Background/Purpose:

Active matrix metalloproteinase-3 (MMP-3) is a prognostic marker of rheumatoid arthritis (RA). Recently, we developed the MMP-3 probe which can specifically detect an active MMP-3.

Methods:

The aim of this study was to investigate whether detecting and monitoring of active MMP-3 using the MMP-3 probe will be useful to predict therapeutic drug responses in collagen-induced arthritis (CIA) mice. During the period of drug treatments such as methotrexate (MTX) or infliximab (IFX), fluorescence signals in arthritic joint tissues and in serum of CIA mice were monitored using the MMP-3 probe to correlate with MMP-3 mRNA and protein levels. Also, micro-computed tomography (micro-CT), X-ray and histology were performed to confirm drug responses.

Results:

Strong fluorescence signals observed in joint tissues and serum of CIA mice were significantly decreased when drugs were treated (Fig. 1.). The decrease of RA scores in drug-treated CIA mice leads to the fluorescence reductions, which is mainly due to down-regulation of MMP-3 mRNA or protein levels. The results that micro-CT, X-ray (Fig. 2.) and histology clearly showed the markedly decrease of bone and cartilage destruction were consistent with the fluorescence reduction by down-regulation of active MMP-3 in drug-treated CIA mice.

Conclusion:

We suggested that the MMP-3 probe could detect and monitor active MMP-3 of CIA mice serum in treatment course, and thereby predicting the drug response or resistance to RA therapies at an earlier stage. We hope that the MMP-3 probe will be a promising tool for drug discovery, development and drug responses in RA therapy.

Figure 1. In vivo monitoring of RA activities and active MMP-3 levels using “smart probe” in arthritic joints of CIA mice with or without MTX or IFX treatment.

Figure 2. Three-dimensional reconstructions of micro-CT images and bone volume analysis using micro-CT in the knee joints and the paws of normal (n=5), CIA (n=5), and MTX (n=5) or IFX (n=5)-treated CIA mice at 3, 5, and 7 weeks after the first immunization.