Accelerated development of aging-associated and instability-induced osteoarthritis in osteopontin-deficient mice.
OBJECTIVE
To investigate the role of osteopontin (OPN) in the development of osteoarthritis (OA) under in vivo and in vitro conditions.


METHODS
Both instability-induced and aging-associated OA models were generated using OPN-deficient (OPN-/-) and control wild-type (WT) mice. An in vitro cartilage degradation model was also used, to evaluate the effect of OPN on proteoglycan loss from joint cartilage.


RESULTS
OPN deficiency exacerbated both aging-associated and instability-induced OA. Both structural changes and an increased loss of proteoglycan from cartilage tissue were augmented in the absence of OPN. OPN deficiency also led to the induction of matrix metalloproteinase 13 (MMP-13), which degrades a major component of the cartilage matrix protein type II collagen. Both the loss of proteoglycan and the induction of the collagen-degrading enzyme MMP-13 facilitated the development of OA.


CONCLUSIONS
OPN plays a pivotal role in the progression of both instability-induced and aging-associated spontaneous OA. OPN is a critical intrinsic regulator of cartilage degradation via its effects on MMP-13 expression and proteoglycan loss.
Matsui
Yuichiro
Y
Institute for Genetic Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Iwasaki
Norimasa
N
Kon
Shigeyuki
S
Takahashi
Daisuke
D
Morimoto
Junko
J
Matsui
Yutaka
Y
Denhardt
David T
DT
Rittling
Susan
S
Minami
Akio
A
Uede
Toshimitsu
T
D000375:Aging; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007593:Joint Instability / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D053495:Osteopontin / Q000172:deficiency* / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013264:Stifle / Q000378:metabolism / Q000473:pathology / Q000601:surgery
D011509:Proteoglycans; D012333:RNA, Messenger; D053495:Osteopontin; D053509:Matrix Metalloproteinase 13