralized matrix) and their cytoplasmic projections (>50 per cell) through which osteocytes communicate with each other and with osteoclasts and osteoblasts on the bone surface. Osteocytes are also unique among cells of the osteoblastic lineage because of their ability to express sclerostin, the product of the Sost gene (18, 19, 20). Loss of function mutations of SOST in humans causes the high bone mass disorders, Van Buchem’s disease (21) and sclerosteosis (22), and an anti-sclerostin antibody increases bone formation in mice (23). Conversely, transgenic mice overexpressing SOST exhibit low bone mass (18). Remarkably, increased Wnt/ß-catenin signaling is a normal physiological response to mechanical loading in bone, because activation of this pathway enhances the sensitivity of osteocytes to strain (24). This strongly suggests that Wnt/ß-catenin signaling plays a critical role in bone adaptation to mechanical loading, be that body weight or exercise.
The paramount importance of the Wnt signaling for bone mass is now explained by the essential role of ß-catenin in determining the commitment of multipotential mesenchymal progenitors to the osteoblastic lineage (25, 26). In addition to promoting osteoblastogenesis, Wnt/ß-catenin signaling inhibits adipogenesis, an alternative fate of the multipotential mesenchymal progenitors, by blocking the expression of peroxisomal proliferator-activated receptor-
and CCAAT enhancer binding protein-
(27). Moreover, Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by both ß-catenin-dependent and -independent signaling cascades; the latter involves Src/ERK and phosphatidylinositol 3-kinase/AKT kinases (28). In line with the antiapoptotic effect of Wnt signaling, both overexpression of the LRP5 G171V mutation or deletion of the Wnt antagonist SFRP-1 in mice reduce osteoblast and osteocyte apoptosis, suggesting that the increased functional life span of osteoblasts is responsible, at least in part, for the favorable effects of Wnt signaling in bone (17, 29). Lastly, ß-catenin activation causes decreased osteoclastogenesis and bone resorption by increasing the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation, whereas ß-catenin deletion is associated with increased osteoclastogenesis, increased bone resorption, and decreased osteoprotegerin expression (30, 31). Thus, Wnt/ß-catenin signaling increases bone mass by stimulating osteoblastogenesis and suppressing osteoblast apoptosis, adipogenesis, and osteoclastogenesis.
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AGING AND OXIDATIVE STRESS
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Reactive oxygen species (ROS), the radical forms of oxygen, arise in the mitochondria as byproducts of respiration and oxidase activity. In addition to normal intracellular metabolism, external stimuli, such as inflammatory cytokines, growth factors, environmental toxins, chemotherapeutics, UV light, or ionizing radiation, contribute to ROS production. A rise in the level of ROS has two important effects: it can damage proteins, lipids, and DNA, leading to cell death or it can trigger the activation of specific physiological signaling pathways (32, 33, 34, 35). To counteract the adverse effects of oxidative stress, cells possess intricate antioxidant defense mechanisms, and survival depends on the ability of the cells to adapt to or resist the stress and to repair or replace the damaged molecules. When this fails, cells undergo apoptosis.
An extensive body of literature indicates that ROS play a significant role in the pathogenesis of metabolic, cardiovascular, ophthalmologic, and neurodegenerative diseases and that the exponential increase of the incidence of these conditions with age may be due to the sharing of common mechanisms with the aging process per se. Furthermore, oxidative stress has been inversely correlated with longevity in flies, nematodes, and mammals (33, 36). The p53 tumor suppressor and the adapter protein p66shc represent key components of a signal transduction pathway that not only is activated by increased intracellular ROS and converts oxidative signals into apoptosis but also generates ROS in the mitochondria (37, 38, 39). Strikingly, an activating mutation of p53 causes early onset of aging-associated phenotypes in mice (40). Conversely, deletion of p66shc increases resistance to oxidative stress, as well as life span, by as much as 30% (37).
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CELLULAR DEFENSE AGAINST OXIDATIVE DAMAGE: THE ROLE OF FORKHEAD BOX O (FOXOS)
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One of the major cell defense mechanisms against oxidative damage involves up-regulation of the transcription of free radical scavenging enzymes such as Mn superoxide dismutase, catalase, as well as DNA-damage repair genes such as Gadd45 (41, 42, 43, 44), by members of the FOXO transcription factors. FOXOs represent a subclass of a large family of forkhead proteins characterized by the presence of a winged-helix DNA-binding domain called Forkhead box. FOXOs have been evolutionary conserved from Caenorhabditis elegans and Drosophila to humans and are involved in cell differentiation, cell cycle arrest, and DNA repair during cellular stress, as well as glucose and lipid metabolism. FOXOs shuttle between the cytoplasm and the nucleus depending on the phosphorylation of specific sites by a distinct set of kinases. Phosphorylation of FOXOs in response to growth factors such as insulin and IGFs, via phosphatidylinositol 3-kinase and AKT kinases, favors their retention in the cytoplasm. On the other hand, phosphorylation of FOXOs (in different sites) in response to oxidative stress results in their translocation in the nucleus where they transactivate several cyclins, cyclin-dependent kinase inhibitors, DNA repair, and apoptosis control genes, as well as antioxidant enzymes such as Mn superoxide dismutase and catalase (Fig. 1
).
FOXOs not only promote mammalian cell survival by inducing cell cycle arrest and quiescence in response to oxidative stress (41, 45, 46, 47, 48, 49), but also regulate longevity in model organisms (50). Moreover, Tothova et al. (51) have very recently provided compelling evidence from studies of hematopoiesis in mice with conditional deletion of FOXO1, FOXO3, and FOXO4 that FOXO deficiency enforces cell fate decisions of stem cells, driving them into the cell cycle and terminal differentiation at the expense of self-renewal. These workers were able to reverse completely the FOXO-deficient hematopoietic stem cell phenotype by administration of the antioxidant N-acetyl cysteine (NAC), demonstrating that physiological oxidative stress is a critical determinant of the long-term regenerative potential of stem cells.
In addition to FOXO, cell defense against oxidative stress involves a thiol-reducing buffer consisting of oligopeptides with redox-active sulfhydryl moieties, the most abundant of which are glutathione and thioredoxin. With this mechanism, peroxides are reduced to harmless alcohols in a reaction in which glutathione peroxidase oxidizes glutathione to the glutathione disulfide and glutathione reductase converts it back into glutathione (52).
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AGING AND THE DEVELOPMENT OF OSTEOPOROSIS
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One view of age-related bone loss has been that when all extraskeletal mechanisms have been discovered, they will collectively explain the phenomenon completely. However, several lines of evidence strongly suggest that there must be additional age-related mechanisms intrinsic to bone. Indeed, age-related loss of bone mass and strength is an invariable feature of human biology, affecting women and men alike. In women, bone loss is accelerated for 5–10 yr after menopause because of the abrupt decline of estrogens, but, after this phase has subsided, bone loss continues at about the same rate as in elderly eugonadal males. Moreover, recent population-based longitudinal studies demonstrate that substantial trabecular bone loss begins as early as the 20’s in young adult women and men, long before any hormonal changes (53). The extent to which estrogen (or androgen) deficiency contributes to age-related bone loss and the slower rate of decline of skeletal assets during the late postmenopausal years, and the molecular and cellular mechanisms of such putative interactions, have heretofore remained unknown.
The universality of age-associated bone loss irrespective of sex steroid status notwithstanding, age is by far a more critical determinant of fracture risk than bone mass in humans, indicating that age-related increase in fracture risk reflects a loss of bone strength that is only partly accounted for by loss of bone mass (54). Whereas an increased propensity to fall due to age-related decline in neuromuscular function is a factor, there are also age-related changes in the bone itself. Such changes include disrupted architecture, altered composition of the bone mineral and matrix, delayed repair of fatigue microdamage, and inadequate bone size. The most recently appreciated qualitative factor is loss of osteocytes (55, 56), former osteoblasts entombed into the mineralized matrix. Osteocyte death may influence the signals necessary for mechanical adaptation and repair and also lead to long-term changes in bone hydration. These lines of evidence have strongly suggested to us the possibility that organismal aging per se, rather than an age-associated failure of other organs and tissues, may be the predominant mechanism of the bone fragility disease, which has become synonymous with osteoporosis—just one of the many features and risk factors underlying the problem of fractures.
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OXIDATIVE DAMAGE IS A FUNDAMENTAL PATHOGENETIC MECHANISM OF SKELETAL INVOLUTION
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During the last couple of years, work from our group has established several previously unappreciated age-related changes in both female and male C57BL/6 mice that may provide critical clues into the mechanisms of the age-related decline of bone strength and mass, and the influence of sex steroid deficiency in this process (80). Briefly, we have determined that female or male C57BL/6 mice lose bone strength and mass progressively between the ages of 4–31 months. These changes are temporally associated with decreased rate of remodeling as evidenced by decreased osteoblast and osteoclast numbers and decreased bone formation rate, as well as increased osteoblast and osteocyte apoptosis. These changes are also temporally linked with increased ROS levels and decreased glutathione reductase activity, as well as a corresponding increase in the phosphorylation of p53 and p66shc, the two key components of a signaling cascade that, as mentioned above, is activated by ROS and influences apoptosis and life span in invertebrates and mammals. Of particular interest is the fact that these mice do not show significant changes in sex hormone levels with age nor do they show changes in female and male reproductive organs, strongly suggesting that the skeletal changes we observed must mainly reflect some other aspect of aging. The exact same changes in oxidative stress are acutely reproduced by gonadectomy in either females or males and prevented by NAC. In addition, we have established that the bone protective effects of estrogens or androgens result from direct antioxidant actions on bone cells. Consistent with our observations temporally linking increased oxidative stress with increased osteoblast apoptosis and decreased osteoblast number and bone formation rate in aging C57BL/6 mice, in studies by Chambers and colleagues (57), both osteoblast numbers and bone formation were decreased in 2-month-old mice treated with the glutathione inhibitor buthionine sulfoximine. Likewise, in agreement with our findings with the 5-month-old ovariectomized C57BL/6 mice, these workers had shown that the antioxidants NAC and ascorbate, or inhibition of H2O2 by pegylated catalase, prevented the increased osteoclastogenesis and loss of bone caused by acute loss of estrogens in 2-month-old mice (57, 58).
These novel mechanistic insights strongly support the notion that organismal aging per se (specifically the increased oxidative stress associated with aging) rather than age-associated failure of other organs (e.g. loss of ovarian function at menopause) is the fundamental pathogenetic mechanism of the age-related bone loss and strength in both females and males. Loss of estrogens or androgens merely accelerates the effects of aging on bone by decreasing defense against oxidative stress. However, acute loss of sex steroids causes a transient increase in the rate of bone remodeling, underlined by an increase in osteoclastogenesis and osteoblastogenesis and a corresponding increase in both bone resorption and formation, albeit, with the former exceeding the latter. In contrast, aging C57BL/6 mice and elderly individuals (without vitamin D deficiency and secondary hyperparathyroidism) exhibit a low rate of bone remodeling, as well as a decrease in osteoblast number and bone formation relative to resorption. In fact, the hallmark of age-associated osteoporosis is decreased bone formation resulting from decreased osteoblastogenesis and increased osteoblast apoptosis (59, 60). Decreased osteoblastogenesis might be caused, in part, by excessive production of adipocytes at the expense of the production of osteoblasts (61). That shift may result from a switch in the fate of mesenchymal stem cells that can give rise to either cell type, as well as an increase in the apoptosis of osteoblast progenitors.
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OXIDATIVE STRESS ANTAGONIZES WNT SIGNALING BY DIVERTING ß-CATENIN FROM TCF- TO FOXO-MEDIATED TRANSCRIPTION IN BONE CELLS
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Activation of FOXO-mediated transcription by oxidative stress requires binding of FOXOs to ß-catenin (62), the protein that, as discussed above, is also required for the transcriptional activity of the TCF family of transcription factors (1, 63). We were intrigued by this and the evidence from our own laboratory that oxidative stress is a pivotal pathogenetic factor of age-related loss of bone mass and strength in mice, leading to, among other changes, a decrease in osteoblast number and bone formation (80). We, therefore, went on to test the hypothesis that induction of the FOXO transcription factors by ROS may antagonize Wnt signaling, an essential stimulus for osteoblastogenesis (98). In support of this hypothesis, we found that the expression of FOXO target genes increases, whereas the expression of Wnt target genes decreases, with increasing age in C57BL/6 mice. Moreover, we showed in osteoblastic cell models that 1) oxidative stress (exemplified by H2O2) promotes the association of FOXOs with ß-catenin; 2) ß-catenin is required for the stimulation of FOXO target genes by H2O2; and 3) H2O2 promotes FOXO-mediated transcription at the expense of Wnt-/TCF-mediated transcription and osteoblast differentiation. Furthermore, ß-catenin overexpression is sufficient to prevent FOXO-mediated suppression of TCF transcription. Hence, diversion of the limited pool of ß-catenin from TCF- to FOXO-mediated transcription in osteoblastic cells may account, at least in part, for the attenuation of osteoblastogenesis and bone formation by the age-dependent increase in oxidative stress. Moreover, diversion of ß-catenin from TCF to FOXO may play a role in the reciprocal increase in adipogenesis in the aging bone marrow, as well as the increase in osteoblast and osteocyte apoptosis.
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WNT SIGNALING, ß-CATENIN, GLUCOSE AND LIPID METABOLISM, HYPERTENSION, AND ATHEROSCLEROSIS
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Fascinatingly, it was elucidated very recently that, in addition to its role in bone homeostasis, Wnt/ß-catenin signaling plays a very profound role in atherosclerosis, as well as glucose and lipid metabolism. Indeed, a single missense mutation in LRP6, the coreceptor for the Wnt-signaling pathway, impaired Wnt signaling and had a very strong genetic linkage with early coronary artery disease (CAD) in a large Iranian family (64). Moreover, the LRP6 mutation was genetically linked with hyperlipidemia, hypertension, and diabetes, as well as osteoporosis. Interestingly, all the affected members had normal body mass index (BMI). TCF7L2, formerly and more commonly known as TCF4, is a transcription factor that partners with ß-catenin in the canonical Wnt-signaling pathway. A noncoding variant of the TCF7L2 gene has recently emerged as the strongest type 2 diabetes susceptibility gene to date, providing further evidence that the canonical Wnt-signaling pathway may also play a role in glucose homeostasis (65, 66, 67, 68).
In full support of the genetic evidence in humans, TCF4 and ß-catenin regulate glucagon-like peptide-1 secretion gene in mice (69). In addition to LRP6 and TCF7L2, overexpression of Wnt10b in two murine models of obesity with marked hyperinsulinemia and insulin resistance (the ob/ob and the lethal yellow agouti) results in improved glucose homeostasis due to improved insulin sensitivity along with a substantial decline in adipose mass (70). Moreover, in mice, Wnt signaling and ß-catenin are both necessary and sufficient for the proliferation of islet ß-cells (71), via a mechanism whereby Wnts promote the expression of Pitx 2, a direct target of Wnt signaling, and Cyclin D2. This effect leads to ß-cell expansion, increased insulin production and serum insulin levels, and enhanced glucose handling. Lastly, in male mice LRP5 is essential, not only for glucose-induced insulin secretion, but also for normal cholesterol metabolism (72).
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OXIDATIVE STRESS AND FOXOS IN THE PATHOGENESIS OF ATHEROSCLEROSIS AND DIABETES
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Oxidative stress plays a major role in the development of insulin resistance (73). In addition, the antioxidant NAC protects against diabetes in ZDF rats and db/db mice and preserves insulin content and insulin gene expression (74, 75). Moreover, both insulin resistance and atherosclerosis are prevented or retarded by overexpression of ROS scavenging enzymes such as SOD and catalase (73, 76). In addition, genetic deletion of p66shc prevents hyperglycemia-induced endothelial dysfunction (77).
Pancreatic ß-cells (and liver cells) express FOXOs, but the islet is the least well-endowed tissue in terms of intrinsic antioxidant enzyme expression (78). Importantly, in sharp contrast to the beneficial effects of the Wnt-LRP5/6-ß-catenin signaling on glucose and lipid metabolism, FOXOs appear to contribute to at least three critical pathogenetic processes for the development of type 2 diabetes and the metabolic syndrome: 1) impaired ß-cell compensation of insulin resistance; 2) increased hepatic glucose production; and 3) hyperlipidemia. Thus, insulin, glucagon-like peptide-1, or insulin growth factor signaling induces PI3/AKT activation and AKT-mediated phosphorylation and nuclear exclusion of FOXO1. Exclusion of FOXO1 is critical for the ability of insulin and the other growth factors to stimulate ß-cell proliferation and survival, and thereby expansion of ß-cell mass in the pancreas. Consistent with this, ablation of one allele of FOXO1 restores ß-cell proliferation in mice that lack the insulin receptor substrate 2 and suffer from ß-cell failure (79). As discussed in the previous section, the adverse effect of FOXO on ß-cell proliferation is in sharp contrast with the necessary and sufficient role of the Wnt-LRP5/6-ß-catenin signaling on ß-cell proliferation.
In contrast to insulin, ROS promote FOXO1 translocation into the nucleus of ß-cells by a mechanism that involves activation of JNK and the phosphorylation of FOXO in a site distinct from that activated by AKT. As in other cell types, the FOXO-orchestrated response to oxidative stress in pancreatic and liver cells aims to assist them to cope by undergoing cell cycle arrest, DNA damage repair, and resistance to apoptosis. Inexorably, however, this defensive maneuver also leads to insulin resistance. Specifically, JNK-induced phosphorylation by oxidative stress overrides the effects of AKT-induced FOXO phosphorylation, thereby providing a mechanism whereby oxidative stress decreases insulin sensitivity (49, 81). Consistent with this scenario, deletion of JNK through genetic knockouts or through a cell-permeable JNK-inhibitory peptide improves insulin sensitivity in mice (82, 83). The antagonism of insulin action by FOXO notwithstanding, with chronic oxidative stress and long-term hyperglycemia (the so-called glucose toxicity), the FOXO-orchestrated compensatory response is overwhelmed by ubiquitin-dependent degradation of FOXO1 by the proteasome, contributing to increased ß-cell apoptosis and decreased ß-cell mass. Long-term exposure to high glucose also decreases -glutamylcysteine ligase expression, and this causes a decrease in glutathione levels.
In agreement with the aforementioned evidence, haploinsufficiency of FOXO1 restores insulin sensitivity and rescues the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenetic genes and increasing adipocyte expression of insulin-sensitizing genes (84). On the other hand, a gain of function mutation of FOXO1 targeted to liver and pancreatic ß-cells results in diabetes arising from a combination of increased glucose production by the liver and impaired ß-cell compensation. Lastly, overexpression of FOXO1 in skeletal muscles reduces muscle mass and impairs glycemic control after oral glucose or ip insulin administration (85).
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CONCLUDING THOUGHTS AND A WORKING HYPOTHESIS
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Fairly recent evidence reviewed in this article indicates that canonical Wnt/ß-catenin/TCF-mediated gene transcription promotes the accrual of bone mass and favors improved insulin/glucose and lipid homeostasis. Conversely, FOXO-mediated transcription has adverse effects on all these areas of metabolism favoring the development of diseases such as osteoporosis, type 1 and type 2 diabetes, hyperlipidemia, hypertension, and CAD. For such diverse and seemingly unrelated diseases, attenuation of Wnt/ß-catenin-mediated transcription as a common pathogenetic mechanism is remarkable and certainly unexpected. Nonetheless, the recent report by Mani et al. (64) leaves little doubt that a single genetic defect in signaling downstream of LRP6 can indeed be sufficient for the development of all these diseases in one person. Is it possible that beyond the rare genetic abnormalities of Wnt/ß-catenin/TCF, the development of the acquired forms of these common and multifactorial diseases of old age share attenuation of Wnt/ß-catenin/TCF signaling as a common pathogenetic mechanism?
During the last few years, considerable epidemiological evidence, including an association between angiographically documented CAD and low bone mineral density (BMD), has strongly suggested a mechanistic association between osteoporosis and atherosclerosis (86, 87, 88). Likewise, it has been long appreciated that type 1 diabetics have decreased bone mass (89). Furthermore, in older men and women, the metabolic syndrome is associated with low BMD and osteoporotic nonvertebral fractures, but only after adjusting for BMI (90). The genetic studies of Mani et al. strongly suggest that attenuation of Wnt signaling may be one common underlying mechanism accounting for all these associations. Type 2 diabetics, however, have increased BMD relative to nondiabetic age-matched controls (91, 92, 93, 94). The difference in BMD between type 1 and type 2 diabetics is thought to be due to the difference in weight, perhaps along with increased production of sex steroids in the latter (which protect against bone loss) because of the excess adipose tissue usually associated with insulin resistance (91). Be that as it may, in the largest meta-analysis of 60,000 randomly selected subjects from several different countries low BMI was one of the strongest predictors of low BMD and fracture risk, particularly of the hip, in women and men alike, suggesting a strong effect of mechanical load on weight-bearing bones (95, 96), whereas a high BMI appeared to be protective. Moreover, despite higher baseline BMD, elderly type 2 diabetics have more rapid bone loss at the femoral neck than nondiabetics, and this is partly accounted for by a greater weight loss (97).
We have discussed evidence from our work suggesting that indeed diversion of ß-catenin from TCF- to FOXO-mediated transcription is a potential mechanism for age-related bone loss in mice; and that aging and the associated increase in oxidative stress may contribute to this diversion, and thereby to loss of bone mass and strength. We have also discussed evidence that FOXOs contribute to the development of diabetes and the metabolic syndrome, whereas antioxidants, such as NAC, are surprisingly effective against the development of both bone loss and diabetes in animal models. Putting it all together, it is very tempting to speculate that antagonism of Wnt signaling by oxidative stress with increasing age may by a common mechanism that contributes to the development not only of involutional osteoporosis, but other diseases such as insulin resistance, hyperlipidemia, and CAD, all of which are far more prevalent with advancing age. If that were the case, one is tempted to speculate further that development of more effective antioxidants or drugs targeted to potentiate Wnt signaling may be pharmacotherapeutic strategies for several diseases associated with old age. Most remarkably, increased Wnt/ß-catenin signaling is a normal physiological response to mechanical loading in bone (24). However, there is no reason to expect that mechanical loading should have an impact on Wnt signaling in the organs involved in insulin production and glucose homeostasis. Hence, we suspect that a differential response to mechanical loading of the Wnt/ß-catenin signaling in bone vs. tissues involved in glucose homeostasis may account, at least in part, for the paradox that BMD is increased with insulin resistance and obesity, but decreased in lean diabetics or in nonobese patients with metabolic syndrome (64, 90).
In closing, we have pointed out elsewhere (98) that it is somewhat ironic that the adverse effects of aging on bone may be mediated by the attenuation of the same factors (Wnt/ß-catenin) used to build the skeleton during development and growth. It now seems likely that with advancing age and the associated increase in oxidative stress, homeostatic mechanisms of not only bone, but also glucose and lipid metabolism, are "gone [astray] with the Wnts."
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ACKNOWLEDGMENTS
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We wish to thank several members of the Faculty of the Division of Endocrinology and Metabolism, in particular Steven Elbein, M.D., Neda Rasouli, M.D., Phil Kern, M.D., Robert Jilka, Ph.D., Teresita Bellido, Ph.D., Charles O’Brien, Ph.D., Lilian Plotkin, Ph.D., and Robert Weinstein, M.D., for helpful discussions of the ideas presented in this minireview and for critiquing it. We also thank Robyn DeWall for assistance in the preparation of the manuscript.
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FOOTNOTES
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This work was supported by the National Institutes of Health (Grants P01AG13918 and R01AR51187), the Department of Veterans Affairs (Veterans Affairs Merit Review Grant and a Research Enhancement Award Program), and Tobacco Settlement funds provided by the University of Arkansas for Medical Sciences College of Medicine.
Disclosure Statement: The authors have nothing to disclose.
First Published Online July 10, 2007
Abbreviations: BMD, Bone mineral density; BMI, body mass index; CAD, coronary artery disease; FOXO, forkhead box O; fz, frizzled; GSK-3ß, glycogen synthase kinase 3ß; JNK, c-Jun N-terminal kinase; LEF, lymphoid-enhancer binding factor; LRP, low density lipoprotein receptor-related protein; NAC, N-acetyl cysteine; ROS, reactive oxygen species; SFRP, secreted fz-related protein; Sost, sclerostin; TCF, T-cell factor.
Received for publication May 17, 2007.
Accepted for publication June 29, 2007.
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ABSTRACT
INTRODUCTION
