Abstract
Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.
Highlights
Osteoarthritis (OA) is the most common musculoskeletal disorder that affects nearly300 million people in the world population that are over 60 years of age
synovial fibroblasts (SF) and articular chondrocytes (AC) grown in a stable isotope labeling with amino acids (SILAC) medium were put together in co-culture and treated with 45 kDa fibronectin fragments (Fn-fs) as a stimulus of inflammation and extracellular matrix (ECM) destruction in the presence and absence of vasoactive intestinal peptide (VIP) to elucidate which proteins are modulated by this neuropeptide
Among the proteins modulated by VIP in the SILAC analysis, we decided to validate those involved in the inflammatory response, chitinase-3-like protein 1 (CHI3L1) and PTX3, which is a common process that takes place in OA, worsening the disease progression
Summary
Osteoarthritis (OA) is the most common musculoskeletal disorder that affects nearly. 300 million people in the world population that are over 60 years of age. Variations in the composition and physical properties of the ECM lead to the development of many diseases, including cancer and rheumatic diseases, such as OA and RA, among others [12,13,14] In this sense, the integrity of ECM composition is crucial to the regular function of load-bearing tissues, such as cartilage in OA [15]. Given the absence of specific therapies for the treatment of OA, the exploration of biomarkers that enable the development of new therapeutical approaches is crucial In this context, we proposed to analyze the set of secreted proteins in chondrocyte and synoviocyte co-cultures, joint cell types involved in crucial physiological processes in OA. We studied the modulating role of the endogenous peptide VIP in this secretome, providing novel VIP-modulated proteins involved in the main events that take place during the OA pathology: the inflammatory process, the activation of the complement system, and the cartilage ECM-degradation
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