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Ghania Ramdani Department of Medicine, University of California, San Diego, La Jolla, California, USA

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Nadine Schall Department of Medicine, University of California, San Diego, La Jolla, California, USA
The Institute for Pharmacology and Toxicology, University of Bonn, Bonn, Germany

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Hema Kalyanaraman Department of Medicine, University of California, San Diego, La Jolla, California, USA

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Nisreen Wahwah Department of Medicine, University of California, San Diego, La Jolla, California, USA

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Sahar Moheize Department of Medicine, University of California, San Diego, La Jolla, California, USA

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Jenna J Lee Department of Bioengineering, University of California, San Diego, La Jolla, California, USA

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Robert L Sah Department of Bioengineering, University of California, San Diego, La Jolla, California, USA

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Alexander Pfeifer The Institute for Pharmacology and Toxicology, University of Bonn, Bonn, Germany

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Darren E Casteel Department of Medicine, University of California, San Diego, La Jolla, California, USA

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Renate B Pilz Department of Medicine, University of California, San Diego, La Jolla, California, USA

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NO/cGMP signaling is important for bone remodeling in response to mechanical and hormonal stimuli, but the downstream mediator(s) regulating skeletal homeostasis are incompletely defined. We generated transgenic mice expressing a partly-activated, mutant cGMP-dependent protein kinase type 2 (PKG2R242Q) under control of the osteoblast-specific Col1a1 promoter to characterize the role of PKG2 in post-natal bone formation. Primary osteoblasts from these mice showed a two- to three-fold increase in basal and total PKG2 activity; they proliferated faster and were resistant to apoptosis compared to cells from WT mice. Male Col1a1-Prkg2 R242Q transgenic mice had increased osteoblast numbers, bone formation rates and Wnt/β-catenin-related gene expression in bone and a higher trabecular bone mass compared to their WT littermates. Streptozotocin-induced type 1 diabetes suppressed bone formation and caused rapid bone loss in WT mice, but male transgenic mice were protected from these effects. Surprisingly, we found no significant difference in bone micro-architecture or Wnt/β-catenin-related gene expression between female WT and transgenic mice; female mice of both genotypes showed higher systemic and osteoblastic NO/cGMP generation compared to their male counterparts, and a higher level of endogenous PKG2 activity may be responsible for masking effects of the PKG2R242Q transgene in females. Our data support sexual dimorphism in Wnt/β-catenin signaling and PKG2 regulation of this crucial pathway in bone homeostasis. This work establishes PKG2 as a key regulator of osteoblast proliferation and post-natal bone formation.

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Diego Safian Reproductive Biology Group, Division Developmental Biology, Department of Biology, Institute of Biodynamics and Biocomplexity, Faculty of Science, University of Utrecht, NL-3584 CH Utrecht, The Netherlands

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Najoua Ryane Reproductive Biology Group, Division Developmental Biology, Department of Biology, Institute of Biodynamics and Biocomplexity, Faculty of Science, University of Utrecht, NL-3584 CH Utrecht, The Netherlands

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Jan Bogerd Reproductive Biology Group, Division Developmental Biology, Department of Biology, Institute of Biodynamics and Biocomplexity, Faculty of Science, University of Utrecht, NL-3584 CH Utrecht, The Netherlands

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Rüdiger W Schulz Reproductive Biology Group, Division Developmental Biology, Department of Biology, Institute of Biodynamics and Biocomplexity, Faculty of Science, University of Utrecht, NL-3584 CH Utrecht, The Netherlands
Reproduction and Developmental Biology Group, Institute of Marine Research, Nordnes, Bergen, Norway

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, including genes belonging to the Wnt pathway ( Crespo et al. 2016 ). The Wnt signaling system is a conserved cell-to-cell communication system that consists of several Wnt ligands and receptors. This system operates in branches that differ in their

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Lucia Zhang Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

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Kathy K Lee Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

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Kim S Sugamori Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

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Marc D Grynpas Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

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Jane Mitchell Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

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cPTH ( Fig. 5B ). Since Wnt signalling is known to be required for osteoblast differentiation, we examined mRNA levels encoding several proteins involved in Wnt pathways in metaphyseal trabecular bone samples ( Fig. 5C , D and E ). Sost, encoding

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Diego Safian Reproductive Biology Group, Division Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology , Faculty of Science, University of Utrecht, Utrecht, The Netherlands

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Jan Bogerd Reproductive Biology Group, Division Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology , Faculty of Science, University of Utrecht, Utrecht, The Netherlands

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Rüdiger W Schulz Reproductive Biology Group, Division Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology , Faculty of Science, University of Utrecht, Utrecht, The Netherlands
Reproduction and Developmental Biology Group, Institute of Marine Research, Nordnes, Bergen, Norway

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et al. 2016 , Crespo et al. 2016 ). Since a previous report indicated that Fsh modulated the transcript levels of Wnt pathway-associated genes but did not regulate the expression of Wnt ligands ( Crespo et al. 2016 ), we hypothesized that the β

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Virginia Rider Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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Kazuto Isuzugawa Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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Meryl Twarog Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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Stacy Jones Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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Brent Cameron Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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Kazuhiko Imakawa Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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Jianwen Fang Department of Biology, Pittsburg State University, Pittsburg, Kansas 66762, USA
Laboratory of Animal Breeding, Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045, USA

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. In summary, this study reveals that progesterone activates Wnt signaling in uterine stromal cells. Activation of the canonical Wnt pathway results in the accumulation of β-catenin in the stromal cell cytoplasm. However, translocation of β-catenin and

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Weijuan Shao Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada

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Wenjuan Liu Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

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Ping Liang Department of Biological Sciences, Brock University, St. Catherine, Canada

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Zhuolun Song Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
Department of Physiology, University of Toronto, Toronto, Canada

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Odisho Israel Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada

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Gerald J Prud’homme Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

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Qinghua Wang Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, Canada

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Tianru Jin Divsion of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
Department of Physiology, University of Toronto, Toronto, Canada

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Gamma-aminobutyric acid (GABA) administration attenuates streptozotocin (STZ)-induced diabetes in rodent models with unclear underlying mechanisms. We found that GABA and Sitagliptin possess additive effect on pancreatic β-cells, which prompted us to ask the existence of common or unique targets of GLP-1 and GABA in pancreatic β-cells. Effect of GABA on expression of thioredoxin-interacting protein (TxNIP) was assessed in the INS-1 832/13 (INS-1) cell line, WT and GLP-1R–/– mouse islets. GABA was also orally administrated in STZ-challenged WT or GLP-1R–/– mice, followed by immunohistochemistry assessment of pancreatic islets. Effect of GABA on Wnt pathway effector β-catenin (β-cat) was examined in INS-1 cells, WT and GLP-1R–/– islets. We found that GABA shares a common feature with GLP-1 on inhibiting TxNIP, while this function was attenuated in GLP-1R–/– islets. In WT mice with STZ challenge, GABA alleviated several ‘diabetic syndromes’, associated with increased β-cell mass. These features were virtually absent in GLP-1R–/– mice. Knockdown TxNIP in INS-1 cells increased GLP-1R, Pdx1, Nkx6.1 and Mafa levels, associated with increased responses to GABA or GLP-1 on stimulating insulin secretion. Cleaved caspase-3 level can be induced by high-glucose, dexamethasone, or STZ in INS-1 cell, while GABA treatment blocked the induction. Finally, GABA treatment increased cellular cAMP level and β-cat S675 phosphorylation in WT but not GLP-1R–/– islets. We, hence, identified TxNIP as a common target of GABA and GLP-1 and suggest that, upon STZ or other stress challenge, the GLP-1R-cAMP-β-cat signaling cascade also mediates beneficial effects of GABA in pancreatic β-cell, involving TxNIP reduction.

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Binbin Guan Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China
Department of Endocrinology, FuJian Union hospital, Fuzhou, P R China

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Wenyi Li Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Fengying Li Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Yun Xie Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Qicheng Ni Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Yanyun Gu Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Xiaoying Li Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Qidi Wang Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Hongli Zhang Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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Guang Ning Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P R China

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-catenin, the characteristic protein of the Wnt pathway, in the nucleus of INS-1 cells ( Fig. 4A ). Overexpression of SFRP5 in INS-1 cells blocked this translocation under the high glucose condition ( Fig. 4A ). These data indicated that high glucose may

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Juan Pedro Martinez-Barbera Developmental Biology and Cancer Programme, Institute of Child Health, Birth Defects Research Centre, University College London, 30 Guilford Street, WC1N 1EH London, UK

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human ACP revealed an association with mutations in CTNNB1 , the gene that encodes β-catenin, a central regulator of the Wnt pathway ( Sekine et al . 2002 , Kato et al . 2004 , Buslei et al . 2005 , Oikonomou et al . 2005 , Brastianos et al

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Won Bae Kim Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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Christopher J Lewis Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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Kelly D McCall Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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Ramiro Malgor Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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Aimee D Kohn Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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Randall T Moon Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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Leonard D Kohn Edison Biotechnology Institute and College of Osteopathic Medicine, Ohio University, The Ridges, Athens, Ohio 45701, USA
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA

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studied is the ‘Wnt/β-catenin’ pathway, often termed the ‘canonical Wnt pathway’, which regulates the cellular level of β-catenin. In the absence of Wnt signaling, β-catenin levels are low due to proteasome-mediated degradation. The β-catenin is targeted

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R Hardy School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK

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M S Cooper School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK

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the wnt pathway and DKK1 in particular, has been proposed to be the central regulator of bone remodelling in inflammatory arthritis (summarised in Fig. 3 ). Further examination of the whole wnt pathway (which consists of a variety of agonists

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