Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling.
OBJECTIVE
The membrane-anchored metalloproteinase disintegrin ADAM15 is up-regulated in osteoarthritis and has been implicated in proteolysis and cell-matrix interactions. To address its role in cartilage metabolism, we performed an analysis of joint morphology in aging mice with a targeted inactivation of the ADAM15 gene (ADAM15(-/-)). In addition, a human chondrocyte cell line overexpressing ADAM15 was used to investigate the role of ADAM15 in an in vitro model of chondrocyte-matrix interactions.


METHODS
Knee joint sections from 3-, 6-, and 12-14-month-old ADAM15(-/-) and wild-type (WT) 129/SvJ mice were examined for synovial hyperplasia, cartilage degradation, and osteophyte formation. Stable transfection of the human T/C28a4 chondrocyte cell line with full-length human ADAM15 complementary DNA led to the establishment of ADAM15-overexpressing chondrocytes that were further analyzed for their capability to adhere to and to survive on cartilage matrix molecules (fibronectin and types II and VI collagen) under conditions of serum starvation. ADAM15 expression was investigated by reverse transcription-polymerase chain reaction and Western blotting.


RESULTS
Aging ADAM15(-/-) mice exhibited accelerated development of osteoarthritic lesions compared with WT mice, and the difference was statistically significant at age 12 months. The osteoarthritic changes preferentially affected male ADAM15(-/-) mice. ADAM15 overexpression in T/C28a4 cells led to the specific reinforcement of chondrocyte adhesion to cartilage types II and VI collagen, and this was associated with enhanced cell viability under conditions of serum starvation.


CONCLUSIONS
The accelerated development of murine osteoarthritis in ADAM15 deficiency as well as the proadhesive and cell survival-promoting in vitro effect of ADAM15 overexpression suggest a homeostatic rather than a destructive role of ADAM15 in cartilage remodeling.
Böhm
Beate B
BB
Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
Aigner
Thomas
T
Roy
Barbara
B
Brodie
Thomas A
TA
Blobel
Carl P
CP
Burkhardt
Harald
H
D051722:ADAM Proteins; D000375:Aging / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D019902:Chondrocytes / Q000201:enzymology* / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020370:Osteoarthritis, Knee / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013264:Stifle / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology; D014162:Transfection
D008565:Membrane Proteins; D012333:RNA, Messenger; D051722:ADAM Proteins; C490902:Adam15 protein, mouse; D008666:Metalloendopeptidases