title: YAP-mediated regulation of the chondrogenic phenotype in response to matrix elasticity.
abstract: Matrix elasticity exerts considerable influence on the phenotype of terminally differentiated chondrocytes via physical cues. The Yes-associated protein (YAP) transcription co-activator is recognized as a key mediator that may be involved in the nuclear transduction of physical cues controlling cellular behavior and function. However, whether substrate elasticity in the regulation of the chondrocyte phenotype is associated with YAP remains unclear. In this work, we developed micropatterned substrates with varying stiffnesses to investigate the function of YAP and its related Hippo pathway kinases in the regulation of chondrocyte phenotype on soft and stiff substrates. We found that the phenotypic variation of chondrocytes in response to substrate stiffness is concomitant with the changes in YAP localization. The downregulation of YAP expression helps to maintain the chondrogenic phenotype while inhibiting chondrocyte proliferation. Furthermore, the change in the chondrocyte phenotype response to LATS1 kinase inactivation in the Hippo pathway varies significantly between soft and stiff substrates. We also found that LATS1 kinase inactivation promotes chondrocyte dedifferentiation only on stiff substrate. Collectively, these findings reveal that YAP may be involved in the changes that occur in chondrocytes cultured on substrates with different stiffnesses and that these changes do not entirely depend on the Hippo pathway kinase LATS1. Importantly, our findings indicate that YAP inactivation is conducive to the maintenance of the chondrogenic phenotype, thereby providing new insight into articular cartilage repair and regeneration mechanisms.
authors.affiliation: Department of Orthopaedics, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhong
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Linan
authors.initials: L
authors.lastname: Li
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.forename: Shouyu
authors.initials: S
authors.lastname: Wang
authors.forename: Xifu
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002358:Cartilage, Articular / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004129:Dimethylpolysiloxanes / Q000737:chemistry; D004548:Elasticity; D005786:Gene Expression Regulation; D006244:Hardness; D008297:Male; D010641:Phenotype; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins
chemical_list: D000180:Acrylic Resins; D051017:Apoptosis Regulatory Proteins; D004129:Dimethylpolysiloxanes; D034741:RNA, Small Interfering; D055758:SOX9 Transcription Factor; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; C016680:polyacrylamide gels; C013830:baysilon; D017346:Protein Serine-Threonine Kinases
references.citation: Science. 2009 Jan 30;323(5914):642-4
references.pmid: 19179533
references.citation: N Engl J Med. 1994 Oct 6;331(14):889-95
references.pmid: 8078550
references.citation: Dev Cell. 2004 Apr;6(4):483-95
references.pmid: 15068789
references.citation: Clin Orthop Relat Res. 2000 May;(374):212-34
references.pmid: 10818982
references.citation: Development. 2011 Sep;138(18):3907-14
references.pmid: 21831922
references.citation: Nature. 2011 Jun 08;474(7350):179-83
references.pmid: 21654799
references.citation: Stem Cells Dev. 2013 Jul 15;22(14):2083-93
references.pmid: 23442010
references.citation: Biomaterials. 2011 Jun;32(16):3921-30
references.pmid: 21397942
references.citation: J Cell Sci. 2011 Apr 15;124(Pt 8):1195-205
references.pmid: 21444750
references.citation: Nat Protoc. 2008;3(8):1253-60
references.pmid: 18714293
references.citation: Dev Biol. 2012 Jan 1;361(1):103-15
references.pmid: 22037235
references.citation: Clin Orthop Relat Res. 2002 Sep;(402):21-37
references.pmid: 12218470
references.citation: Dev Cell. 2010 Oct 19;19(4):491-505
references.pmid: 20951342
references.citation: Cell. 2012 Aug 17;150(4):780-91
references.pmid: 22863277
references.citation: Curr Protoc Cell Biol. 2010 Jun;Chapter 10:Unit 10.16
references.pmid: 20521229
references.citation: Genes Dev. 2010 Jun 1;24(11):1106-18
references.pmid: 20516196
references.citation: J Cell Sci. 2010 Feb 1;123(Pt 3):297-308
references.pmid: 20130138
references.citation: Mol Biol Cell. 2012 Sep;23(18):3731-42
references.pmid: 22833566
references.citation: Cell. 2007 Sep 21;130(6):1120-33
references.pmid: 17889654
references.citation: Nat Rev Mol Cell Biol. 2009 Jan;10(1):21-33
references.pmid: 19197329
references.citation: J Cell Sci. 2011 Apr 1;124(Pt 7):1136-44
references.pmid: 21385842
references.citation: Arthritis Rheum. 2011 Jul;63(7):1938-49
references.pmid: 21425129
references.citation: Genes Dev. 2007 Nov 1;21(21):2747-61
references.pmid: 17974916
references.citation: Nat Rev Mol Cell Biol. 2012 Sep;13(9):591-600
references.pmid: 22895435
references.citation: Nat Cell Biol. 2011 Aug 01;13(8):877-83
references.pmid: 21808241
references.citation: Tissue Eng Part A. 2010 Apr;16(4):1281-90
references.pmid: 19903088