Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis.
Human osteoarthritis is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multifactorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecan is cleaved at a specific 'aggrecanase' site in human osteoarthritic cartilage; this cleavage can be performed by several members of ADAMTS family of metalloproteases. The relative contribution of individual ADAMTS proteases to cartilage destruction during osteoarthritis has not been resolved. Here we describe experiments with a genetically modified mouse in which the catalytic domain of ADAMTS5 (aggrecanase-2) was deleted. After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice. This is the first report of a single gene deletion capable of abrogating the course of cartilage destruction in an animal model of osteoarthritis. These results demonstrate that ADAMTS5 is the primary 'aggrecanase' responsible for aggrecan degradation in a murine model of osteoarthritis, and suggest rational strategies for therapeutic intervention in osteoarthritis.
Glasson
Sonya S
SS
Department of Women's Health and Bone, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA.
Askew
Roger
R
Sheppard
Barbara
B
Carito
Brenda
B
Blanchet
Tracey
T
Ma
Hak-Ling
HL
Flannery
Carl R
CR
Peluso
Diane
D
Kanki
Kim
K
Yang
Zhiyong
Z
Majumdar
Manas K
MK
Morris
Elisabeth A
EA
D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism*; D020134:Catalytic Domain; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005270:Femur Head; D017353:Gene Deletion; D006132:Growth Plate / Q000378:metabolism; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D008666:Metalloendopeptidases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D011509:Proteoglycans; D012333:RNA, Messenger; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D008666:Metalloendopeptidases; C083641:aggrecanase