Mechanical Motion Promotes Expression of Prg4 in Articular Cartilage Via Multiple CREB-dependent, Fluid Flow Shear Stress-induced Signaling Pathways

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2014 Jan 23

PMID 24449269

Citations 73

Authors

Hiroyasu Ogawa

Elena Kozhemyakina

Han-Hwa Hung

Alan J Grodzinsky

Andrew B Lassar

Affiliations

Soon will be listed here.

Abstract

Lubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca(++)-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.

Citing Articles

A conserved transcription factor regulatory program promotes tendon fate.

Niu X, Melendez D, Raj S, Cai J, Senadeera D, Mandelbaum J Dev Cell. 2024; 59(23):3106-3123.e12.

PMID: 39216481 PMC: 11781300. DOI: 10.1016/j.devcel.2024.08.006.

Prg4-Expressing Chondroprogenitor Cells in the Superficial Zone of Articular Cartilage.

Ignatyeva N, Gavrilov N, Timashev P, Medvedeva E Int J Mol Sci. 2024; 25(11).

PMID: 38891793 PMC: 11171992. DOI: 10.3390/ijms25115605.

Histological and immunohistochemical analyses of articular cartilage during onset and progression of pre- and early-stage osteoarthritis in a rodent model.

Takahashi I, Takeda K, Toyama T, Matsuzaki T, Kuroki H, Hoso M Sci Rep. 2024; 14(1):10568.

PMID: 38719877 PMC: 11079058. DOI: 10.1038/s41598-024-61502-8.

Regenerative capacity of human pluripotent stem cell-derived articular chondrocytes in vitro.

Raftery R, Pregizer S, Kocher S, Craft A J Orthop Res. 2024; 42(8):1841-1851.

PMID: 38433390 PMC: 11222035. DOI: 10.1002/jor.25823.

Structural and Molecular Changes of Human Chondrocytes Exposed to the Rotating Wall Vessel Bioreactor.

Steinwerth P, Bertrand J, Sandt V, Marchal S, Sahana J, Bollmann M Biomolecules. 2024; 14(1).

PMID: 38254625 PMC: 10813504. DOI: 10.3390/biom14010025.

References

Batra N, Burra S, Siller-Jackson A, Gu S, Xia X, Weber G . Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels. Proc Natl Acad Sci U S A. 2012; 109(9):3359-64. PMC: 3295295. DOI: 10.1073/pnas.1115967109. View

Swann D, Silver F, Slayter H, Stafford W, Shore E . The molecular structure and lubricating activity of lubricin isolated from bovine and human synovial fluids. Biochem J. 1985; 225(1):195-201. PMC: 1144569. DOI: 10.1042/bj2250195. View

Nugent G, Schmidt T, Schumacher B, Voegtline M, Bae W, Jadin K . Static and dynamic compression regulate cartilage metabolism of PRoteoGlycan 4 (PRG4). Biorheology. 2006; 43(3,4):191-200. View

Ke J, Zhang C, Harikumar K, Zylstra-Diegel C, Wang L, Mowry L . Modulation of β-catenin signaling by glucagon receptor activation. PLoS One. 2012; 7(3):e33676. PMC: 3306284. DOI: 10.1371/journal.pone.0033676. View

Sugimoto Y, Narumiya S . Prostaglandin E receptors. J Biol Chem. 2007; 282(16):11613-7. DOI: 10.1074/jbc.R600038200. View

Adriouch S, Dox C, Welge V, Seman M, Koch-Nolte F, Haag F . Cutting edge: a natural P451L mutation in the cytoplasmic domain impairs the function of the mouse P2X7 receptor. J Immunol. 2002; 169(8):4108-12. DOI: 10.4049/jimmunol.169.8.4108. View

Xia X, Batra N, Shi Q, Bonewald L, Sprague E, Jiang J . Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/beta-catenin signaling. Mol Cell Biol. 2009; 30(1):206-19. PMC: 2798309. DOI: 10.1128/MCB.01844-08. View

Knight M, McGlashan S, Garcia M, Jensen C, Poole C . Articular chondrocytes express connexin 43 hemichannels and P2 receptors - a putative mechanoreceptor complex involving the primary cilium?. J Anat. 2009; 214(2):275-83. PMC: 2667885. DOI: 10.1111/j.1469-7580.2008.01021.x. View

Long F, Schipani E, Asahara H, Kronenberg H, Montminy M . The CREB family of activators is required for endochondral bone development. Development. 2001; 128(4):541-50. DOI: 10.1242/dev.128.4.541. View

10.

Chen X, Macica C, Nasiri A, Broadus A . Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis Rheum. 2008; 58(12):3788-97. PMC: 2599803. DOI: 10.1002/art.23985. View

11.

Burnstock G . Purinergic signalling: Its unpopular beginning, its acceptance and its exciting future. Bioessays. 2012; 34(3):218-25. DOI: 10.1002/bies.201100130. View

12.

Gosset M, Berenbaum F, Thirion S, Jacques C . Primary culture and phenotyping of murine chondrocytes. Nat Protoc. 2008; 3(8):1253-60. DOI: 10.1038/nprot.2008.95. View

13.

Li J, Burr D, Turner C . Suppression of prostaglandin synthesis with NS-398 has different effects on endocortical and periosteal bone formation induced by mechanical loading. Calcif Tissue Int. 2002; 70(4):320-9. DOI: 10.1007/s00223-001-1025-y. View

14.

Ahn S, Olive M, Aggarwal S, Krylov D, Ginty D, Vinson C . A dominant-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos. Mol Cell Biol. 1998; 18(2):967-77. PMC: 108809. DOI: 10.1128/MCB.18.2.967. View

15.

Kisiday J, Kurz B, DiMicco M, Grodzinsky A . Evaluation of medium supplemented with insulin-transferrin-selenium for culture of primary bovine calf chondrocytes in three-dimensional hydrogel scaffolds. Tissue Eng. 2005; 11(1-2):141-51. DOI: 10.1089/ten.2005.11.141. View

16.

Kahn J, Shwartz Y, Blitz E, Krief S, Sharir A, Breitel D . Muscle contraction is necessary to maintain joint progenitor cell fate. Dev Cell. 2009; 16(5):734-43. DOI: 10.1016/j.devcel.2009.04.013. View

17.

Macica C, Liang G, Nasiri A, Broadus A . Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model. Arthritis Rheum. 2011; 63(11):3333-43. PMC: 3197958. DOI: 10.1002/art.30515. View

18.

Lefebvre V, Bhattaram P . Vertebrate skeletogenesis. Curr Top Dev Biol. 2010; 90:291-317. PMC: 3077680. DOI: 10.1016/S0070-2153(10)90008-2. View

19.

Galea G, Sunters A, Meakin L, Zaman G, Sugiyama T, Lanyon L . Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4. FEBS Lett. 2011; 585(15):2450-4. PMC: 3149668. DOI: 10.1016/j.febslet.2011.06.019. View

20.

Li J, Liu D, Ke H, Duncan R, Turner C . The P2X7 nucleotide receptor mediates skeletal mechanotransduction. J Biol Chem. 2005; 280(52):42952-9. DOI: 10.1074/jbc.M506415200. View