Understanding the role of tissue degrading enzymes and their inhibitors in development and disease

Cartilage and the underlying bone are destroyed in severe cases of arthritis preventing joints from functioning normally. Cartilage and bone collagen can be specifically cleaved by the collagenases, members of the matrix metalloproteinase family (MMPs), whilst cartilage aggrecan is degraded by members of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin repeats) family of proteinases. Intracellular cysteine proteinases are involved in bone resorption by osteoclasts and the serine proteinases are involved in activating MMPs. Together, these enzymes act in concert during normal growth and development, especially within the growth plate; however they are also involved in tissue destruction during disease. Synthetic MMP inhibitors have been investigated as a means to block tissue destruction in arthritis but have been unsuccessful, although recent trials with doxycycline suggest this may block joint destruction in osteoarthritis. It is likely that combinations of therapy will be required to ensure that joint destruction is prevented in arthritis patients.

Key words: metalloproteinase, cartilage, collagen, extracellular matrix, growth plate, arthritis, inhibitor

Abbreviations: ADAM, a disintegrin and metalloproteinase, ADAMTS, A Disintegrin And Metalloproteinase with ThromboSpondin motifs, Ala, alanine, BMP, bone morphogenetic protein, ECM, extracellular matrix, FDA, Food and Drug Administration, FLRG, follistatin-related gene, Glu, glutamine, GPI, glycosylphosphatidyl inositol, HDAC, histone deacetylase, HDACi, histone deacetylase inhibitor, IGF, insulin-like growth factor, IGFBP, insulin-like growth factor binding protein, IkB, Inhibitor of kappa B, IL, interleukin, Jak-STAT, janus kinase-signal tranducer and activator of transcription, Ki, kinetic inhibition constant (reversible), MAPK, mitogen-activated protein kinase, MAPK-JNK, mitogen-activated protein kinase–c-Jun NH2-terminal kinase, MMP, matrix metalloproteinases, MRI, magnetic resonance imaging, mRNA, messenger ribonucleic acid, NF-κB, nuclear factor kappa B, OA, osteoarthritis, OSM, oncostatin M, PI3, phosphatidylinositol-3 protein, RA, rheumatoid arthritis, Runx, runt transcription factor family, Sox, SRY-related transcription factor family, TGF, transforming growth factor, TIMP, tissue inhibitors of metalloproteinases, TNF, tumour necrosis factor, tPA, tissue-type plasminogen activator, uPA, urokinase-type plasminogen activator, US, United States of America, VEGF, vascular endothelial growth factor