Gone with the Wnts: β-Catenin, T-Cell Factor, Forkhead Box O, and Oxidative Stress in Age-Dependent Diseases of Bone, Lipid, and Glucose Metabolism

Abstract

The Wnt/beta-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. beta-Catenin mediates canonical Wnt signaling by binding to and activating members of the T-cell factor (TCF) transcription factor family. Similar to the Wnt/beta-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. beta-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 beta-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/beta-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.

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…We found elevated sclerostin in serum, and decreased activated b-catenin in STZ mice, consistent with other reports of diabetic animals and patients with elevated Sclerostin levels [50,51,138,162]. While we did find elevated bcatenin in antibody-treated groups, consistent with elevated Wnt signaling and promotion of osteogenesis, we also saw an unexpected and very highly elevated level of sclerostin protein in the bone and blood of antibody-treated animals.…”

“…Reduced Wnt signaling and increased Wnt antagonism have been associated with increased oxidative stress, and reduced osteoblast activity [50,162,163]. Oxidative stress activates FOXO signaling, which competes for b-catenin in the cell, to reduce activation of Wnt target genes.…”

“…Activation of Wnt signaling activates the Akt/PKB pathway; PKB then phosphorylates and sequesters FOXO in the cytoplasm, and prevents it from competing with b-catenin [164]. As Sost is an antagonist of b-catenin-mediated Wnt signaling, reduction of bioactive SOST through SostAb treatment activates b-catenin signaling, potentially mitigating the effects of oxidative stress and competition by activated FOXO [162]. Thus, Wnt signaling may be suppressed by a mechanism that is independent of Sost, but can be mitigated by promoting Wnt signaling through inhibition of Sost.…”

Circulating microRNA signature of genotype‐by‐age interactions in the long‐lived Ames dwarf mouse

“…Moreover, overexpression of FoxO1 in skeletal muscle reduced muscle mass and impaired glycemic control (Kamei et al ., 2004). Furthermore, FoxOs appear to contribute to impaired β‐cell compensation of insulin resistance, increased hepatic glucose production, and hyperlipidemia, which are critical pathogenic processes conducing to type 2 diabetes and metabolic syndrome (Manolagas & Almeida, 2007). Mounting evidence including the rescue of insulin sensitivity on FoxO1 haploinsufficient mice and the induction of diabetes in FoxO1 gain‐of‐function mutant mouse shed light on these pathogenetic roles of FoxO proteins (Nakae et al ., 2002).…”

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

“…In addition, Wnt signaling promotes osteoblast survival (41) and interacts with bone morphogenetic protein 2 (BMP2) (42) and PTH signaling (43) to increase osteoblastogenesis. Also, changes in Wnt signaling contribute to age-related bone loss in mice (44). Mechanical loading upregulates Wnt signaling in MSC (45), suggesting that the combination of reduced b-catenin signaling and decreased mechanical stimulation with age may contribute to the age-related decline in bone formation.…”