Purpose: We have previously reported (OARSI 2018) that in vivo labelling of proteins in mice, using chow containing 13C6-Lysine, is a reliable way to measure incorporation of new proteins into articular cartilage and other connective tissues across the life course. In this study we apply the same method to examine new protein synthesis occurring in the articular cartilage early after destabilisation of the medial meniscus (DMM), a well-accepted model of osteoarthritis. The aim of the study was to identify cellular and extracellular matrix proteins with dysregulated synthesis during early OA development to understand molecular events at the protein level and to identify potential biomarkers of early disease. Methods: Fifteen C57BL6 male mice were divided into three groups (n=5): Naïve, Sham and DMM. DMM or Sham surgery was performed at the age of 12 weeks. One week later, all animals were fed with the heavy SILAC diet (13C6-Lys-SILAC, SILANTES GmbH) for 10 days. Mice were culled and knee articular cartilage was micro-dissected and plasma collected. Samples were stored at -80 degrees Celsius prior to proteolytic digestion with trypsin and subsequent analysis of peptides by HPLC mass spectrometry. Mass-spectrometric data were analysed using Maxquant software for peptide/protein identification. Results: By proteomics analysis, 410 proteins were quantified in cartilage and 163 in plasma two weeks after surgery. Heavy isotope incorporation was quantified in 85% of cartilage (348) and 95% (153) of plasma proteins. Both Sham and DMM surgery stimulated new protein synthesis significantly in both tissues, median DMM= 0.67, median Sham=0.55, median Naïve= 0.47. (Kruskal-Wallis test, p=0.0001), with DMM having the highest effect. Cartilage pairwise comparisons revealed 62 proteins that increased synthesis significantly in the DMM versus Naïve group, but only one protein, Lumican, that increased significantly (-Log adj p value= 3.17) when DMM was compared with Sham. Plasma pairwise comparisons revealed no statistically significant differences in any of the three pairs. Focussing initially on extracellular matrix proteins: increased synthesis of collagens 1a1, 2a1, 6a1, 6a2, 6a3, 10a1, 11a1, 12a1, and 15a1 (-Log fold change=0.3-2.8) was seen in DMM compared with naive animals, but only collagen 10a1 reached statistical significance (-Log adj p value=2.20 ). All but collagens 2a1, 11a1 and 15a1 increased synthesis upon DMM when compared with Sham, (-Log fold change =0.01-0.04), however the increase was not significant. Interestingly, Collagen 14a1, was not detected in the Naïve group but was vastly synthesised in both Sham and DMM groups. In the case of proteoglycans, Aggrecan, Asporin, Biglycan, Chondroitin sulfate proteoglycan., Perlecan and Lumican increased synthesis upon DMM and Sham surgeries (compared with Naïve), but only Lumican was significantly increased in DMM compared with Sham. (-Log adj p value= 3.17). Synthesis of Chondroadherin, Decorin, ECM2, Mimecan, Osteomodulin, Prelamin and Lubricin didn’t increase. Conclusions: In vivo metabolic labelling with a heavy SILAC diet is able to demonstrate changes in the incorporation of newly synthesised proteins in mice 17 days after DMM or Sham surgery. Abundant extracellular matrix proteins such as collagens and proteoglycans are clearly regulated and are especially amenable to this type of analysis. The small leucine-rich proteoglycan Lumican was the only protein with statistically significant increase between the DMM and Sham groups. Other statistically significant changes might be masked by a strong Sham surgery response at this early time point. Later time points are being analysed.