Expression and activity of ADAMTS-5 in synovium.
ADAMTS proteinases, belonging to the adamalysin subfamily of metalloproteinases, have been implicated in a variety of cellular events such as morphogenesis, cell migration, angiogenesis, ovulation and extracellular matrix breakdown. Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) have been identified in cartilage and are largely responsible for cartilage aggrecan breakdown. We have shown previously that synovium, the membrane lining diarthrodial joints, generates soluble aggrecanase activity. We report here the expression, localization and activity of ADAMTS-5 from human arthritic and bovine synovium. ADAMTS-5 was expressed constitutively in synovium with little or no transcriptional regulation by recombinant human interleukin-1 alpha or all-trans-retinoate, factors previously shown to upregulate aggrecanase activity in cartilage. Aggrecanase activity generated by synovium in vitro and recombinant ADAMTS-5 cleaved aggrecan extensively, resulting in aggrecan fragments similar to those generated by chondrocyte-derived aggrecanases, and the activity was inhibited by heparin. ADAMTS-5 was immunolocalized in human arthritic synovium, where staining was mostly pericellular, particularly in the synovial lining and around blood vessels; some matrix staining was also seen. The possibility that synovium-derived ADAMTS-5 may play a role in cartilage aggrecan breakdown is discussed.
Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK. mdp96mnv@sheffield.ac.uk
M N
MN
Vankemmelbeke
I
I
Holen
A G
AG
Wilson
M Z
MZ
Ilic
C J
CJ
Handley
G S
GS
Kelner
M
M
Clark
C
C
Liu
R A
RA
Maki
D
D
Burnett
D J
DJ
Buttle
D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; D053674:Aggrecans; D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000201:enzymology; D015153:Blotting, Western; D002356:Cartilage / Q000201:enzymology / Q000378:metabolism; D002417:Cattle; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008970:Molecular Weight; D010003:Osteoarthritis / Q000201:enzymology / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020539:Sequence Analysis, Protein; D013583:Synovial Membrane / Q000201:enzymology* / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D053674:Aggrecans; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D010446:Peptide Fragments; D011509:Proteoglycans; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014212:Tretinoin; D006493:Heparin; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D008666:Metalloendopeptidases