ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein.
Loss of articular cartilage because of extracellular matrix breakdown is the hallmark of arthritis. Degradative fragments of cartilage oligomeric matrix protein (COMP), a prominent noncollagenous matrix component in articular cartilage, have been observed in the cartilage, synovial fluid, and serum of arthritis patients. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, remain largely unknown. ADAMTS-12 (a disintegrin and metalloprotease with thrombospondin motifs) was shown to associate with COMP both in vitro and in vivo. ADAMTS-12 selectively binds to only the epidermal growth factor-like repeat domain of COMP of the four functional domains tested. The four C-terminal TSP-1-like repeats of ADAMTS-12 are shown to be necessary and sufficient for its interaction with COMP. Recombinant ADAMTS-12 is capable of digesting COMP in vitro. The COMP-degrading activity of ADAMTS-12 requires the presence of Zn2+ and appropriate pH (7.5-9.5), and the level of ADAMTS-12 in the cartilage and synovium of patients with both osteoarthritis and rheumatoid arthritis is significantly higher than in normal cartilage and synovium. Together, these findings indicate that ADAMTS-12 is a new COMP-interacting and -degrading enzyme and thus may play an important role in the COMP degradation in the initiation and progression of arthritis.
Liu
Chuan-ju
CJ
Department of Orthopaedic Surgery, Musculoskeletal Research Center, New York University Hospital for Joint Diseases, New York, New York 10003, USA. chuanju.liu@med.nyu.edu
Kong
Wei
W
Xu
Ke
K
Luan
Yi
Y
Ilalov
Kiril
K
Sehgal
Bantoo
B
Yu
Shuang
S
Howell
Ronald D
RD
Di Cesare
Paul E
PE
D051722:ADAM Proteins / Q000378:metabolism*; D000071096:ADAMTS Proteins; D001842:Bone and Bones / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D047468:Immunoprecipitation; D064235:Matrilin Proteins; D016133:Polymerase Chain Reaction; D011485:Protein Binding
D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C496252:ADAMTS12 protein, human