Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

Meng, Jingru; Xue, Ming; Wang, Ning; Jiang, Min; Bi, Long; Wang, Yunying; Li, Mingkai; Zhang, Huinan; Xue, Xiaonan; Zhao, Ying; Yu, Zhibin; He, Gong-Hao; Luo, Xue‐Gang

doi:10.1016/j.stemcr.2016.03.010

Cited by 49 publications

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“…These studies indicated that Exendin-4 promotes osteoblast differentiation to increase bone formation. Furthermore, our previous studies also showed that Exendin-4 mediates its effects on bone formation via the PI3K-AKT signaling pathway [48], although the source of BMSCs recruited to the bone resorptive sites was not clarified. However, our results showed that Exendin-4 increased the trabecular number and thickness and enhanced the rate of bone formation to promote bone mass, which is consistent with other reports [3].…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway

Wang

Gao

Jia

et al. 2017

Cell Physiol Biochem

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Background/Aims: The synthesis and degradation processes involved in bone remodeling are critically regulated by osteoblasts and osteoclasts. The GLP-1 receptor agonist Exendin-4 is beneficial for osteoblast differentiation and increases the number of osteoblasts. Methods:We constructed an ovariectomized model to evaluate the impact of Exendin-4 on bone formation in osteoporosis. A macrophage-depleted model was also created to investigate the effect of macrophages on bone formation. Thirty-two female WT C57BL/6 mice (aged 3 months) were randomly assigned to a normal control group and four ovariectomized (OVX) subgroups: OVX + vehicle group, OVX + Exendin-4 (4.2 μg/kg/day) group, OVX + chloride phosphate liposome group and OVX + chloride phosphate liposome + Exendin-4 group. Results: In this study, we found that Exendin-4 not only increased the number of osteoblasts and decreased the number of osteoclasts, but also increased the number of bone marrow stromal cells (BMSCs) at the bone surface. Moreover, we found that OVX mice treated with Exendin-4 increased TGF-β1 levels at the bone surface compared with that in OVX mice. Besides, Exendin-4 promoted the polarization of bone marrow-derived macrophages into M2 subtype and increased TGF-β1 secretion by the M2 subtype. Finally, we found that Exendin-4 induced macrophage polarization via the cAMP-PKA-STAT3 signaling pathway. Conclusion: Exendin-4 promotes bone marrow-derived macrophage polarization to the M2 subtype and induces BMSC migration to the bone surface via PKA-STAT3 signaling.

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Section: Discussionmentioning

confidence: 99%

Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway

Wang

Gao

Jia

et al. 2017

Cell Physiol Biochem

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“…In ovariectomy-induced osteoporosis, the use of exenatide at a concentration as low as 1 µg/kg/day for 16 weeks, led to improvement in maximum load and stiffness as well as Young's modulus and ultimate stress, suggesting amelioration in bone microarchitecture and/or tissue material properties (Ma et al 2013). In the rat tail suspension model, the administration of exenatide (4.2 µg/kg/day) for 4 weeks resulted in higher value for maximum loading, stiffness, stress and Young's modulus, suggesting here again ameliorations in bone microarchitecture and/or tissue material properties (Meng et al 2016). However, bone strength has not been measured after treatment with liraglutide.…”

Section: Effects Of Glp-1ras On Bone Strengthmentioning

confidence: 96%

“…It has been reported that 3 μg/kg/day and 4.2 μg/kg/day exenatide induced bone formation by osteoblast activation in old ovariectomised (OVX) rats (Ma et al 2013) and in hindlimb-unloading rats (Meng et al 2016) by promoting the osteogenic differentiation and inhibiting BMSC adipogenic differentiation. A decrease of osteoclastic surfaces was also observed (Ma et al 2013).…”

Section: Experimental Studiesmentioning

confidence: 99%

“…A study has indeed identified potential skeletal beneficial effects of 10 nM of exenatide by promoting osteoblastogenesis and restraining adipogenesis through a β-catenin pathway, during bone marrow mesenchymal stem cell (BMMSC) differentiation (Meng et al 2016). Despite increased osteoblastogenesis, no direct effect of GLP-1RAs on bone nodule mineralisation in vitro was shown with up to 100 nM of exenatide and 1000 nM of liraglutide (Ma et al 2013, Pereira et al 2015.…”

Section: In Vitro Studiesmentioning

confidence: 99%

“…They demonstrated positive effects on trabecular bone microarchitecture in the axial and appendicular skeleton evidenced by amelioration of structural parameters in lumbar vertebra and long bones as early as 4-week treatment. Indeed, both liraglutide and exenatide treatments resulted in higher bone volume/total volume (BV/TV) values (24%-148%, depending on dose and treatment duration) and higher values for trabecular number (Tb.N), thickness (Tb.Th) and reduction in separation (Tb.Sp) (Ma et al 2013, Pereira et al 2015, Meng et al 2016, Sun et al 2016. When comparing the effects of both GLP-1RAs, liraglutide (0.3 mg/kg/day) was more potent than exenatide (10 µg/kg/day) (Pereira et al 2015).…”

Section: Effects Of Glp-1ras On Bone Microarchitecturementioning

confidence: 99%

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Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

Mabilleau

Pereira

Chenu

2018

Journal of Endocrinology

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Type 2 diabetes mellitus (T2DM) leads to bone fragility and predisposes to increased risk of fracture, poor bone healing and other skeletal complications. In addition, some anti-diabetic therapies for T2DM can have notable detrimental skeletal effects. Thus, an appropriate therapeutic strategy for T2DM should not only be effective in re-establishing good glycaemic control but also in minimising skeletal complications. There is increasing evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk.

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Glucagon‐like peptide‐1 receptor undergoes importin‐α‐dependent nuclear localization in rat aortic smooth muscle cells

et al. 2020

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Edited by Lukas Alfons HuberGlucagon-like peptide 1 receptor (GLP-1R) belongs to the family B of G protein-coupled receptors (GPCRs) and has antidiabetic and cardioprotective effects. Classical GLP-1R at the plasma membrane undergoes desensitization and internalization and is recycled back to the plasma membrane under the control of GLP-1 in islet b-cells. However, the subcellular localization of GLP-1R in the vascular system remains unclear. Here, we find that GLP-1R is localized in the nucleus of rat aortic smooth muscle cells (RASMCs) and in the tunica media. We identify a functional nuclear localization signal (NLS; 412-442aa) at the C-terminal region of GLP-1R. Nuclear import of GLP-1R is mediated by an importin-a-dependent pathway and regulated by phosphorylation of Ser416 in the NLS. Upon leaving the nucleus, GLP-1R promotes cell proliferation in RASMCs. These findings may provide insights into the cardiovascular functions of GLP-1R.

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Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

Cited by 49 publications

References 0 publications

Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway

Exendin-4 Induces Bone Marrow Stromal Cells Migration Through Bone Marrow-Derived Macrophages Polarization via PKA-STAT3 Signaling Pathway

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

Glucagon‐like peptide‐1 receptor undergoes importin‐α‐dependent nuclear localization in rat aortic smooth muscle cells

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