Molecular determinants of neutrophil extracellular vesicles that drive cartilage regeneration in inflammatory arthritis

Objective This study was undertaken to establish the potential therapeutic profile of neutrophil-derived extracellular vesicles (EVs) in experimental inflammatory arthritis and associate pharmacological activity with specific EV components, focussing on microRNAs. Methods Neutrophil EVs were administered intra-articularly through a prophylactic or therapeutic protocol to male C57BL/6 mice undergoing serum-transfer induced inflammatory arthritis. Transcriptomic analysis of knees was performed on joints following EV administration, Naïve and arthritic mice (untreated), n=4/group, and EV-treated diseased mice (intra-articular administration) with contralateral (vehicle-treated) n=8/group. Comparison of healthy donor and rheumatoid arthritis (RA) patient neutrophil EVs was performed. Results EVs afforded cartilage protection with an increase in Collagen-II and reduced Collagen-X expression within the joint. To gain mechanistic insights, RNA sequencing of the arthritic joints was conducted. A total of 5,231 genes were differentially expressed (P<0.05), with 257 unique to EV treatment. EVs affected key regenerative pathways involved in joint development, including Wnt and Notch signalling. This wealth of genomic alteration prompted to identify microRNAs in EVs, 10 of which are associated with RA. As a proof-of-concept, we focused on miR-455-3p, which was detected in both healthy donor and RA EVs. EV addition to chondrocyte cultures elevated miR-455-3p and exerted anti-catabolic effects upon IL-1β stimulation; these effects were blocked by actinomycin or miR-455-3p antagomir. Conclusion Neutrophils from RA patients yielded EVs with composition, efficacy and miR-455-3p content similar to those of healthy volunteers, suggesting that neutrophil EVs could be developed as an autologous treatment to protect and repair joint tissue of patients affected by inflammatory arthritides

Biomechanical considerations in the pathogenesis of osteoarthritis of the knee

Osteoarthritis is the most common joint disease and a major cause of disability. The knee is the large joint most affected. While chronological age is the single most important risk factor of osteoarthritis, the pathogenesis of knee osteoarthritis in the young patient is predominantly related to an unfavorable biomechanical environment at the joint. This results in mechanical demand that exceeds the ability of a joint to repair and maintain itself, predisposing the articular cartilage to premature degeneration. This review examines the available basic science, preclinical and clinical evidence regarding several such unfavorable biomechanical conditions about the knee: malalignment, loss of meniscal tissue, cartilage defects and joint instability or laxity

Joint surface defects: clinical course and cellular response in spontaneous and experimental lesions

Joint surface defects (JSD) involving the articular cartilage and the subchondral bone are a common clinical problem in rheumatology and orthopaedics. The recent availability of accurate imaging for diagnosis and efficacious therapeutic options has stirred new interest in their natural history and biology. The evidence that some of these lesions can heal spontaneously whereas others precipitate osteoarthritis has raised important questions as to which lesions should be treated, when, and how. Evidence of repair of some of these lesions has also stimulated research into which factors contribute to successful healing and which ones determine chronic evolution and development of osteoarthritis (OA). Older anatomical observations, together with novel molecular tools and experimental models, have revealed a complex cellular and molecular response of cartilage to focal defects, which could explain differences in healing responses between individuals, and may provide clues to stimulating intrinsic tissue repair. In the first part of this review we will discuss clinical aspects of these lesions in the patient, with particular emphasis on their biology and natural history. In the second part we will summarize the data coming from in vitro and in vivo models of cartilage injury and regeneration, focussing on the molecular control of cartilage homeostasis after creation of cartilage surface defects