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The Institute for Pharmacology and Toxicology, University of Bonn, Bonn, Germany
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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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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
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
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Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 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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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
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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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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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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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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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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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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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
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto, Canada
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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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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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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.
Department of Endocrinology, FuJian Union hospital, Fuzhou, 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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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
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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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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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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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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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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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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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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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
