Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules' interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health.

Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans / C. Cambria, F. Ingegnoli, E. Borzi, L. Cantone, L.A. Coletto, A.S. Rizzuto, O. De Lucia, S. Briguglio, M. Ruscica, R. Caporali, V. Bollati, M. Buoli, F. Antonucci. - In: CELLS. - ISSN 2073-4409. - 11:15(2022 Jul 23), pp. 2276.1-2276.20. [10.3390/cells11152276]

Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans

C. Cambria
Co-primo
;
F. Ingegnoli
Co-primo
;
L. Cantone;L.A. Coletto;A.S. Rizzuto;O. De Lucia;S. Briguglio;M. Ruscica;R. Caporali;V. Bollati;M. Buoli
Penultimo
;
F. Antonucci
Ultimo
2022

Abstract

Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules' interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health.
EVs; neurons; osteoarthritis; rheumatoid arthritis; synaptic transmission; Hippocampus; Humans; Mood Disorders; Synovial Fluid; Arthritis, Rheumatoid; Extracellular Vesicles; Osteoarthritis
Settore MED/16 - Reumatologia
Settore MED/25 - Psichiatria
Settore BIO/14 - Farmacologia
PRIN201719FANTO_01 - Early dysfunctions of intercellular signalling in brain disorders - ANTONUCCI, FLAVIA - PRIN2017 - PRIN bando 2017 - 2019
PSRL320FINGE_01 - Piano Sviluppo Unimi - Linea 3 - Bando SEED 2019 - Progetto RESTYLE - INGEGNOLI, FRANCESCA ANNA - PSR_LINEA3_ / Piano di sviluppo di ricerca - Bando SoE-SEED- Linea 3 - 2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/935846
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