Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis.
Arthritis is characterised by the proteolytic degradation of articular cartilage leading to a loss of joint function. Articular cartilage is composed of an extracellular matrix of proteoglycans and collagens. We have previously shown that serine proteinases are involved in the activation cascades leading to cartilage collagen degradation. The aim of this study was to use an active-site probe, biotinylated fluorophosphonate, to identify active serine proteinases present on the chondrocyte membrane after stimulation with the pro-inflammatory cytokines IL-1 and oncostatin M (OSM), agents that promote cartilage resorption. Fibroblast activation protein alpha (FAPalpha), a type II integral membrane serine proteinase, was identified on chondrocyte membranes stimulated with IL-1 and OSM. Real-time PCR analysis shows that FAPalpha gene expression is up-regulated by this cytokine combination in both isolated chondrocytes and cartilage explant cultures and is significantly higher in cartilage from OA patients compared to phenotypically normal articular cartilage. Immunohistochemistry analysis shows FAPalpha expression on chondrocytes in the superficial zone of OA cartilage tissues. This is the first report demonstrating the expression of active FAPalpha on the chondrocyte membrane and elevated levels in cartilage from OA patients. Its cell surface location and expression profile suggest that it may have an important pathological role in the cartilage turnover prevalent in arthritic diseases.
Milner
Jennifer M
JM
Musculoskeletal Research Group, Newcastle University, Newcastle upon Tyne, UK.
Kevorkian
Lara
L
Young
David A
DA
Jones
Debra
D
Wait
Robin
R
Donell
Simon T
ST
Barksby
Emma
E
Patterson
Angela M
AM
Middleton
Jim
J
Cravatt
Benjamin F
BF
Clark
Ian M
IM
Rowan
Andrew D
AD
Cawston
Timothy E
TE
D000818:Animals; D002356:Cartilage / Q000378:metabolism; D002358:Cartilage, Articular / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D019902:Chondrocytes / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology*; D010450:Endopeptidases; D018093:Gelatinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M; D010003:Osteoarthritis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D000099167:Fibroblast Activation Protein Alpha
D016207:Cytokines; D010450:Endopeptidases; D018093:Gelatinases; D007375:Interleukin-1; D008565:Membrane Proteins; D053683:Oncostatin M; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C508351:OSM protein, human