Early and stable upregulation of collagen type II, collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading.
While morphologic and biochemical aspects of degenerative joint disease (osteoarthritis [OA]) have been elucidated by numerous studies, the molecular mechanisms underlying the progressive loss of articular cartilage during OA development remain largely unknown. The main focus of the present study was to gain more insight into molecular changes during the very early stages of mechanically induced cartilage degeneration and to relate molecular alterations to histological changes at distinct localizations of the joint. Studies on human articular cartilage are hampered by the difficulty of obtaining normal tissue and early-stage OA tissue, and they allow no progressive follow-up. An experimental OA model in dogs with a slow natural history of OA (Pond-Nuki model) was therefore chosen. Anterior cruciate ligament transection (ACLT) was performed on 24 skeletally mature dogs to induce joint instability resulting in OA. Samples were taken from different joint areas after 6, 12, 24 and 48 weeks, and gene expression levels of common cartilage molecules were quantified in relation to the histological grading (modified Mankin score) of adjacent tissue. Histological changes reflected early progressive degenerative OA. Soon after ACLT, chondrocytes responded to the altered mechanical conditions by significant and stable elevation of collagen type II, collagen type I and YKL40 expression, which persisted throughout the study. In contrast to the mild to moderate histological alterations, these molecular changes were not progressive and were independent of the joint localization (tibia, femur, lateral, medial) and the extent of matrix degeneration. MMP13 remained unaltered until 24 weeks, and aggrecan and tenascinC remained unaltered until 48 weeks after ACLT. These findings indicate that elevated collagen type II, collagen type I and YKL40 mRNA expression levels are early and sensitive measures of ACLT-induced joint instability independent of a certain grade of morphological cartilage degeneration. A second phase of molecular changes in OA may begin around 48 weeks after ACLT with altered expression of further genes, such as MMP13, aggrecan and tenascin. Molecular changes observed in the present study suggest that dog cartilage responds to degenerative conditions by regulating the same genes in a similar direction as that observed for chondrocytes in late human OA.
Lorenz
Helga
H
Division of Experimental Orthopedics, University of Heidelberg, Germany. helga.lorenz@ok.uni-heidelberg.de
Wenz
Wolfram
W
Ivancic
Mate
M
Steck
Eric
E
Richter
Wiltrud
W
D054392:Adipokines; D053674:Aggrecans; D000818:Animals; D000070598:Anterior Cruciate Ligament Injuries; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D000071451:Chitinase-3-Like Protein 1; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D024043:Collagen Type II / Q000096:biosynthesis* / Q000235:genetics; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D004285:Dogs; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D007593:Joint Instability / Q000150:complications; D037102:Lectins; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D020370:Osteoarthritis, Knee / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019063:Tenascin / Q000096:biosynthesis / Q000235:genetics
D054392:Adipokines; D053674:Aggrecans; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D011508:Chondroitin Sulfate Proteoglycans; D024042:Collagen Type I; D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D037102:Lectins; D037181:Lectins, C-Type; D019063:Tenascin; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13