Loss of wnt/β-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes

Song, Lun; Liu, Minlin; Ono, Noriaki; Bringhurst, F. Richard; Kronenberg, Henry M.; Guo, Jun

doi:10.1002/jbmr.1694

Cited by 215 publications

(201 citation statements)

References 41 publications

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“…Wnt stimulation, ␤-catenin overexpression, or expression of Lrp5 G171V increased oxidation and gene expression. These data indicate that lipid metabolism is pos-itively correlated with the level of signaling through Lrp5 and accord with the influence of Wnt-Lrp5 signaling on osteoblast differentiation and bone matrix mineralization (6,61,62). In addition, they suggest that the disturbances in bone architecture and whole-body metabolism arising in humans from mutations in LRP5 may be linked.…”

Section: Discussionsupporting

confidence: 60%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

131

104

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fThe Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of ␤-catenin and thereby induce the expression of key enzymes required for fatty acid ␤-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism. Wnt signaling regulates nearly all aspects of osteoblast function, from initial fate specification (1) to the control of osteoclast differentiation (2). In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3, 4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5-7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9, 10) likely due to an increase in the number of mineralizing osteoblasts (11).Like other metabolically active cells, osteoblasts require a supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix (12). When energy input fails to meet demand, normal bone accrual ceases, a phenomenon that is evident clinically by the arrest of longitudinal bone growth and osteopenia observed in undernourished children and adults (13, 14). Therefore, osteoblasts must possess mechanisms to acquire and regulate the utilization of fuel macromolecules, as well as the ability to communicate energy needs with other tissues.Recent studies have delineated a role for the osteoblast in a bone-pancreas endocrine loop that contributes to the regulation of glucose metabolism, as well as bone acquisition. Insulin receptor signaling in the osteoblast regulates the activity of the osteogenic transcription factor Runx2 and is required for the attainment of a mature phenotype as well as normal postnatal bone acquisition (15). In addition, insulin actions regulate the production and bioavailability of osteocalcin (15, 16), a bone-derived hormone that in ...

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Section: Discussionsupporting

confidence: 60%

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

Frey

Ellis

et al. 2015

Molecular and Cellular Biology

131

104

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“…Intriguingly, if Dox was given until 2 or 4 months post-natally, there was a dramatic loss of trabecular bone with a concomitant increase in bone marrow adiposity. Additionally, ex vivo analyses revealed enhanced adipocyte differentiation of adult BMSCs in culture, suggesting that β-catenin suppresses adipogenesis (150). Genetic deletion of Cnntb1 within mature osteoblasts (using Ocn-Cre) results in dramatic reductions in trabecular and cortical bone mass due to defective osteoblast differentiation (62,134).…”

Section: Glycogen Synthase Kinasementioning

confidence: 99%

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

2013

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The Wnt signaling pathway plays key roles in differentiation and development and alterations in this signaling pathway are causally associated with numerous human diseases. While several laboratories were examining roles for Wnt signaling in skeletal development during the 1990s, interest in the pathway rose exponentially when three key papers were published in 2001-2002. One report found that loss of the Wnt co-receptor, Low-density lipoprotein related protein-5 (LRP5), was the underlying genetic cause of the syndrome Osteoporosis pseudoglioma (OPPG). OPPG is characterized by early-onset osteoporosis causing increased susceptibility to debilitating fractures. Shortly thereafter, two groups reported that individuals carrying a specific point mutation in LRP5 (G171V) develop high-bone mass. Subsequent to this, the causative mechanisms for these observations heightened the need to understand the mechanisms by which Wnt signaling controlled bone development and homeostasis and encouraged significant investment from biotechnology and pharmaceutical companies to develop methods to activate Wnt signaling to increase bone mass to treat osteoporosis and other bone disease. In this review, we will briefly summarize the cellular mechanisms underlying Wnt signaling and discuss the observations related to OPPG and the high-bone mass disorders that heightened the appreciation of the role of Wnt signaling in normal bone development and homeostasis. We will then present a comprehensive overview of the core components of the pathway with an emphasis on the phenotypes associated with mice carrying genetically engineered mutations in these genes and clinical observations that further link alterations in the pathway to changes in human bone. Keywords: Wnt signaling; mouse models; Lrp5/Lrp6; β-catenin; skeletal phenotypes Bone Research (2013) 1: 27-71. doi: 10.4248/BR201301004 Overview of Wnt signal transductionWnts are a family of 19 mammalian proteins characterized by a conserved pattern of cysteine residues( 1). Wnts can activate several signaling pathways after binding to their cognate receptors, however, the bulk of this review will focus on the best characterized of these pathways, the so-called canonical pathway (Figure 1). This pathway results in the stabilization of the β-catenin protein and subsequent transactivation of target genes (2). It is initiated by Wnt ligands binding to a receptor complex that includes a member of the Frizzled (Fzd) family of seven-transmembrane receptors and either Lrp5, or the related Lrp6 protein(3). Engagement of this complex results in the phosphorylation of the cytoplasmic domain of Lrp5 or Lrp6, creating a binding site for the Axin protein.In the absence of an upstreamsignal, Axin exists in a multiprotein complex that also includes Adenomatous polyposis coli (APC) and the serine/ threonine protein kinase, Glycogen synthase kinase 3 α/β. This complex facilitates β-catenin for GSK3-dependent phosphorylation, targeting it for ubiquitin-depen- 28 dent proteolysis. Binding of Axin to phosphoryl...

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“…52,53 Shifts in the expression or function of these and other effectors disrupt the homeostatic balance between adipogenic and osteogenic differentiation of MPCs. [54][55][56][57][58][59] While the general consensus is that diabetic hyperglycemia is associated with increased adipogenesis in the marrow, inhibition of fat cell formation and promotion of osteoblastic differentiation following the administration of exogenous glucose has also been reported. 60, 61 Shilpa and colleagues found that culturing 3T3-L1 preadipocytes in extremely high glucose levels of 105 mM resulted in diminished adipogenesis, with downregulation of PPARg and C/EBPa relative to cells cultured in 25 mM glucose concentration.…”

Section: Mechanisms Of Enhanced Marrow Adipogenesis In Diabetesmentioning

confidence: 99%

“…139 Conversely, deletion of b-catenin in osterix-expressing cells (early osteoblast lineage) leads to a striking reduction in bone mass and an increase in bone marrow adiposity. 141 These studies suggest that one mechanism of diabetic bone phenotype may be depletion of available progenitor cells through commitment to one lineage. However, treatment of diabetic mice with the PPARg antagonist bisphenol-A-diglycidyl ether (BADGE) inhibits adipogenesis without suppression of osteoblast markers and consequent bone loss.…”

Section: Diabetic Medicationsmentioning

confidence: 99%