The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration

Tharmalingam, Sujeenthar; Hampson, David R.

doi:10.3389/fphys.2016.00190

Cited by 42 publications

(31 citation statements)

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“…In addition, it has been reported that genes downstream of G-protein coupled receptor (GPCR) signaling pathways may be the earliest response to calcium-based ceramics [ 52 ]. Indeed, calcium sensing receptor (CaSR), a receptor belonging to the GPCR family, modulates the chemotactic response of MSCs in response to extracellular calcium [ 5 , 6 , 53 ]. It has been reported that CaSO 4 induces a significant increment in Smad3 and Smad6 expression [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

2017

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BackgroundOsteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC) recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca2+-containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO4) on MSC migration. In addition, to evaluate the influence of CaSO4 on MSC differentiation and the potential molecular mechanisms involved.MethodsA circular calvarial bone defect (5 mm diameter) was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO4 concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO4 effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO4 treatment was also evaluated by qPCR.ResultsCaSO4 increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO4 significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO4-containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO4 and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO4 effects on MSC migration.ConclusionsSpecific CaSO4 concentrations induce bone regeneration of calvarial defects in part by acting on the host’s undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO4 regulates BMP-2-induced MSC migration by differentially activating the PI3K/AKT pathway. Altogether, these results suggest that CaSO4 scaffolds could have potential applications for bone regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0713-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

2017

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“…Overexpression of the CaSR prevented the mesenchymal transition and the acquisition of stem cell-like properties in the HT29 colon cancer cell line (Aggarwal et al, 2015a ) reducing the metastatic properties of the cells. Another mechanism by which CaSR might regulate adhesion and migration is the regulation of the activity of integrins, adhesion receptors that mediate cell migration (Tharmalingam and Hampson, 2016 ). Interestingly, 1,25D 3 also affects integrin signaling, as it has been shown that 1,25D 3 inhibited ionizing radiation-mediated upregulation of several integrins in keratinocytes (Muller et al, 2006 ).…”

Section: Effect Of Casr Expression and Functionality On Vitamin D Actmentioning

confidence: 99%

Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer

Aggarwal

Kállay

2016

Front. Physiol.

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There is epidemiological evidence for the cancer preventive effect of dietary calcium (Ca2+) and vitamin D. This effect is strongest in colorectal cancer (CRC). The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25D3), bound to its receptor, the vitamin D receptor (VDR) regulates the expression of hundreds of different genes in a cell- and tissue-specific manner. While Ca2+ acts through multiple mechanisms and pathways, some of its effects are mediated by the calcium-sensing receptor (CaSR). The joint action of Ca2+ and 1,25D3 is due to the fact that both regulate some of the main processes involved in the development of various cancers, such as proliferation, differentiation, apoptosis, migration, and inflammation. Moreover, 1,25D3, bound to VDR can induce translation of the CaSR, while the amount and activity of the CaSR affects 1,25D3 signaling. However, the complexity of the cross-talk between the CaSR and the vitamin D system goes beyond regulating similar pathways and affecting each other's expression. Our aim was to review some of the mechanisms that drive the cross-talk between the vitamin D system and the CaSR with a special focus on the interaction in CRC cells. We evaluated the molecular evidence that supports the epidemiological observation that both vitamin D and calcium are needed for protection against malignant transformation of the colon and that their effect is modulated by the presence of a functional CaSR.

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“…2) According to recent data, 3) cardiac fibroblasts are highly activated during diabetes, which results in dynamic balance disorder of cardiac extracellular matrix synthesis and deposition, along with the excessive deposition of collagen, thus leading to myocardial fibrosis and cardiac dysfunction. 4,5) Calcium sensing receptor (CaSR) is a member of the C family of the G protein coupling receptor superfamily and is widely expressed in both prokaryotic and eukaryotic cells. CaSR is involved in regulating the homeostasis of calcium and other metal ions, cell secretion, proliferation, differentiation, chemotaxis, apoptosis, gene expression, membrane potential, ion channel switching and aging.…”

Section: Introductionmentioning

confidence: 99%

Calhex231 Alleviates High Glucose-Induced Myocardial Fibrosis via Inhibiting Itch-Ubiquitin Proteasome Pathway in Vitro

Yuan

et al. 2019

Biological & Pharmaceutical Bulletin

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Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and features myocardial fibrosis as its main pathological feature. Calcium sensing receptor (CaSR) is a G protein-coupled receptor, which involves in myocardial fibrosis by regulation of calcium homeostasis. Calhex 231 , the CaSR inhibitor, is not clear whether it regulates myocardial fibrosis in DCM. In the present study, type 1 diabetic (T1D) rats and primary neonatal rat cardiac fibroblasts were used to observe the role of Calhex 231. In vivo experiments showed that in the T1D group, contractile dysfunction and the deposition of collagen I and III were obvious after 12 weeks. In vitro experiments, we found that high glucose (HG) could increase the expression of CaSR, α-smooth muscle actin (α-SMA), transforming growth factor-β 1 (TGF-β 1) collagen I/III, matrix metalloproteinase-2 (MMP-2), MMP9, along with cardiac fibroblast migration and proliferation. We further demonstrated that CaSR activation increased intracellular Ca 2 concentration and upregulated the expression of Itch (atrophin-1 interacting protein 4), which resulted in increasing the ubiquitination levels of Smad7 and upregulating the expression of p-Smad2, p-Smad3. However, treatment with Calhex 231 clearly inhibited the above-mentioned changes. Collectively these results suggest that Calhex 231 could inhibit Itch-ubiquitin proteasome and TGF-β 1 /Smads pathways, and then depress the proliferation of cardiac fibroblasts, along with the reduction deposition of collagen, alleviate glucose-induced myocardial fibrosis. Our findings indicate an important new mechanism for myocardial fibrosis, and suggest Calhex 231 would be a new therapeutic agent for the treatment of DCM.

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The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration

Cited by 42 publications

References 129 publications

Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer

Calhex<sub>231</sub> Alleviates High Glucose-Induced Myocardial Fibrosis <i>via</i> Inhibiting Itch-Ubiquitin Proteasome Pathway <i>in Vitro</i>

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