title: Osteoarthritis year 2010 in review: pathomechanisms.
abstract: Osteoarthritis is characterized by progressive breakdown of articular cartilage. This review summarizes findings of the last year, which shed new light on mechanisms and factors involved in cartilage loss. Evidence is accumulating that the transcription factor hypoxia-inducible factor-2α (HIF-2α) is highly enhanced in OA cartilage and drives catabolic metalloproteinases, including the pivotal MMP-13. In addition, HIF-2α suppresses chondrocyte autophagy, herein promoting chondrocyte apoptosis. The crucial role of MMP-13 is further underlined by reduced OA pathology in MMP-13 deficient mice. An intriguing mechanism to drive MMP-13 production is activation of the chondrocyte discoidin domain receptor (DDR-2) receptor through interaction with denuded collagen type II. The latter might occur in a proteoglycan depleted peri-cellular matrix, where DDR-2 expression is enhanced in OA cartilage and transgenic suppression attenuates experimental OA. The initiating role of ADAMTS-5 in proteoglycan loss appears dependent on interaction with the transmembrane proteoglycan syndecan-4, since syndecan-4 deficient mice are less prone to experimental OA and display reduced ADAMTS-5 activity. Both aging and the osteoarthritis (OA) process itself induce deranged transforming growth factor-β (TGFβ)-receptor expression, causing a shift to dominant usage of the receptor ALK-1, in stead of ALK5 and resulting in a TGFβ mediated catabolic pathway. ALK-1 rather than TGFβ is a promising therapeutic target. Finally, the alarmins S100A8 and 9 have long been considered as markers of inflammatory joint destruction, but now appear to be catabolic mediators.
authors.affiliation: Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Med Center (RUNMC), The Netherlands. w.vandenberg@reuma.umcn.nl
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism* / Q000503:physiopathology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011975:Receptors, Mitogen / Q000378:metabolism; D053671:Syndecan-4 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D000070818:Discoidin Domain Receptors; D053509:Matrix Metalloproteinase 13; D020794:Receptor Protein-Tyrosine Kinases; D011975:Receptors, Mitogen; D053671:Syndecan-4; D016212:Transforming Growth Factor beta; D000099162:Endothelial PAS Domain-Containing Protein 1