Mitogen-activated Protein Kinases As Therapeutic Targets in Osteoarthritis

Overview

Journal Curr Opin Rheumatol

Specialty Rheumatology

Date 2008 Aug 14

PMID 18698181

Citations 69

Authors

Richard F Loeser

Elizabeth A Erickson

David L Long

Affiliations

Soon will be listed here.

Abstract

Purpose Of Review: The mitogen-activated protein (MAP) kinases are intracellular signaling proteins which play a central role in controlling the activity of pathways that regulate production and activity of multiple mediators of joint tissue destruction. The therapeutic potential of MAP kinase inhibition in osteoarthritis was reviewed.

Recent Findings: Results from basic research studies support the role of MAP kinases as central mediators that regulate expression of proinflammatory cytokines and metalloproteinases but also as potential pain mediators as well. Cell culture and animal model studies suggest that inhibition of MAP kinases might slow progression of osteoarthritis but trials of MAP kinase inhibitors in humans with osteoarthritis have not yet been reported. Safety concerns of the currently available inhibitors have limited their initial use to trials in conditions considered more severe than osteoarthritis.

Summary: MAP kinase inhibition has the potential to slow disease progression in osteoarthritis and also might reduce pain; however, safety concerns have limited the use of general MAP kinase inhibitors in humans. Further understanding of the function of specific isoforms of the MAP kinases as well as upstream and downstream effectors may lead to the development of more specific inhibitors with less toxicity that could eventually be used as structure-modifying drugs for osteoarthritis.

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References

Medicherla S, Ma J, Mangadu R, Jiang Y, Zhao J, Almirez R . A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther. 2006; 318(1):132-41. DOI: 10.1124/jpet.105.098020. View

Masuko K, Murata M, Nakamura H, Yudoh K, Nishioka K, Kato T . Sphingosine-1-phosphate attenuates proteoglycan aggrecan expression via production of prostaglandin E2 from human articular chondrocytes. BMC Musculoskelet Disord. 2007; 8:29. PMC: 1847513. DOI: 10.1186/1471-2474-8-29. View

Gabay O, Gosset M, Levy A, Salvat C, Sanchez C, Pigenet A . Stress-induced signaling pathways in hyalin chondrocytes: inhibition by Avocado-Soybean Unsaponifiables (ASU). Osteoarthritis Cartilage. 2007; 16(3):373-84. DOI: 10.1016/j.joca.2007.06.016. View

Boileau C, Martel-Pelletier J, Brunet J, Schrier D, Flory C, Boily M . PD-0200347, an alpha2delta ligand of the voltage gated calcium channel, inhibits in vivo activation of the Erk1/2 pathway in osteoarthritic chondrocytes: a PKCalpha dependent effect. Ann Rheum Dis. 2005; 65(5):573-80. PMC: 1798126. DOI: 10.1136/ard.2005.041855. View

Fan Z, Soder S, Oehler S, Fundel K, Aigner T . Activation of interleukin-1 signaling cascades in normal and osteoarthritic articular cartilage. Am J Pathol. 2007; 171(3):938-46. PMC: 1959501. DOI: 10.2353/ajpath.2007.061083. View

Pelletier J, Fernandes J, Brunet J, Moldovan F, Schrier D, Flory C . In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. Arthritis Rheum. 2003; 48(6):1582-93. DOI: 10.1002/art.11014. View

Starkman B, Cravero J, DelCarlo M, Loeser R . IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J. 2005; 389(Pt 3):723-9. PMC: 1180722. DOI: 10.1042/BJ20041636. View

Krzeski P, Buckland-Wright C, Balint G, Cline G, Stoner K, Lyon R . Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res Ther. 2007; 9(5):R109. PMC: 2212568. DOI: 10.1186/ar2315. View

Ruettger A, Schueler S, Mollenhauer J, Wiederanders B . Cathepsins B, K, and L are regulated by a defined collagen type II peptide via activation of classical protein kinase C and p38 MAP kinase in articular chondrocytes. J Biol Chem. 2007; 283(2):1043-51. DOI: 10.1074/jbc.M704915200. View

10.

Johnson G, Nakamura K . The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta. 2007; 1773(8):1341-8. PMC: 1995559. DOI: 10.1016/j.bbamcr.2006.12.009. View

11.

Bogoyevitch M . Therapeutic promise of JNK ATP-noncompetitive inhibitors. Trends Mol Med. 2005; 11(5):232-9. DOI: 10.1016/j.molmed.2005.03.005. View

12.

Badger A, Griswold D, Kapadia R, Blake S, Swift B, Hoffman S . Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum. 2000; 43(1):175-83. DOI: 10.1002/1529-0131(200001)43:1<175::AID-ANR22>3.0.CO;2-S. View

13.

Boileau C, Martel-Pelletier J, Brunet J, Tardif G, Schrier D, Flory C . Oral treatment with PD-0200347, an alpha2delta ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible nitric oxide synthase gene expression and synthesis in cartilage chondrocytes. Arthritis Rheum. 2005; 52(2):488-500. DOI: 10.1002/art.20809. View

14.

Liacini A, Sylvester J, Li W, Huang W, Dehnade F, Ahmad M . Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Exp Cell Res. 2003; 288(1):208-17. DOI: 10.1016/s0014-4827(03)00180-0. View

15.

Hegen M, Gaestel M, Nickerson-Nutter C, Lin L, Telliez J . MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol. 2006; 177(3):1913-7. DOI: 10.4049/jimmunol.177.3.1913. View

16.

Han Z, Boyle D, Chang L, Bennett B, Karin M, Yang L . c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest. 2001; 108(1):73-81. PMC: 209341. DOI: 10.1172/JCI12466. View

17.

Goldring M, Goldring S . Osteoarthritis. J Cell Physiol. 2007; 213(3):626-34. DOI: 10.1002/jcp.21258. View

18.

Cha H, Boyle D, Inoue T, Schoot R, Tak P, Pine P . A novel spleen tyrosine kinase inhibitor blocks c-Jun N-terminal kinase-mediated gene expression in synoviocytes. J Pharmacol Exp Ther. 2006; 317(2):571-8. DOI: 10.1124/jpet.105.097436. View

19.

Ehling A, Schaffler A, Herfarth H, Tarner I, Anders S, Distler O . The potential of adiponectin in driving arthritis. J Immunol. 2006; 176(7):4468-78. DOI: 10.4049/jimmunol.176.7.4468. View

20.

Im H, Muddasani P, Natarajan V, Schmid T, Block J, Davis F . Basic fibroblast growth factor stimulates matrix metalloproteinase-13 via the molecular cross-talk between the mitogen-activated protein kinases and protein kinase Cdelta pathways in human adult articular chondrocytes. J Biol Chem. 2007; 282(15):11110-21. PMC: 2895271. DOI: 10.1074/jbc.M609040200. View