GSK-3 inhibition by an orally active small molecule increases bone mass in rats

Marsell, Richard; Sisask, Gregor; Nilsson, Yvonne; Sundgren‐Andersson, Anna K.; Andersson, Ulf; Larsson, Sune; Nilsson, Olle; Ljunggren, Östen; Jonsson, Kenneth B.

doi:10.1016/j.bone.2011.11.007

Cited by 57 publications

(44 citation statements)

References 28 publications

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“…Similar results were observed with CA-β-catenin mice [23]. However, oral administration of AZD2858, a GSK-3 inhibitor, had no influence on the number of osteoclasts in mice [22]. Glass and colleagues suggested this difference might be caused by the fact that Wnt/β-catenin signaling in osteoblasts at different stages has variable effects on osteoclastogenesis [23].…”

Section: Discussionmentioning

confidence: 53%

“…However, controversies exist regarding the role of the Wnt/β-catenin signaling pathway in osteoblastogenesis and osteoclastogenesis [22-26]. Using a mouse model with a Lrp6rs/rs mutation, Kubota et al showed that mutant mice have low bone mass, owing to accelerated bone resorption [11].…”

Section: Discussionmentioning

confidence: 99%

“…Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism [19]. Moreover, oral administration of different types of GSK-3 inhibitors leads to increased bone formation [20,22]. Recently it was shown by Chen and colleagues that deletion of β-catenin in osteoblasts greatly reduced bone formation activity and indirectly increased osteoclast number and activity [36].…”

Section: Discussionmentioning

confidence: 99%

“…Enhanced Wnt/β-catenin signaling or deficiency/neutralization of Wnt antagonists is associated with increased bone formation and/or decreased bone resorption, suggesting potential therapeutic application in low bone volume conditions [15-22]. However, controversies exist with regard to several issues, including safety, dosage, duration of treatment, and mechanisms of intervention on osteoblastogenesis and osteoclastogenesis [22-26]. To date, there have been no data demonstrating the effects of Wnt/β-catenin signaling pathway on bone growth and remodeling at different postnatal stages.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Constitutive β-Catenin Activation on Vertebral Bone Growth and Remodeling at Different Postnatal Stages in Mice

et al. 2013

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Background and ObjectiveThe Wnt/β-catenin signaling pathway is essential for controlling bone mass; however, little is known about the variable effects of the constitutive activation of β-catenin (CA-β-catenin) on bone growth and remodeling at different postnatal stages. The goal of the present study was to observe the effects of CA-β-catenin on vertebral bone growth and remodeling in mice at different postnatal stages. In particular, special attention was paid to whether CA-β-catenin has detrimental effects on these processes.MethodsCatnblox(ex 3) mice were crossed with mice expressing the TM-inducible Cre fusion protein, which could be activated at designated time points via injection of tamoxifen. β-catenin was stabilized by tamoxifen injection 3 days, and 2, 4, 5, and 7 months after birth, and the effects lasted for one month. Radiographic imaging, micro-computed tomography, immunohistochemistry, and safranin O and tartrate-resistant acid phosphatase staining were employed to observe the effects of CA-β-catenin on vertebral bone growth and remodeling.ResultsCA-β-catenin in both early (3 days after birth) and late stages (2, 4, 5, and 7 months after birth) increased bone formation and decreased bone resorption, which together increased vertebral bone volume. However, when β-catenin was stabilized in the early stage, vertebral linear growth was retarded, and the mice demonstrated shorter statures. In addition, the newly formed bone was mainly immature and located close to the growth plate. In contrast, when β-catenin was stabilized in the late stage, vertebral linear growth was unaffected, and the newly formed bone was mainly mature and evenly distributed throughout the vertebral body.ConclusionsCA-β-catenin in both early and late stages of growth can increase vertebral bone volume, but β-catenin has differential effects on vertebral growth and remodeling when activated at different postnatal stages.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Constitutive β-Catenin Activation on Vertebral Bone Growth and Remodeling at Different Postnatal Stages in Mice

et al. 2013

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“…More than 50 GSK-3 inhibitors have been described including: lithium [300], AR-A014418 (beta, IC 50 =104 nM) [301], AZD1080 (alpha & beta, orally active, brain permeable, with K i s of 6.9 nM and 31 nM respectively) [302], AZD2858 (alpha & beta IC 50 s of 68 nM) [303], BIO (alpha & beta IC50 of 5 nM) [304], CHIR-99021 (alpha & beta, IC 50 s of 10 nM/6.7 nM) [305], CHIR-98014 (alpha & beta, IC 50 of 0.65) [306], LY2090314 (alpha & beta, IC 50 s of 1.5 nM and 0.9 nM respectively) [307], SB-216763 (alpha & beta, IC 50 s of 34.3 nM) [308, 309], SB-415286 (alpha & beta IC 50 s of 78 nM and 31 nM respectively) [310, 311], TDZD-8 (beta, IC 50 of 2 microM [312] and TWS119 (beta, IC 50 s of 30 nM) [313]. Most GSK-3 inhibitors are ATP-competitive and do not differentiate between either GSK-3alpha or GSK-3beta [28].…”

Section: Gsk-3 Inhibitorsmentioning

confidence: 99%

GSK-3 as potential target for therapeutic intervention in cancer

et al. 2014

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The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.

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Therapeutic Targetingof the Wnt Signaling Network

Rudge

Dale

2014

WNT Signaling in Development and Disease

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GSK-3 inhibition by an orally active small molecule increases bone mass in rats

Cited by 57 publications

References 28 publications

Effects of Constitutive β-Catenin Activation on Vertebral Bone Growth and Remodeling at Different Postnatal Stages in Mice

Effects of Constitutive β-Catenin Activation on Vertebral Bone Growth and Remodeling at Different Postnatal Stages in Mice

GSK-3 as potential target for therapeutic intervention in cancer

Therapeutic Targetingof the Wnt Signaling Network

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