Shear- and compression-induced chondrocyte transcription requires MAPK activation in cartilage explants
Authors
Fitzgerald, Jonathan B.Jin, Moonsoo
Chai, Diana H.
Siparsky, Patrick
Fanning, Paul J.
Grodzinsky, Alan J.
UMass Chan Affiliations
Department of Orthopedics and Physical RehabilitationDocument Type
Journal ArticlePublication Date
2008-03-19Keywords
ADAM ProteinsAnimals
Cartilage
Cattle
Chondrocytes
MAP Kinase Signaling System
Matrix Metalloproteinase 13
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Models, Biological
RNA, Messenger
Stress, Mechanical
Time Factors
*Transcription, Genetic
p38 Mitogen-Activated Protein Kinases
Orthopedics
Rehabilitation and Therapy
Metadata
Show full item recordAbstract
Chondrocytes regulate the composition of cartilage extracellular matrix in response to mechanical signals, but the intracellular pathways involved in mechanotransduction are still being defined. Mitogen-activated protein kinase (MAPK) pathways are activated by static and dynamic compression of cartilage, which simultaneously induce intratissue fluid flow, pressure gradients, cell, and matrix deformation. First, to determine whether cell and matrix deformation alone could induce MAPK activation, we applied dynamic shear to bovine cartilage explants. Using Western blotting, we measured ERK1/2 and p38 activation at multiple time points over 24 h. Distinct activation time courses were observed for different MAPKs: a sustained 50% increase for ERK1/2 and a delayed increase in p38 of 180%. We then investigated the role of MAPK activation in mechano-induced chondrocyte gene expression. Cartilage explants were preincubated with inhibitors of ERK1/2 and p38 activation before application of 1-24 h of three distinct mechanical stimuli relevant to in vivo loading (50% static compression, 3% dynamic compression at 0.1 Hz, or 3% dynamic shear at 0.1 Hz). mRNA levels of selected genes involved in matrix homeostasis were measured using real-time PCR and analyzed by k-means clustering to characterize the time- and load-dependent effects of the inhibitors. Most genes examined required ERK1/2 and p38 activation to be regulated by these loading regimens, including matrix proteins aggrecan and type II collagen, matrix metalloproteinases MMP13, and ADAMTS5, and transcription factors downstream of the MAPK pathway, c-Fos, and c-Jun. Thus, we demonstrated that the MAPK pathway is a central conduit for transducing mechanical forces into biological responses in cartilage.Source
J Biol Chem. 2008 Mar 14;283(11):6735-43. Epub 2007 Dec 17. Link to article on publisher's siteDOI
10.1074/jbc.M708670200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43058PubMed ID
18086670Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M708670200