Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis

Takada, Ichiro; Kouzmenko, Alexander; Kato, Shigeaki

doi:10.1038/nrrheum.2009.137

Cited by 437 publications

(353 citation statements)

References 40 publications

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“…12,57 Importantly, increased PPARg expression antagonizes Runx2, which in turn inhibits the osteogenic differentiation of mesenchymal progenitor cells, resulting in inconsistent bone formation. 31,57,58 NELL-1 can function as a downstream mediator of Runx2 because NELL1 expression is directly regulated by Runx2 binding to its promoter region 59 and Nell1 overexpression can partially rescue Runx2 haploinsufficiency. 8 In addition, NELL-1 regulates Runx2 bioactivity by enhancing its phosphorylation.…”

Section: Proposed Molecular Mechanisms Of Nell-1 and Bmp2 Effects Onmentioning

confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

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Section: Proposed Molecular Mechanisms Of Nell-1 and Bmp2 Effects Onmentioning

confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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“…We also found aberrantly up-regulated expression of Wnt-5a in human prostate tumors. Wnt-5a is a noncanonical Wnt ligand involved in cell proliferation and differentiation, particularly during embryonic development (34,44,45).…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer

Takahashi

Watanabe

Okada

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in prostatic epithelial cells through Cre-ER T2 -mediated targeted somatic mutagenesis. Such AR point mutant mice (AR pe-T877A/Y ) developed hypertrophic prostates with responses to both an androgen antagonist and estrogen, although no prostatic tumor was seen. In prostate cancer model transgenic mice, the onset of prostatic tumorigenesis as well as tumor growth was significantly potentiated by introduction of the AR T877A mutation into the prostate. Genetic screening of mice identified Wnt-5a as an activator. Enhanced Wnt-5a expression was detected in the malignant prostate tumors of patients, whereas in benign prostatic hyperplasia such aberrant up-regulation was not obvious. These findings suggest that a noncanonical Wnt signal stimulates development of prostatic tumors with AR hyperfunction.antiandrogen | hormone-refractory state | TRAMP

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“…Activation of the Wnt/beta-catenin signaling leads to osteogenesis, but not to adipogenesis. The canonical Wnt/beta-catenin-PPAR gamma system regulates the molecular switching of osteablastogenesis versus adipogenesis [6]. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of both adipogenic transcription factors C/EBP alpha and PPAR gamma.…”

Section: Deactivation Of the Wnt/beta-catenin Pathway Induces Activatmentioning

confidence: 99%

“…Two major systems play a key role in the pathophysiology of NDs, i.e., the canonical Wnt/betacatenin pathway and PPAR gamma. Several studies have demonstrated the opposite interaction between the canonical Wnt/beta-catenin pathway and the PPAR gamma [1][2][3][4][5][6][7]. It has recently been shown that certain NDs can be divided into two classes [8]: on one hand, NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated.…”

Section: Introductionmentioning

confidence: 99%

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

Lecarpentier¹,

Vallée²

2016

Update on Amyotrophic Lateral Sclerosis

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Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset debilitating neurodegenerative diseases (NDs) which is characterized by a chronic progressive degeneration of upper and lower motor neurons, resulting in muscular atrophy, paralysis and ultimately death. It has been established that in ALS, the canonical Wnt/ beta-catenin pathway is upregulated. Peroxisome proliferator-activated receptor gamma (PPAR gamma) generally varies in opposite way compared with the Wnt/betacatenin signaling. Several studies carried out on ALS transgenic mice have shown the beneficial effects induced after treatment by PPAR agonists partly due to antiinflammatory effects induced by PPAR gamma. The coupling between the Wnt/betacatenin signaling and PPAR gamma has led to divide NDs into two classes: NDs in which the Wnt/beta-catenin pathway is upregulated whereas PPAR gamma is downregulated (ALS, Parkinson's disease, Huntington's disease and Friedreich's ataxia); and NDs in which the Wnt-beta-catenin pathway is downregulated while PPAR gamma is upregulated (Alzheimer's disease, bipolar disorder and schizophrenia).

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Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis

Cited by 437 publications

References 40 publications

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer

Amyotrophic Lateral Sclerosis: Role of the Canonical Wnt/Beta- Catenin Pathway and PPAR Gamma

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