Human NR4A1 adenoviral particles

Osteoarthritis (OA) is a common joint disease for which there is currently no effective treatment strategy. Abnormal mechanical stimulation has been shown to be an important factor in the pathogenesis of OA. It has been reported that histone demethylase JMJD3 mediates a variety of physiological and pathological processes, including cell differentiation, proliferation, autophagy, and apoptosis. In this work, researchers confirmed in vitro and in vivo that JMJD3 is upregulated in abnormal force-induced cartilage damage. Functionally, inhibition of JMJD3 with its inhibitor GSK-J4 or downregulation of JMJD3 by adenovirus infection of sh-JMJD3 alleviated abnormal force-induced chondrocyte damage. Mechanistic studies showed that abnormal force induced JMJD3 expression, which then demethylated H3K27me3 at the NR4A1 promoter to promote its expression. Further experiments showed that NR4A1 could regulate chondrocyte apoptosis, cartilage degeneration, extracellular matrix degradation, and inflammatory responses. In vivo, anterior cruciate ligament transection (ACLT) was performed to construct an OA model and validate the therapeutic effect of GSK-J4. More importantly, the researchers used a peptide-siRNA nanoplatform to deliver si-JMJD3 into articular cartilage, and the severity of joint degeneration was significantly reduced. In summary, these findings suggest that JMJD3 is flow-responsive and epigenetically regulates OA progression.

Here, the researchers investigated the biological effects of NR4A1 on chondrocytes by infection with NR4A1 adenovirus (Ad-NR4A1). NR4A1 was successfully overexpressed in chondrocytes infected with Ad-NR4A1 compared with the Ad-NC group (Figure 1a, b). Apoptosis assays showed that NR4A1 induced apoptotic activity in chondrocytes (Figure 1c). In addition, NR4A1 overexpression suppressed COLII and SOX9, while promoting COX-2 and MMP13 expression (Figure 1d, e). Proinflammatory mediators (TNF-α, IL-1β, and IL-6) were significantly induced in the Ad-NR4A1 group (Figure 1d).

Figure 1. NR4A1 regulates the physiological activities of primary chondrocytes. (Jin Y, et al., 2022)