Knee osteoarthritis (OA) is a major cause of disability in the elderly, however, there are few studies to estimate the global prevalence, incidence, and risk factors of knee OA. For this study, we searched PUBMED, EMBASE and SCOPUS from inception to April 4, 2020, without language restriction. We identified eligible studies with information on the prevalence or incidence of knee OA in population-based observational studies and extracted data from published reports. We did random-effects meta-analysis to generate estimates. This study was registered with PROSPERO (CRD42020181035). Out of 9570 records identified, 88 studies with 10,081,952 participants were eligible for this study. The pooled global prevalence of knee OA was 16⋅0% (95% CI, 14⋅3%-17⋅8%) in individuals aged 15 and over and was 22⋅9% (95% CI, 19⋅8%-26⋅1%) in individuals aged 40 and over. Correspondingly, there are around 654⋅1 (95% CI, 565⋅6–745⋅6) million individuals (40 years and older) with knee OA in 2020 worldwide. The pooled global incidence of knee OA was 203 per 10,000 person-years (95% CI, 106–331) in individuals aged 20 and over. Correspondingly, there are around annual 86⋅7 (95% CI, 45⋅3–141⋅3) million individuals (20 years and older) with incident knee OA in 2020 worldwide. The prevalence and incidence varied substantially between individual countries and increased with age. The ratios of prevalence and incidence in females and males were 1⋅69 (95% CI, 1⋅59–1⋅80, p<0⋅00) and 1⋅39 (95% CI, 1⋅24–1⋅56, p<0⋅00), respectively. Our study provides the global prevalence (16⋅0% [95% CI, 14⋅3%-17⋅8%]) and incidence (203 per 10,000 person-years [95% CI, 106–331]) of knee OA. These findings can be used to better assess the global health burden of knee OA. Further prospective cohort studies are warranted to identify modifiable risk factors for providing effectively preventive strategies in the early stages of the disease. This work was supported by grants from the 10.13039/501100001809National Natural Science Foundation of China (nos. 81772384 and 81572174).

The development of safe and efficient gene carriers is the key to the clinical success of gene therapy. The present study was designed to develop and evaluate the chitosan-graft-polyethylenimine (CP)/DNA nanoparticles as novel non-viral gene vectors for gene therapy of osteoarthritis. The CP/DNA nanoparticles were produced through a complex coacervation of the cationic polymers with pEGFP after grafting chitosan (CS) with a low molecular weight (Mw) PEI (Mw = 1.8 kDa). Particle size and zeta potential were related to the weight ratio of CP:DNA, where decreases in nanoparticle size and increases in surface charge were observed as CP content increased. The buffering capacity of CP was significantly greater than that of CS. The transfection efficiency of CP/DNA nanoparticles was similar with that of the Lipofectamine™ 2000, and significantly higher than that of CS/DNA and PEI (25 kDa)/DNA nanoparticles. The transfection efficiency of the CP/DNA nanoparticles was dependent on the weight ratio of CP:DNA (w/w). The average cell viability after the treatment with CP/DNA nanoparticles was over 90% in both chondrocytes and synoviocytes, which was much higher than that of PEI (25 kDa)/DNA nanoparticles. The CP copolymers efficiently carried the pDNA inside chondrocytes and synoviocytes, and the pDNA was detected entering into nucleus. These results suggest that CP/DNA nanoparticles with improved transfection efficiency and low cytotoxicity might be a safe and efficient non-viral vector for gene delivery to both chondrocytes and synoviocytes.

Chondrocyte senescence has recently been proposed as a key pathogenic mechanism in the etiology of osteoarthritis (OA). Nevertheless, the precise molecular mechanisms underlying chondrocyte senescence remain poorly understood. To address this knowledge gap, we conducted an investigation into the involvement of Sirtuin 4 (Sirt4) in chondrocyte senescence. Our experimental findings revealed a downregulation of Sirt4 expression in TBHP-induced senescent chondrocytes in vitro, as well as in mouse OA cartilage. Additionally, we observed that the knockdown of Sirt4 in chondrocytes promoted cellular senescence and cartilage degradation, while the overexpression of Sirt4 protected the cells against TBHP-mediated senescence of chondrocytes and cartilage degradation. Moreover, our findings revealed elevated levels of reactive oxygen species (ROS), abnormal mitochondrial morphology, compromised mitochondrial membrane potential, and reduced ATP production in Sirt4 knockdown chondrocytes, indicative of mitochondrial dysfunction. Conversely, Sirt4 overexpression successfully mitigated TBHP-induced mitochondrial dysfunction. Further analysis revealed that Sirt4 downregulation impaired the cellular capacity to eliminate damaged mitochondria by inhibiting Pink1 in chondrocytes, thereby enhancing the accumulation of ROS and facilitating chondrocyte senescence. Notably, the overexpression of Pink1 counteracted the effects of Sirt4 knockdown on mitochondrial dysfunction. Importantly, our study demonstrated the promise of gene therapy employing a lentiviral vector encoding mouse Sirt4, as it successfully preserved the integrity of articular cartilage in mouse models of OA. In conclusion, our findings provide compelling evidence that the overexpression of Sirt4 enhances mitophagy, restores mitochondrial function, and protects against chondrocyte senescence, thereby offering a novel therapeutic target and potential strategy for the treatment of OA.

Osteoarthritis (OA), a common joint disease in elderly, causes serious social and economic burdens worldwide. Previous studies indicated that some differentially expressed circular RNAs (circRNAs) participated in the initiation and progression of OA. These findings suggested that circRNAs may act as promising diagnostic biomarkers and therapeutic targets for OA. In this review, we summarize the biogenesis and biological functions of circRNAs and explore the underlying roles of circRNAs in OA, which may enlighten further studies and contribute to the early diagnosis and intervention of OA.