TIMP2 deficient mice develop accelerated osteoarthritis via promotion of angiogenesis upon destabilization of the medial meniscus.
Vascular invasion into the normally avascular articular surface is a hallmark of advanced osteoarthritis (OA). In this study, we demonstrated that the expression of tissue inhibitor of metalloproteinases-2 (TIMP2), an anti-angiogenic factor, was present at high levels in normal articular chondrocytes, and was drastically decreased shortly after destabilization of the medial meniscus (DMM). We also investigated the anti-angiogenic properties of TIMP2 via knockout. We hypothesized that the loss of TIMP2 could accelerate osteoarthritis development via promotion of angiogenesis. Loss of TIMP2 led to increased periarticular vascular formation 1 month post DMM, compared to wild-type mice, and did so without altering the expression pattern of matrix metalloproteinases and vascular endothelial growth factors. The increased vascularization eventually resulted in a severe degeneration of the articular surface by 4 months post DMM. Our findings suggest that reduction of TIMP2 levels and increased angiogenesis are possible primary events in OA progression. Inhibiting or delaying angiogenesis by TIMP2 expression or other anti-angiogenic therapies could improve OA prevention and treatment.
Department of Orthopedics, Second Xiangya Hospital, Central South University, Changsha, Hunan Province 410011, PR China. 098102097@csu.edu.cn
Meng
M
Mi
Shanshan
S
Shi
Tianfang
T
Li
Jonathan
J
Holz
Yi-Jang
YJ
Lee
Tzong-Jen
TJ
Sheu
Qiande
Q
Liao
Tao
T
Xiao
D000818:Animals; D004195:Disease Models, Animal; D020782:Matrix Metalloproteinases; D008592:Menisci, Tibial / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000503:physiopathology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000502:physiology*; D042442:Vascular Endothelial Growth Factors
D042442:Vascular Endothelial Growth Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases