Blockade of LGR4 inhibits proliferation and odonto/osteogenic differentiation of stem cells from apical papillae

Zhou, Meng; Guo, Shuyu; Yuan, Lichan; Zhang, Yuxin; Zhang, Mengnan; Chen, Huimin; Lu, Mengting; Yang, Jianrong; Ma, Junqing

doi:10.1007/s10735-017-9737-0

Cited by 20 publications

(18 citation statements)

References 43 publications

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“…It has been reported that LGR4, 5, and 6 are strong potentiators of Wnt/β‐catenin signaling . Several studies have highlighted the crucial role of LGR4 in the promotion of osteoblast differentiation by activating the Wnt signaling pathway . Intriguingly, in the present study, BMP9 had no effect on the expression level of the LGR4 gene but dramatically augmented the expression of the LGR6 gene.…”

Section: Discussioncontrasting

confidence: 56%

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Zhou

Yang

Jing

et al. 2020

Journal of Bone and Mineral Research

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Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice.

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Section: Discussioncontrasting

confidence: 56%

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Zhou

Yang

Jing

et al. 2020

Journal of Bone and Mineral Research

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“…Regarding the mesenchymal compartment, the complementary expression patterns of RANK and LGR4 in the dental pulp and dental follicle (observed at day 5 in the first molar) suggest the existence of a differential impact of RANKL on mesenchymal cells in both these sites with a probable histogenesis function. Interestingly, the expression pattern of LGR4, in the complex formed by the tooth, periodontium and alveolar bone, appeared to change sequentially from the initial morphogenesis stage [24] to the dental eruption stage [25,26], suggesting a dynamic/evolutive function of this receptor for RANKL and R-spondin2 throughout dental development, the modalities of which remain to be elucidated in future studies.…”

Section: Discussionmentioning

confidence: 95%

Origins of Alterations to Rankl Null Mutant Mouse Dental Root Development

Gama

Vargas-Franco

Mesa

et al. 2020

IJMS

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The purpose of the present study was to assess the early stages of development of mouse first molar roots in the osteopetrotic context of RANKL invalidation in order to demonstrate that the radicular phenotype observed resulted not only from defective osteoclasts, but also from loss of cell-to-cell communication among dental, periodontium and alveolar bone cells involving RANKL signaling. Two experimental models were used in this study: Rankl mutants with permanent RANKL invalidation, and C57BL/6J mice injected during the first postnatal week with a RANKL neutralizing antibody corresponding to a transient RANKL invalidation. The dento-alveolar complex was systematically analyzed using micro-CT, and histological and immunohistochemical approaches. These experiments showed that the root elongation alterations observed in the Rankl-/- mice were associated with reduced proliferation of the RANK-expressing HERS cells with a significant decrease in proliferating cell nuclear antigen (PCNA) expression and a significant increase in P21 expression. The phenotypic comparison of the adult first molar root at 35 days between permanent and transitory invalidations of RANKL made it possible to demonstrate that alterations in dental root development have at least two origins, one intrinsic and linked to proliferation/differentiation perturbations in dental-root-forming cells, the other extrinsic and corresponding to disturbances of bone cell differentiation/function.

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“…Cell cycle arrest is an important mechanism to inhibit cell proliferation. Many factors inhibit cell proliferation by modulating cell cycle progression . It is well known that the core of the cell cycle regulation mechanism is a group of cell cycle dependent protein kinase (CDKs), which is dependent on their regulatory subunit cyclins.…”

Section: Discussionmentioning

confidence: 99%

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

Chen

Xiao

Yang

et al. 2018

J of Cellular Biochemistry

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Extracellular adenosine diphosphate (ADP) mediates a wide range of physiological effects as an extracellular signaling molecule, including platelet aggregation, vascular tone, cell proliferation, and apoptosis by interacting with plasma membrane P2 receptors. However, the effect of ADP on cell proliferation was contradictory. In this study, we found that ADP significantly inhibited cell proliferation of human umbilical vein endothelial cells at high concentrations (50 to 100 µM). Treatment with ADP did not induce cell apoptosis but instead induced cell cycle arrest in the S phase, which may be partly due to the downregulation of cyclin B1. The inhibition of cell proliferation was blocked by suramin, a nonspecific antagonist of the P2 receptors, and high concentrations of ADP significantly upregulated the messenger RNA (mRNA) and protein expression of P2Y11 in endothelial cells. Moreover, the downregulation of P2Y11 by RNA interference reversed the inhibition of cell proliferation. In addition, ADP (100 µM) can induce the formation of cytosolic autophagy in endothelial cells and a rapid phosphorylation of extracellular signal regulated kinase (ERK) 1/2, which is a canonical signal molecule downstream of P2Y receptors, accompanied by a mRNA expression of proinflammatory cytokines such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Taken together, our study excludes a mechanism for extracellular ADP impairing endothelial cells proliferation via P2Y11 receptor by downregulating cyclin B1 and arresting cell cycle at the S phase, besides, ADP induces cell autophagy and mRNA expression of inflammatory cytokines, whether it is mediated by Erk signaling pathways needs further studies to confirm.

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Blockade of LGR4 inhibits proliferation and odonto/osteogenic differentiation of stem cells from apical papillae

Cited by 20 publications

References 43 publications

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Origins of Alterations to Rankl Null Mutant Mouse Dental Root Development

Adenosine diphosphate–sensitive P2Y11 receptor inhibits endothelial cell proliferation by induction of cell cycle arrest in the S phase and induces the expression of inflammatory mediators

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