Trypsin-2 Degrades Human Type II Collagen and Is Expressed and Activated in Mesenchymally Transformed Rheumatoid Arthritis Synovitis Tissue Mathias Stenman,

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Trypsin-2 Degrades Human Type II Collagen and Is Expressed and Activated in Mesenchymally Transformed Rheumatoid Arthritis Synovitis Tissue Mathias Stenman, Mari Ainola, Leena Valmu, Anders Bjartell, Guofeng Ma, Ulf-Håkan Stenman, Timo Sorsa, Reijo Luukkainen, Yrjö T. Konttinen The American Journal of Pathology Volume 167, Issue 4, Pages 1119-1124 (October 2005) DOI: 10.1016/S0002-9440(10)61200-X Copyright © 2005 American Society for Investigative Pathology Terms and Conditions

Figure 1 A: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrates that TRY-2 is an interstitial collagenase able to cleave type II collagen at multiple sites to small molecular weight fragments. Lane 1: Human homotrimeric collagen II substrate only, intact α2 chains. Lane 2: TRY-2 cleaves intact, triple helical human type II collagen monomers at multiple sites to small molecular weight collagen fragments. Lane 3: TRY-2-mediated collagenolysis inhibited by the presence of its specific inhibitor TATI. Lane 4: MMP-8 (neutrophil collagenase, collagenase-2), a positive collagenase control, produces classical ¾ and ¼ fragments as a result of action on the single initial cleavage site for mammalian collagenases. Lanes 5 and 6: MMP-9 (gelatinase B, 92-kd type IV collagenase; lane 5) and bovine trypsin (lane 6) not able to cleave type II collagen. B: Lane 1: Intact type II collagen. Lane 2: TRY-2 cleaves type II collagen. Lane 3: TRY-2 collagenolysis inhibited by TATI. Lane 4: MMP-inhibitor GM 6001 (Ilomastat) does not inhibit TRY-2-mediated collagenolysis of type II collagen. Lanes 5 and 6: MMP-8 produces classic ¾ and ¼ fragments of type II collagen (lane 5) that is inhibited by GM 6001 (Ilomastat) (lane 6). C: Lane 1: Zymography gels demonstrate gelatin substrate only. Lane 2: TRY-2 is also a gelatinase able to cleave gelatin (denatured collagen). Lanes 3 and 4: MMP-8 is not gelatinolytic (lane 3), whereas MMP-9 is gelatinolytic (lane 4). It is not possible to demonstrate inhibition of TRY-2 by TATI using zymography because TRY-2-TATI complexes dissociate in this assay. The American Journal of Pathology 2005 167, 1119-1124DOI: (10.1016/S0002-9440(10)61200-X) Copyright © 2005 American Society for Investigative Pathology Terms and Conditions

Figure 2 Time-resolved immunofluorometric assay results of parallel serum and synovial fluid samples from 26 RA patients. The concentrations of TRY-1, TRY-2, TATI, and TRY-2-API are shown on a logarithmic scale. Boxes indicate median values and quartiles. The American Journal of Pathology 2005 167, 1119-1124DOI: (10.1016/S0002-9440(10)61200-X) Copyright © 2005 American Society for Investigative Pathology Terms and Conditions

Figure 3 Alkaline phosphatase-anti-alkaline phosphatase staining of human TRY-2 in RA synovial membrane. A and B: The synovial lining cell layer and stromal sublining fibroblast-like cells stain for TRY-2. C: Staining control in which normal rabbit IgG was used instead of and at the same concentration as the primary rabbit anti-human TRY-2 IgG. Hematoxylin counterstaining. Original magnifications: ×20 (A and C); ×40 (B). The American Journal of Pathology 2005 167, 1119-1124DOI: (10.1016/S0002-9440(10)61200-X) Copyright © 2005 American Society for Investigative Pathology Terms and Conditions

Figure 4 RT-PCR of RA synovial membrane samples showing amplified 627-bp TRY-2 bands and internal controls of 295-bp β-actin bands. Lane 1: DNA ladder, lane 2: negative control without sample, lanes 3–7: RA samples. The American Journal of Pathology 2005 167, 1119-1124DOI: (10.1016/S0002-9440(10)61200-X) Copyright © 2005 American Society for Investigative Pathology Terms and Conditions