RRC ID 62214
Author Allen JL, Cooke ME, Alliston T.
Title ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation.
Journal Mol Biol Cell
Abstract Cells encounter physical cues such as extracellular matrix (ECM) stiffness in a microenvironment replete with biochemical cues. However, the mechanisms by which cells integrate physical and biochemical cues to guide cellular decision making are not well defined. Here we investigate mechanisms by which chondrocytes generate an integrated response to ECM stiffness and transforming growth factor β (TGFβ), a potent agonist of chondrocyte differentiation. Primary murine chondrocytes and ATDC5 cells grown on 0.5-MPa substrates deposit more proteoglycan and express more Sox9, Col2α1, and aggrecan mRNA relative to cells exposed to substrates of any other stiffness. The chondroinductive effect of this discrete stiffness, which falls within the range reported for articular cartilage, requires the stiffness-sensitive induction of TGFβ1. Smad3 phosphorylation, nuclear localization, and transcriptional activity are specifically increased in cells grown on 0.5-MPa substrates. ECM stiffness also primes cells for a synergistic response, such that the combination of ECM stiffness and exogenous TGFβ induces chondrocyte gene expression more robustly than either cue alone through a p38 mitogen-activated protein kinase-dependent mechanism. In this way, the ECM stiffness primes the TGFβ pathway to efficiently promote chondrocyte differentiation. This work reveals novel mechanisms by which cells integrate physical and biochemical cues to exert a coordinated response to their unique cellular microenvironment.
Volume 23(18)
Pages 3731-42
Published 2012-9-1
DOI 10.1091/mbc.E12-03-0172
PII mbc.E12-03-0172
PMID 22833566
PMC PMC3442419
MeSH Aggrecans / genetics Aggrecans / metabolism Animals Blotting, Western Cell Differentiation / drug effects* Cell Line Cells, Cultured Chondrocytes / cytology Chondrocytes / drug effects* Chondrocytes / metabolism Collagen Type II / genetics Collagen Type II / metabolism Extracellular Matrix / chemistry Extracellular Matrix / metabolism* Gene Expression / drug effects Mice Phosphorylation / drug effects Physical Phenomena Reverse Transcriptase Polymerase Chain Reaction SOX9 Transcription Factor / genetics SOX9 Transcription Factor / metabolism Signal Transduction Smad3 Protein / metabolism Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism Transforming Growth Factor beta / pharmacology* rho-Associated Kinases / metabolism
IF 3.791
Human and Animal Cells ATDC5(RCB0565)