Collagenase 3 (MMP13) modulates activation of Transforming Growth Factor b (TGFb) by hypertrophic growth plate chondrocytes

Abstract

MMP13 expression is concomitant with onset of chondrocyte hypertrophy in the growth plate and can activate TGFβ produced by chondrocytes. Our previous binding studies indicated significant binding of a 19 amino acid MMP13‐derived peptide with the large latent TGFβ complex. Bioinformatics data indicate the site of interaction within close proximity of a non‐catalytic region in MMP13. We hypothesized that MMP13‐derived peptide could competitively inhibit MMP13 binding leading to reduced TGFβ activation. Serum‐free, primary hypertrophic chondrocyte cultures were treated with 10, 100 and 250nM of the peptide and endogenously activated TGFβ measured via ELISA and immunoblot. At 24 hours, the 250nM dose of peptide significantly induced a 5‐fold decrease in activated TGFβ without any change in the total TGFβ produced and this effect was reduced by 48 hours. These data suggest that the MMP13‐19 peptide can interfere with TGFβ activation without effects on total TGFβ produced. In osteoarthritis, aberrant activation of TGFβ?leads to cartilage degradation and inhibitors of the MMP catalytic domain have been used to stop this degradation, but with detrimental side‐effects. This study describes a method of reversible targeted disruption of MMP13 interaction with the TGFβ large latent complex independent of the catalytic site promising novel therapeutic approaches in the treatment of osteoarthritis. Supported by CCDAGrant Funding SourceCCDA