Research data for Development of a translational strategy for using TIMP-3 to inhibit aggrecanase activity in osteoarthritis

These data files contain the raw data from the ELISAs used to measure the concentration of the LAP-TIMP-3 protein in mouse sera after injection of the proteins either intravenously (Pk data i.v) or intraperitoneally (Pk data i.p). There is also a file that contains the raw data, again from ELISAs, measuring the levels of LAP-TIMP-3 proteins after injection of varying concentrations of the LAP-TIMP-3 NoCLV protein (Pk dosage data).
Access to these ELISA data will allow readers to perform the pharmacokinetic analyses as described in the published work.
Article abstractObjectiveTherapeutic potential of selective aggrecanase inhibition in osteoarthritis (OA) was previously demonstrated using a variant of endogenous tissue inhibitor of metalloproteinase-3 (TIMP-3); however, this relied on transgenic mice overexpressing TIMP-3. Here, we develop a translational approach for harnessing the aggrecanase-selective inhibitory activity of TIMP-3 using the latency associated peptide (LAP) technology.
MethodsWe successfully produced and purified recombinant LAP-TIMP-3 fusion proteins and determined the pharmacokinetics of these proteins in vivo following systemic injection. Surgical and non-surgical mouse models of OA were used to establish the therapeutic potential of these proteins in reducing aggrecanase activity in mouse joints affected by OA.
ResultsThe presence of the LAP conferred favourable TIMP-3 pharmacokinetics, with effective delivery of LAP-TIMP-3 to knee joints after systemic injection. We find that LAP-TIMP-3 also effectively reduced aggrecanase activity in OA-affected joints, both in spontaneously-occurring OA and in the destabilisation of the medial meniscus (DMM) model of OA. We also found that reductions in aggrecanase activity in articular cartilage correlated with improved disease scores, but only in earlier stages of disease.
ConclusionsThis study describes the potential of LAP-TIMP-3 as a therapeutic agent in OA, showing delivery to the cartilage of joints affected by OA after systemic administration and lower levels of the neoepitope of aggrecan in articular cartilage in mild disease (mean difference versus vehicle control for LAP-TIMP-3: 535 [95% CI: 336, 733] and for LAP-mutTIMP-3: 522 [95% CI: 323, 720] arbitrary units). These first in vivo data will inform further explorations into dose optimization and timing.