title: Mechanical impact induces cartilage degradation via mitogen activated protein kinases.
abstract: OBJECTIVE
  To determine the activation of Mitogen activated protein (MAP) kinases in and around cartilage subjected to mechanical damage and to determine the effects of their inhibitors on impaction-induced chondrocyte death and cartilage degeneration.
  
  
  METHODS
  The phosphorylation of MAP kinases was examined with confocal microscopy and immunoblotting. The effects of MAP kinase inhibitors on impaction-induced chondrocyte death and proteoglycan (PG) loss were determined with fluorescent microscopy and 1, 9-Dimethyl-Methylene Blue (DMMB) assay. The expression of catabolic genes at mRNA levels was examined with quantitative real-time PCR.
  
  
  RESULTS
  Early p38 activation was detected at 20 min and 1h post-impaction. At 24h, enhanced phosphorylation of p38 and extracellular signal-regulated protein kinase (ERK)1/2 was visualized in chondrocytes from in and around impact sites. The phosphorylation of p38 was increased by 3.0-fold in impact sites and 3.3-fold in adjacent cartilage. The phosphorylation of ERK-1 was increased by 5.8-fold in impact zone and 5.4-fold in adjacent cartilage; the phosphorylation of ERK-2 increased by 4.0-fold in impacted zone and 3.6-fold in adjacent cartilage. Furthermore, the blocking of p38 pathway did not inhibit impaction-induced ERK activation. The inhibition of p38 or ERK pathway significantly reduced injury-related chondrocyte death and PG losses. Quantitative Real-time PCR analysis revealed that blunt impaction significantly up-regulated matrix metalloproteinase (MMP)-13, Tumor necrosis factor (TNF)-α, and ADAMTS-5 expression.
  
  
  CONCLUSIONS
  These findings implicate p38 and ERK mitogen activated protein kinases (MAPKs) in the post-injury spread of cartilage degeneration and suggest that the risk of post-traumatic osteoarthritis (PTOA) following joint trauma could be decreased by blocking their activities, which might be involved in up-regulating expressions of MMP-13, ADAMTS-5, and TNF-α.
authors.affiliation: Department of Orthopaedics and Rehabilitation, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ding
authors.forename: E
authors.initials: E
authors.lastname: Heying
authors.forename: N
authors.initials: N
authors.lastname: Nicholson
authors.forename: N J
authors.initials: NJ
authors.lastname: Stroud
authors.forename: G A
authors.initials: GA
authors.lastname: Homandberg
authors.forename: J A
authors.initials: JA
authors.lastname: Buckwalter
authors.forename: D
authors.initials: D
authors.lastname: Guo
authors.forename: J A
authors.initials: JA
authors.lastname: Martin
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology / Q000293:injuries* / Q000378:metabolism*; D002417:Cattle; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D019902:Chondrocytes / Q000201:enzymology / Q000502:physiology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000032:analysis; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D011509:Proteoglycans; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Arthritis Rheum. 1998 Feb;41(2):284-9
references.pmid: 9485086
references.citation: J Cell Physiol. 2003 Dec;197(3):356-69
references.pmid: 14566965
references.citation: Cell Mol Life Sci. 2002 Jan;59(1):5-18
references.pmid: 11846033
references.citation: J Orthop Res. 2000 Jan;18(1):25-34
references.pmid: 10716275
references.citation: J Rheumatol. 2001 Nov;28(11):2509-19
references.pmid: 11708426
references.citation: Arch Pharm Res. 2008 Jun;31(6):786-93
references.pmid: 18563362
references.citation: J Biol Chem. 2008 Sep 12;283(37):25171-25177
references.pmid: 18625709
references.citation: Arch Biochem Biophys. 1995 Sep 10;322(1):87-96
references.pmid: 7574698
references.citation: Nat Med. 2009 Sep;15(9):1072-6
references.pmid: 19684582
references.citation: J Biomech Eng. 1999 Oct;121(5):433-41
references.pmid: 10529909
references.citation: J Orthop Res. 2006 Feb;24(2):220-8
references.pmid: 16435355
references.citation: Clin Orthop Relat Res. 2004 Jun;(423):7-16
references.pmid: 15232420
references.citation: J Biol Chem. 2008 Jan 11;283(2):1043-51
references.pmid: 17991740
references.citation: Autoimmunity. 1998;28(4):197-208
references.pmid: 9892501
references.citation: Rev Chir Orthop Reparatrice Appar Mot. 1976 Jul-Aug;62(5):493-500
references.pmid: 137473
references.citation: J Cell Physiol. 2009 Jun;219(3):642-51
references.pmid: 19180563
references.citation: Rheumatology (Oxford). 2006 Oct;45(10):1201-9
references.pmid: 16571608
references.citation: Arthritis Rheum. 1998 Sep;41(9):1632-8
references.pmid: 9751096
references.citation: Biorheology. 2006;43(3,4):517-21
references.pmid: 16912423
references.citation: J Mol Cell Cardiol. 2007 Aug;43(2):137-47
references.pmid: 17583725
references.citation: J Orthop Res. 2001 Jul;19(4):703-11
references.pmid: 11518282
references.citation: Instr Course Lect. 2000;49:481-9
references.pmid: 10829201
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3094-9
references.pmid: 9501221
references.citation: Inflamm Res. 2009 Mar;58(3):161-9
references.pmid: 19190855
references.citation: Ann Anat. 2005 Nov;187(5-6):473-85
references.pmid: 16320827
references.citation: J Bone Joint Surg Am. 1977 Dec;59(8):1068-76
references.pmid: 591538
references.citation: J Orthop Res. 1998 Jul;16(4):490-9
references.pmid: 9747792
references.citation: J Orthop Trauma. 2003 Oct;17(9):635-41
references.pmid: 14574191
references.citation: J Biol Chem. 2003 Apr 18;278(16):13680-7
references.pmid: 12591927
references.citation: Inflamm Res. 2008 Jul;57(7):306-13
references.pmid: 18545934
references.citation: J Bone Joint Surg Am. 2009 Aug;91(8):1890-7
references.pmid: 19651946
references.citation: Curr Opin Rheumatol. 2004 Sep;16(5):634-9
references.pmid: 15314507
references.citation: Am J Epidemiol. 1989 Aug;130(2):278-88
references.pmid: 2750727
references.citation: Int J Exp Pathol. 2009 Oct;90(5):463-79
references.pmid: 19765101
references.citation: Arthritis Rheum. 2000 Jan;43(1):215-25
references.pmid: 10643718
references.citation: Arch Biochem Biophys. 1991 Apr;286(1):20-9
references.pmid: 1897947
references.citation: Osteoarthritis Cartilage. 2008 Oct;16(10):1253-62
references.pmid: 18396067
references.citation: J Bone Joint Surg Br. 2007 Oct;89(10):1388-95
references.pmid: 17957084
references.citation: Arthritis Rheum. 2006 May;54(5):1509-17
references.pmid: 16649187
references.citation: Apoptosis. 2004 May;9(3):265-77
references.pmid: 15258458
references.citation: J Cell Sci. 1998 Mar;111 ( Pt 5):573-83
references.pmid: 9454731
references.citation: Hypertension. 2003 Apr;41(4):903-11
references.pmid: 12642506
references.citation: J Tissue Eng Regen Med. 2009 Feb;3(2):107-16
references.pmid: 19177463
references.citation: Osteoarthritis Cartilage. 2001 Nov;9(8):712-9
references.pmid: 11795990
references.citation: Food Chem Toxicol. 2008 Aug;46(8):2865-70
references.pmid: 18603343
references.citation: J Orthop Res. 2004 May;22(3):678-83
references.pmid: 15099652