Mast Cell–Restricted, Tetramer-Forming Tryptases Induce Aggrecanolysis in Articular Cartilage by Activating Matrix Metalloproteinase-3 and -13 Zymogens

Abstract

Mouse mast cell protease (mMCP)-6-null C57BL/6 mice lost less aggrecan proteoglycan from the extracellular matrix of their articular cartilage during inflammatory arthritis than wild-type (WT) C57BL/6 mice, suggesting that this mast cell (MC)-specific mouse tryptase plays prominent roles in articular cartilage catabolism. We used ex vivo mouse femoral head explants to determine how mMCP-6 and its human ortholog hTryptase-β mediate aggrecanolysis. Exposure of the explants to recombinant hTryptase-β, recombinant mMCP-6, or lysates harvested from WT mouse peritoneal MCs (PMCs) significantly increased the levels of enzymatically active matrix metalloproteinases (MMP) in cartilage and significantly induced aggrecan loss into the conditioned media, relative to replicate explants exposed to medium alone or lysates collected from mMCP-6-null PMCs. Treatment of cartilage explants with tetramer-forming tryptases generated aggrecan fragments that contained C-terminal DIPEN and N-terminal FFGVG neoepitopes, consistent with MMP-dependent aggrecanolysis. In support of these data, hTryptase-β was unable to induce aggrecan release from the femoral head explants obtained from Chloe mice that resist MMP cleavage at the DIPEN↓FFGVG site in the interglobular domain of aggrecan. In addition, the abilities of mMCP-6-containing lysates from WT PMCs to induce aggrecanolysis were prevented by inhibitors of MMP-3 and MMP-13. Finally, recombinant hTryptase-β was able to activate latent pro-MMP-3 and pro-MMP-13 in vitro. The accumulated data suggest that human and mouse tetramer-forming tryptases are MMP convertases that mediate cartilage damage and the proteolytic loss of aggrecan proteoglycans in arthritis, in part, by activating the zymogen forms of MMP-3 and MMP-13 which are constitutively present in articular cartilage.

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

“…Tryptase functions are mostly mediated by signalling via the PAR-2 receptor [70], [71], [73]–[75] and by activating other proteases such as collagenases [31], [72]. Additional analyses showed that the MC content of tryptase was significantly up-regulated in perifollicular MCs in lesional AA skin compared to controls ( Figure 2E–I ).…”

Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing

“…A number of the MC’s serine proteases also can activate numerous metalloproteinase (MMP) zymogens (Lees, Taylor, & Woolley, 1994; Lin et al, 2011; Magarinos et al, 2013). Tetramer-forming MC tryptases, for example, can activate pro-stromelysin/MMP3 which, in turn, can activate latent procollagenase (Gruber et al, 1989) to ultimately cause connective tissue remodeling.…”

Association between rheumatoid arthritis and systemic mastocytosis: a case report and literature review

“…As mentioned above, MCs could activate synovial fibroblasts but also induce MMPs release by chondrocyte. Moreover, tryptase is recognized as a potent activator of MMPs [36].…”