Journal ArticleDOI
Orally Bioavailable GSK-3α/β Dual Inhibitor Increases Markers of Cellular Differentiation In Vitro and Bone Mass In Vivo
N.H. Kulkarni,Jude E. Onyia,Qingqiang Zeng,Xioayan Tian,Min Liu,David L. Halladay,Charles A. Frolik,Thomas A. Engler,Tao Wei,Aidas Kriauciunas,T. John Martin,Masahiko Sato,Henry Uhlman Bryant,Yanfei L. Ma +13 more
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TLDR
The effect of a small molecule GSK‐3 inhibitor was evaluated in pre‐osteoblasts and in osteopenic rats with concomitant increased bone mass and strength in rats.Abstract:
UNLABELLED: GSK-3, a component of the canonical Wnt signaling pathway, is implicated in regulation of bone mass. The effect of a small molecule GSK-3 inhibitor was evaluated in pre-osteoblasts and in osteopenic rats. GSK-3 inhibitor induced osteoblast differentiation in vitro and increased markers of bone formation in vitro and in vivo with concomitant increased bone mass and strength in rats. INTRODUCTION: Inactivation of glycogen synthase kinase -3 (GSK-3) leads to stabilization, accumulation, and translocation of beta-catenin into the nucleus to activate downstream Wnt target genes. To examine whether GSK-3 directly regulates bone formation and mass we evaluated the effect of 603281-31-8, a small molecule GSK-3 alpha/beta dual inhibitor in preosteoblastic cells and in osteopenic rats. MATERIALS AND METHODS: Murine mesenchymal C3H10T1/2 cells were treated with GSK-3 inhibitor (603281-31-8) and assayed for beta-catenin levels, activity of Wnt-responsive promoter, expression of mRNA for bone formation, and adipogenic markers and alkaline phosphatase activity. In vivo, 6-month-old rats were ovariectomized (OVX), allowed to lose bone for 1 month, and treated with GSK-3 inhibitor at 3 mg/kg/day orally for 60 days. At the end of treatment, BMD was measured by DXA, bone formation rate by histomorphometry, vertebral strength (failure in compression), and the expression levels of osteoblast-related genes by real-time PCR. RESULTS: Treatment of C3H10T1/2 cells with the GSK-3 inhibitor increased the levels of beta-catenin accompanied by activation of Wnt-responsive TBE6-luciferase reporter gene. This was associated with an increased expression of mRNA for bone sialoprotein (1.4-fold), collagen alpha1 (I) (approximately 2-fold), osteocalcin (1.2-fold), collagen alpha1(V) (1.5-fold), alkaline phosphatase (approximately 160-fold), and runx2 (1.6-fold), markers of the osteoblast phenotype and bone formation activity. Alkaline phosphatase mRNA expression paralleled alkaline phosphatase activity. The mRNA levels of collagens alpha1 (I), alpha1 (V), biglycan, osteonectin, and runx-2 increased on treatment with the GSK-3 inhibitor in rat femur compared with the OVX control. DXA analyses revealed significant increases in BMC and BMD in cancellous and cortical bone of OVX rats treated with GSK-3 inhibitor. This was associated with increased strength (peak load, energy, and stiffness) assessed by lumbar vertebra load to failure in compression. Histomorphometric analyses showed that 603281-31-8 robustly increased bone formation but did not exclude a small effect on osteoclasts (resorption). CONCLUSIONS: An orally active, small molecule GSK-3 inhibitor induced osteoblast differentiation and increased markers of bone formation in vitro, and increased markers of bone formation, bone mass, and strength in vivo, consistent with a role for the canonical Wnt pathway in osteogenesis.read more
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WNT signaling in bone homeostasis and disease: from human mutations to treatments
Roland Baron,Michaela Kneissel +1 more
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Roland Baron,Georges Rawadi +1 more
TL;DR: The recent identification of a link between bone mass in humans and gain- or loss-of-function mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 or sclerostin has called the attention of academic and industry scientists and clinicians to the importance of this signaling pathway in skeletal biology and disease.
Journal ArticleDOI
Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma
Mariateresa Fulciniti,Pierfrancesco Tassone,Teru Hideshima,Sonia Vallet,Puru Nanjappa,Seth Ettenberg,Zhenxin Shen,Nipun Patel,Yu-Tzu Tai,Dharminder Chauhan,Constantine S. Mitsiades,Rao Prabhala,Noopur Raje,Kenneth C. Anderson,David R. Stover,Nikhil C. Munshi,Nikhil C. Munshi +16 more
TL;DR: DKK1 is confirmed as an important therapeutic target in myeloma and the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth is provided.
References
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A. Michael Parfitt,Marc K. Drezner,Francis H. Glorieux,John A. Kanis,Hartmut H. Malluche,Pierre J. Meunier,Susan M. Ott,Robert R. Recker +7 more
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Journal Article
Bone Histomorphometry : Standardization of Nomenclature, Symbols, and Units
A. M. Parfitt,Marc K. Drezner,Francis H. Glorieux,John A. Kanis,Hartmut H. Malluche,P. J. Meunier,Susan M. Ott,Robert R. Recker +7 more
Journal ArticleDOI
LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development
Yaoqin Gong,R. B. Slee,Naomi Fukai,Georges Rawadi,Sergio Roman-Roman,Anthony M. Reginato,H. W. Wang,Tim Cundy,Francis H. Glorieux,Dorit Lev,M. Zacharin,Konrad Oexle,Jose Marcelino,Wafaa M. Suwairi,Shauna Heeger,G. Sabatakos,Suneel S. Apte,W. N. Adkins,J. Allgrove,M. Arslan-Kirchner,J. A. Batch,Peter Beighton,Graeme C.M. Black,R. G. Boles,L. M. Boon,C. Borrone,Han G. Brunner,G. F. Carle,Bruno Dallapiccola,A. De Paepe,B. Floege,M. L. Halfhide,Barbara Hall,Raoul C.M. Hennekam,Tatsuo Hirose,A. Jans,Harald Jüppner,Chong Ae Kim,K. Keppler-Noreuil,A. Kohlschuetter,Didier Lacombe,M. Lambert,E. Lemyre,T. Letteboer,Leena Peltonen,Rajkumar Ramesar,M. Romanengo,H. Somer,E. Steichen-Gersdorf,Beat Steinmann,Beth A. Sullivan,Andrea Superti-Furga,W. Swoboda,M. J. van den Boogaard,W. Van Hul,Miikka Vikkula,Marcela Votruba,Bernhard Zabel,Teresa Garcia,Roland Baron,Bjorn R. Olsen,Matthew L. Warman +61 more
TL;DR: It is reported that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth and is important for the establishment of peak bone mass.
Journal ArticleDOI
Mechanisms of wnt signaling in development
Andreas Wodarz,Roel Nusse +1 more
TL;DR: Over the past two years the understanding of Wnt signaling has been substantially improved by the identification of Frizzled proteins as cell surface receptors for Wnts and by the finding that beta-catenin, a component downstream of the receptor, can translocate to the nucleus and function as a transcriptional activator.
Journal ArticleDOI
High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5
Lynn M. Boyden,Junhao Mao,Joseph L. Belsky,Lyle Mitzner,Anita Farhi,Mary Ann Mitnick,Dianqing Wu,Karl L. Insogna,Richard P. Lifton +8 more
TL;DR: The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling.
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