Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodelling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodelling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodelling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodelling by spreading senescence to other cell-types. Collectively this study presents the demonstration that senescent cardiomyocytes are major contributors to myocardial remodelling and dysfunction following a myocardial infarction. Therefore, to maximise the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimise senolytic strategies to target this cell lineage.

BackgroundTwo different phenotypes of hand osteoarthritis (HOA) have been defined: nodal hand osteoarthritis (NHOA) and erosive hand osteoarthritis (EHOA). NHOA involve bone enlargement of the underlying interphalangeal joints, which may typically give rise to Heberden’s nodes, synovitis and swelling. EHOA is a particularly aggressive form characterised by an abrupt onset, as well as signs of inflammation and subchondral erosions. In the absence of efficient diagnostic methods, searching for specific biomarkers for each subtype may help to characterise them.ObjectivesTo define a panel of specific protein markers for the characterisation of EHOA and NHOA and its potential use in clinic.MethodsA proteomic approach based on peptide labelling with Isobaric tags for relative and absolute quantitation (iTRAQ) was performed using two different sets of sera (n=55). Samples were classified in 4 groups of study (EHOA, n=10; non-EHOA, n=10; NHOA n=10; non-NHOA, n=5) and 2 control groups (rheumatoid arthritis (RA), n=10 and psoriatic arthritis (PSA), n=10). Serum proteins were digested and peptides from each condition to be compared were differentially labelled with iTRAQ reagents (Sciex). Then, samples were combined and analysed by two-dimensional liquid chromatography coupled to mass spectrometry in a TripleTOF 5600 Mass Spectrometer System (Sciex). Protein identification and quantitation was carried out using ProteinPilot software v.5.0.1.ResultsA total of 257 different proteins were identify with more than two peptides and a total score ≥2 at 95% confidence. In order to identify specific biomarkers for the characterisation of NHOA and EHOA phenotypes, each group was compared with the non-NHOA or non-EHOA respectively, and also with the control groups. After all the comparisons were made, 26 unique different proteins were found specific of the nodular phenotype. Vasorin (VAS) showed elevated levels in patients diagnosed with NHOA when compared to non-NHOA, RA and PSA groups. On the other hand, 36 unique proteins were identified in those patients with EHOA. Extracellular matrix protein 1 (ECM1) was found with higher concentrations in EHOA than in non-EHOA, RA and PSA patients. In addition, both HOA phenotypes were compared to the control groups and a panel of 30 different proteins were defined. Among these proteins, vascular cell adhesion molecule-1 (VCAM1) was found increased in HOA compared to RA and PSA groups.ConclusionsA specific protein profile for the characterisation of EHOA and NHOA disorders has been established. VAS showed elevated levels in patients with NHOA, whereas ECM1 was increased in patients diagnosed with the erosive form of the disease. As none of them were identify in the other phenotype, they might be phenotype-specific biomarkers. In addition, VCAM1 was found with higher levels in both phenotypes of HOA when compared with RA and PSA and might be used to differentiate hand osteoarthritis from other rheumatic diseases.AcknowledgementsFinancial support (IN606A-2016/012) from the Xunta de Galicia and the...

traditional treatments have failed to heal cartilage lesions. In recent years, stem cell-based therapies have been investigated as an alternative approach to treat OA. Mesenchymal Stem Cells (MSCs) have proved safety and demonstrated therapeutic efficacy in the context of pre-clinical studies and are under investigation in the clinics. More than the capacity of these cells to differentiate into chondrocytes, their effect is primarily associated with a paracrine function. The Transforming Growth Factor b (TGFb) pathway plays a critical role in joint homeostasis and MSC function. We therefore investigated whether the therapeutic effect of MSCs could be mediated by members of the TGFb family. Using a secretome analysis, we identified Transforming Growth Factor b Induced (TGFbI), a potential candidate for a chondroprotective