Adenylate cyclase and calmodulin-dependent kinase have opposite effects on osteoclastogenesis by regulating the PKA-NFATc1 pathway

Yoon, San-Hyun; Ryu, Ji Yoon; Lee, Youngkyun; Lee, Zang Hee; Kim, Hong Hee

doi:10.1002/jbmr.310

Cited by 31 publications

(44 citation statements)

References 34 publications

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“…Wnt3a can also trigger the cAMP/PKA pathway[43], which could suppress osteoclast differentiation by PKA-mediated phosphorylation and inactivate the nuclear factor of activated T-cells 1 (NFATC1)[44]. …”

Section: Wnt Signaling Pathwaymentioning

confidence: 99%

Aberrant regulation of Wnt signaling in hepatocellular carcinoma

Liu

Xie

Chen

et al. 2016

WJG

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Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Several signaling pathways, including the wingless/int-1 (Wnt) signaling pathway, have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1 (CTNNB1)-dependent (also known as “canonical”) and CTNNB1-independent (often referred to as “non-canonical”) pathways. Specifically, the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes (the cell-surface receptor complex, the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported, two main non-canonical pathways, Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway, participate in the regulation of hepatocarcinogenesis. Interestingly, the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover, other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore, crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.

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Section: Wnt Signaling Pathwaymentioning

confidence: 99%

Aberrant regulation of Wnt signaling in hepatocellular carcinoma

Liu

Xie

Chen

et al. 2016

WJG

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“…(22) Bone marrow culture, osteoclast differentiation, and TRAP staining Bone marrow cells were isolated by flushing the bone marrow space of femur and tibia of 6-week-old Tie2-Dkk1 TG and WT mice. (23) Cells were incubated with a modified essential medium (a-MEM) containing 10% fetal bovine serum overnight on culture dishes. Nonadherent cells were collected and treated with macrophage colony-stimulating factor (M-CSF; 20 ng/mL) for 3 days on noncoated Petri dishes.…”

Section: Analysis Of Bone Histomorphometrymentioning

confidence: 99%

“…BMMs were seeded in 48-well plates (2 Â 10 4 cells/well) and cultured for 5 days with 30 ng/mL of M-CSF and 100 ng/mL of RANKL to induce osteoclast differentiation. (23) The cells were fixed in 3.7% formaldehyde for 10 minutes, permeabilized with 0.1% Triton X-100 for 1 minute, and stained with the leukocyte acid phosphate assay kit (Sigma, St. Louis, MO, USA) to detect tartrate-resistant acid phosphatase (TRAP) activity. (3,23) The surface area of TRAP-stained multinuclear osteoclasts that contained three or more nuclei were measured by the Osteomeasure system.…”

Section: Analysis Of Bone Histomorphometrymentioning

confidence: 99%

“…(23) The cells were fixed in 3.7% formaldehyde for 10 minutes, permeabilized with 0.1% Triton X-100 for 1 minute, and stained with the leukocyte acid phosphate assay kit (Sigma, St. Louis, MO, USA) to detect tartrate-resistant acid phosphatase (TRAP) activity. (3,23) The surface area of TRAP-stained multinuclear osteoclasts that contained three or more nuclei were measured by the Osteomeasure system. (22) To determine TRAP activity in the tissue section, paraffin sections of 2-week-old mouse metatarsal bones (5-mm thickness) were used.…”

Section: Analysis Of Bone Histomorphometrymentioning

confidence: 99%

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Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Oh¹,

Ryu²,

Jeon³

et al. 2012

Journal of Bone and Mineral Research

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Developing cartilage serves as a template for long-bone development during endochondral ossification. Although the coupling of cartilage and bone development with angiogenesis is an important regulatory step for endochondral ossification, the molecular mechanisms are poorly understood. One possible mechanism involves the action of Dickkopf (DKK), which is a family of soluble canonical Wnt antagonists with four members (DKK1-4). We initially observed opposite expression patterns of Dkk1 and Dkk2 during angiogenesis and chondrocyte differentiation: downregulation of Dkk1 and upregulation of Dkk2. We examined the in vivo role of Dkk1 and Dkk2 in linking cartilage/bone development and angiogenesis by generating transgenic (TG) mice that specifically express Dkk1 or Dkk2 in chondrocytes, hypertrophic chondrocytes, or endothelial cells. Despite specific expression pattern during cartilage development, chondrocyte-and hypertrophic chondrocyte-specific Dkk1 and Dkk2 TG mice showed normal developmental phenotypes. However, Dkk1 misexpression in endothelial cells resulted in defects of endochondral ossification and reduced skeletal size. The defects are caused by the inhibition of angiogenesis in developing bone and subsequent inhibition of apoptosis of hypertrophic chondrocytes and cartilage resorption. ß

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“…Gsα deletion in osteogenic lineage cells expressing osterix and col1a has demonstrated that Gsα plays important roles during skeletal development by regulating mesenchymal cell commitment, osteoblast differentiation, and mineralization without affecting osteoclast function6789. Recent studies have also suggested that cAMP levels are regulated by several mechanisms including Wnt signaling, adenylyl cyclase, and Ca 2+ /Calmodulin-dependent kinases to delicately control osteoclastogenesis1011. In addition, in fibrous dysplasia, a clinical condition in which activating Gsα mutations cause elevated cAMP levels, increased osteoclasts occur primarily in response to osteoblast secretion of interleukin-61213.…”

mentioning

confidence: 99%

Gsα Controls Cortical Bone Quality by Regulating Osteoclast Differentiation via cAMP/PKA and β-Catenin Pathways

Ramaswamy

Kim

Zhang

et al. 2017

Sci Rep

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Skeletal bone formation and maintenance requires coordinate functions of several cell types, including bone forming osteoblasts and bone resorbing osteoclasts. Gsα, the stimulatory subunit of heterotrimeric G proteins, activates downstream signaling through cAMP and plays important roles in skeletal development by regulating osteoblast differentiation. Here, we demonstrate that Gsα signaling also regulates osteoclast differentiation during bone modeling and remodeling. Gnas, the gene encoding Gsα, is imprinted. Mice with paternal allele deletion of Gnas (Gnas+/p−) have defects in cortical bone quality and strength during early development (bone modeling) that persist during adult bone remodeling. Reduced bone quality in Gnas+/p− mice was associated with increased endosteal osteoclast numbers, with no significant effects on osteoblast number and function. Osteoclast differentiation and resorption activity was enhanced in Gnas+/p− cells. During differentiation, Gnas+/p− cells showed diminished pCREB, β-catenin and cyclin D1, and enhanced Nfatc1 levels, conditions favoring osteoclastogenesis. Forskolin treatment increased pCREB and rescued osteoclast differentiation in Gnas+/p− by reducing Nfatc1 levels. Cortical bone of Gnas+/p− mice showed elevated expression of Wnt inhibitors sclerostin and Sfrp4 consistent with reduced Wnt/β-catenin signaling. Our data identify a new role for Gsα signaling in maintaining bone quality by regulating osteoclast differentiation and function through cAMP/PKA and Wnt/β-catenin pathways.

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Adenylate cyclase and calmodulin-dependent kinase have opposite effects on osteoclastogenesis by regulating the PKA-NFATc1 pathway

Cited by 31 publications

References 34 publications

Aberrant regulation of Wnt signaling in hepatocellular carcinoma

Aberrant regulation of Wnt signaling in hepatocellular carcinoma

Misexpression of Dickkopf-1 in endothelial cells, but not in chondrocytes or hypertrophic chondrocytes, causes defects in endochondral ossification

Gsα Controls Cortical Bone Quality by Regulating Osteoclast Differentiation via cAMP/PKA and β-Catenin Pathways

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