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Matrix metalloproteinase 13 (MMP13) can cleave the protease‐sensitive hinge region of theTransforming Growth Factor β (TGFβ) large latent complex
Author(s) -
Reese Betsy,
Routson Stephanie M,
Lau Shukkwan,
Lombard Frederick,
Selim Abdulhafez A,
D'Angelo Marina
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.638.12
Subject(s) - proteases , protease , extracellular matrix , chemistry , matrix metalloproteinase , hinge , peptide , biophysics , substrate (aquarium) , matrix (chemical analysis) , cleave , transforming growth factor , biochemistry , enzyme , microbiology and biotechnology , biology , chromatography , physics , ecology , classical mechanics
In this study, we demonstrate that MMP13 can utilize the protease‐sensitive hinge region of the TGFβ large latent complex as a substrate. Our lab has previously demonstrated that chondrocytes produce a unique large latent TGFβ complex that contains MMP13 in non‐covalent association. Our bioinformatics model suggests that MMP13 associates with the complex in such a way as to line up the catalytic domain with the protease sensitive hinge region, the site of release of the complex from extracellular matrix storage. Kinetic analysis of MMP13 catalytic domain digestion of a fluorescence‐labeled peptide, REHGARS, (the site of release of the TGFβ large latent complex from the extracellular matrix), indicated that the peptide was digested by MMP13 (30 minute slope = −2.580 and p‐value = 0.001 compared to substrate alone), and this activity was sensitive to a general inhibitor of MMP activity. A scrambled sequence of the peptide was not digested by MMP13 (30 minute slope = −0.2196). MMP2 and MMP9 catalytic domains were not as efficient in digestion of the substrate, but proteases present in cartilage extracts from chick embryonic sterna were able to digest the hinge region substrate. This is the first study of its kind indicating the ability of MMP13 to utilize the protease‐sensitive hinge region of the TGFβ large latent complex as a substrate, indicating a role for MMP13 in TGFβ activation. The implications of this finding provide a mechanism of release of matrix stored TGFβ in normal cartilage maturation as well as the aberrant release of articular cartilage stores of TGFβ in osteoarthritis. This work was supported in part by a grant from the Center for Chronic Disorders of Aging.