CTGF Facilitates Cell-cell Communication in Chondrocytes Via PI3K/Akt Signalling Pathway

Overview

Journal Cell Prolif

Date 2021 Feb 1

PMID 33522639

Citations 13

Authors

Zuping Wu

Chenchen Zhou

Quan Yuan

Demao Zhang

Jing Xie

Shujuan Zou

Affiliations

Soon will be listed here.

Abstract

Purposes: Gap junction intercellular communication (GJIC) is essential for articular cartilage to respond appropriately to physical or biological stimuli and maintain homeostasis. Connective tissue growth factor (CTGF), identified as an endochondral ossification genetic factor, plays a vital role in cell proliferation, migration and adhesion. However, how CTGF regulates GJIC in chondrocytes is still unknown. This study aims to explore the effects of CTGF on GJIC in chondrocytes and its potential biomechanism.

Materials And Methods: qPCR was performed to determine the expression of gene profile in the CCN family in chondrocytes. After CTGF treatment, CCK-8 assay and scratch assay were performed to explore cell proliferation and migration. A scrape loading/dye transfer assay was adopted to visualize GJIC in living chondrocytes. Western blot analysis was done to detect the expression of Cx43 and PI3K/Akt signalling. Immunofluorescence staining was used to show protein distribution. siRNA targeting CTGF was used to detect the influence on cell-cell communication.

Results: The CTGF (CCN2) was shown to be the highest expressed member of the CCN family in chondrocytes. CTGF facilitated functional gap junction intercellular communication in chondrocytes through up-regulation of Cx43 expressions. CTGF activated PI3K/Akt signalling to promote Akt phosphorylation and translocation. Suppressing CTGF also reduced the expression of Cx43. The inhibition of PI3K/Akt signalling decreased the expressions of Cx43 and thus impaired gap junction intercellular communication enhanced by CTGF.

Conclusions: For the first time, we provide evidence to show CTGF facilitates cell communication in chondrocytes via PI3K/Akt signalling pathway.

Citing Articles

Oversecretion of CCL3 by Irradiation-Induced Senescent Osteocytes Mediates Bone Homeostasis Imbalance.

Zhao F, Han H, Wang J, Wang J, Zhai J, Zhu G Cells. 2025; 14(4).

PMID: 39996722 PMC: 11853822. DOI: 10.3390/cells14040249.

5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target.

Xu N, Gao Z, Wu D, Chen H, Zhang Z, Zhang L Clin Transl Med. 2025; 15(2):e70189.

PMID: 39956959 PMC: 11830572. DOI: 10.1002/ctm2.70189.

Outer Membrane Vesicles Derived From Fusobacterium nucleatum Trigger Periodontitis Through Host Overimmunity.

Zhang L, Zhang D, Liu C, Tang B, Cui Y, Guo D Adv Sci (Weinh). 2024; 11(47):e2400882.

PMID: 39475060 PMC: 11653712. DOI: 10.1002/advs.202400882.

Spatial Cellular Networks from omics data with SpaCeNet.

Schrod S, Luck N, Lohmayer R, Solbrig S, Volkl D, Wipfler T Genome Res. 2024; 34(9):1371-1383.

PMID: 39231609 PMC: 11529864. DOI: 10.1101/gr.279125.124.

Trophoblast fusion in fetal growth restriction is inhibited by CTGF in a cell-cycle-dependent manner.

Liu K, Wu S, Cui Y, Tao X, Li Y, Xiao X J Mol Histol. 2024; 55(5):895-908.

PMID: 39122896 DOI: 10.1007/s10735-024-10239-9.

References

Tank J, Lindner D, Wang X, Stroux A, Gilke L, Gast M . Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts. J Mol Cell Cardiol. 2013; 66:141-56. DOI: 10.1016/j.yjmcc.2013.11.004. View

Park D, Wallick C, Martyn K, Lau A, Jin C, Warn-Cramer B . Akt phosphorylates Connexin43 on Ser373, a "mode-1" binding site for 14-3-3. Cell Commun Adhes. 2007; 14(5):211-26. PMC: 2673107. DOI: 10.1080/15419060701755958. View

Genetos D, Kephart C, Zhang Y, Yellowley C, Donahue H . Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. J Cell Physiol. 2007; 212(1):207-14. PMC: 2929812. DOI: 10.1002/jcp.21021. View

Salameh A, Krautblatter S, Karl S, Blanke K, Gomez D, Dhein S . The signal transduction cascade regulating the expression of the gap junction protein connexin43 by beta-adrenoceptors. Br J Pharmacol. 2009; 158(1):198-208. PMC: 2795252. DOI: 10.1111/j.1476-5381.2009.00344.x. View

Takigawa M . CCN2: a master regulator of the genesis of bone and cartilage. J Cell Commun Signal. 2013; 7(3):191-201. PMC: 3709051. DOI: 10.1007/s12079-013-0204-8. View

Yamamoto T, Kambe F, Cao X, Lu X, Ishiguro N, Seo H . Parathyroid hormone activates phosphoinositide 3-kinase-Akt-Bad cascade in osteoblast-like cells. Bone. 2006; 40(2):354-9. DOI: 10.1016/j.bone.2006.09.002. View

Liu W, Cui Y, Wei J, Sun J, Zheng L, Xie J . Gap junction-mediated cell-to-cell communication in oral development and oral diseases: a concise review of research progress. Int J Oral Sci. 2020; 12(1):17. PMC: 7293327. DOI: 10.1038/s41368-020-0086-6. View

Davis W, Lehmann P, Li W . Nuclear PI3K signaling in cell growth and tumorigenesis. Front Cell Dev Biol. 2015; 3:24. PMC: 4394695. DOI: 10.3389/fcell.2015.00024. View

Schmidlin M, Lu M, Leuenberger S, Stoecklin G, Mallaun M, Gross B . The ARE-dependent mRNA-destabilizing activity of BRF1 is regulated by protein kinase B. EMBO J. 2004; 23(24):4760-9. PMC: 535089. DOI: 10.1038/sj.emboj.7600477. View

10.

Jiang J, Cherian P . Hemichannels formed by connexin 43 play an important role in the release of prostaglandin E(2) by osteocytes in response to mechanical strain. Cell Commun Adhes. 2003; 10(4-6):259-64. DOI: 10.1080/cac.10.4-6.259.264. View

11.

Perbal B . CCN proteins: multifunctional signalling regulators. Lancet. 2004; 363(9402):62-4. DOI: 10.1016/S0140-6736(03)15172-0. View

12.

Wang A, Xu C . The role of connexin43 in neuropathic pain induced by spinal cord injury. Acta Biochim Biophys Sin (Shanghai). 2019; 51(6):555-561. DOI: 10.1093/abbs/gmz038. View

13.

Bhosale A, Richardson J . Articular cartilage: structure, injuries and review of management. Br Med Bull. 2008; 87:77-95. DOI: 10.1093/bmb/ldn025. View

14.

Zhang D, Li X, Pi C, Cai L, Liu Y, Du W . Osteoporosis-decreased extracellular matrix stiffness impairs connexin 43-mediated gap junction intercellular communication in osteocytes. Acta Biochim Biophys Sin (Shanghai). 2020; 52(5):517-526. DOI: 10.1093/abbs/gmaa025. View

15.

Donahue H, Qu R, Genetos D . Joint diseases: from connexins to gap junctions. Nat Rev Rheumatol. 2017; 14(1):42-51. DOI: 10.1038/nrrheum.2017.204. View

16.

Ihn H . Pathogenesis of fibrosis: role of TGF-beta and CTGF. Curr Opin Rheumatol. 2002; 14(6):681-5. DOI: 10.1097/00002281-200211000-00009. View

17.

de Winter P, Leoni P, Abraham D . Connective tissue growth factor: structure-function relationships of a mosaic, multifunctional protein. Growth Factors. 2008; 26(2):80-91. DOI: 10.1080/08977190802025602. View

18.

Adam O, Lavall D, Theobald K, Hohl M, Grube M, Ameling S . Rac1-induced connective tissue growth factor regulates connexin 43 and N-cadherin expression in atrial fibrillation. J Am Coll Cardiol. 2010; 55(5):469-80. DOI: 10.1016/j.jacc.2009.08.064. View

19.

Nguyen T, Choi J, Lee S, Ye K, Woo S, Lee K . Akt phosphorylation is essential for nuclear translocation and retention in NGF-stimulated PC12 cells. Biochem Biophys Res Commun. 2006; 349(2):789-98. DOI: 10.1016/j.bbrc.2006.08.120. View

20.

Deng Z, Liu Y, Wang C, Fan H, Ma J, Yu H . Involvement of PI3K/Akt pathway in rat condylar chondrocytes regulated by PTHrP treatment. Arch Oral Biol. 2014; 59(10):1032-41. DOI: 10.1016/j.archoralbio.2014.04.012. View