A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation

Bodine, Peter V.N.; Stauffer, Barbara; Ponce-de-Leon, Helga; Bhat, Ramesh A.; Mangine, Annamarie; Seestaller-Wehr, Laura; Moran, Robert A.; Billiard, Julia; Fukayama, Shoichi; Komm, Barry S.; Pitts, Keith; Krishnamurthy, Girija; Gopalsamy, Ariamala; Shi, Mengxiao; Kern, Jeffrey C.; Commons, Thomas J.; Woodworth, Richard P.; Wilson, Matthew A.; Welmaker, Gregory S.; Trybulski, Eugene J.; Moore, William

doi:10.1016/j.bone.2009.02.013

Cited by 113 publications

(86 citation statements)

References 44 publications

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“…These in vivo studies have suggested the possibility of osteoporosis treatment by targeting sclerostin. The deletion of sFRP-1 led to an increase in trabecular but not cortical bone formation in adult mice, and a small molecular inhibitor of sFRP-1 was reported to stimulate bone formation [49,50]. Therefore, sFRP-1 may be another potential target for developing anabolic agents.…”

Section: Wnt and Wnt Antagonistsmentioning

confidence: 99%

Osteoblastogenesis regulation signals in bone remodeling

et al. 2012

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Bone remodeling is essential for adult bone homeostasis. The failure of this process often leads to the development of osteoporosis, a present major global health concern. The most important factor that affects normal bone remodeling is the tightly controlled and orchestrated regulation of osteoblasts and osteoclasts. The present review summarized the recent discoveries related to osteoblast regulation from several signals, including transforming growth factor-β, bone morphogenetic proteins, Wnt signal, Notch, Eph-Ephrin interaction, parathyroid hormone/parathyroid hormone-related peptide, and the leptin-serotonin-sympathetic nervous systemic pathway. The awareness of these mechanisms will facilitate further research that explores bone remodeling and osteoporosis. Future investigations on the endogenous regulation of osteoblastogenesis will increase the current knowledge required for the development of potential drug targets in the treatment of osteoporosis.

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Section: Wnt and Wnt Antagonistsmentioning

confidence: 99%

Osteoblastogenesis regulation signals in bone remodeling

et al. 2012

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“…Published inhibitory drugs that interact with biotargets directly associated with canonical Wnt signaling include WAY-316606 for SFRP (26), niclosamide for frizzled (27), NCS668036 for Dsh (28), pyrvinium for CK1 (24), XAV939 and IWR-1 for TNKS1/2 (4, 22), 2,4-diaminoquinazoline, quercetin, PKF115-584 and ICG-001 for b-catenin and its binding to TCF or CREB (29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

Waaler

Machoň

Tůmová³

et al. 2012

Cancer Research

302

267

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Increased nuclear accumulation of b-catenin, a mediator of canonical Wnt signaling, is found in numerous tumors and is frequently associated with tumor progression and metastasis. Inhibition of Wnt/b-catenin signaling therefore is an attractive strategy for anticancer drugs. In this study, we have identified a novel small molecule inhibitor of the b-catenin signaling pathway, JW55, that functions via inhibition of the PARP domain of tankyrase 1 and tankyrase 2 (TNKS1/2), regulators of the b-catenin destruction complex. Inhibition of TNKS1/2 poly(ADP-ribosyl)ation activity by JW55 led to stabilization of AXIN2, a member of the b-catenin destruction complex, followed by increased degradation of b-catenin. In a dose-dependent manner, JW55 inhibited canonical Wnt signaling in colon carcinoma cells that contained mutations in either the APC (adenomatous polyposis coli) locus or in an allele of b-catenin. In addition, JW55 reduced XWnt8-induced axis duplication in Xenopus embryos and tamoxifen-induced polyposis formation in conditional APC mutant mice. Together, our findings provide a novel chemotype for targeting canonical Wnt/b-catenin signaling through inhibiting the PARP domain of TNKS1/2. Cancer Res; 72(11); 2822-32. Ó2012 AACR.

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“…By screening multiple compounds, one group has identified a compound, diphenylsulfonyl sulfonamide, which inhibits SFRP-1 activity and induces bone formation ex vivo [Bodine et al 2009; …”

Section: Targeting the Extracellular Antagonistsmentioning

confidence: 99%

Wnt signaling in bone formation and its therapeutic potential for bone diseases

Kim

Liu

Wang

et al. 2013

Therapeutic Advances in Musculoskeletal

300

239

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Abstract:The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.

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A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation

Cited by 113 publications

References 44 publications

Osteoblastogenesis regulation signals in bone remodeling

Osteoblastogenesis regulation signals in bone remodeling

A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice

Wnt signaling in bone formation and its therapeutic potential for bone diseases

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