SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity pulsed ultrasound

Abstract

Background

Paraptosis is a novel form of programmed cell death, generally caused by disrupted proteostasis or alterations of redox homeostasis. However, its impact and underlying mechanisms on the pathology of osteoarthritis (OA) are still unclear. This study aimed to investigate the role and regulatory mechanism of SHP2 in chondrocyte paraptosis and the effects influenced by low-intensity pulsed ultrasound (LIPUS).

Methods

SHP2, a MAPK upstream intermediary, has been identified as one of the critical targets of IL-1β-induced paraptosis in the GEO and GeneCard databases. The expression of SHP2 in chondrocytes was regulated by either siRNA knockdown or plasmid overexpression. Additionally, adeno-associated viruses were injected into the knee joints of rats to explore whether SHP2 plays a role in the development of OA. The impact of LIPUS on paraptosis and OA was examined in IL-1β-induced chondrocytes and a post-traumatic OA model, with SHP2 regulation assessed at both cellular and animal levels.

Results

An increase in cellular reactive oxygen species (ROS) caused by IL-1β halts the growth of chondrocytes and induces paraptosis in the chondrocytes. IL-1β-induced paraptosis, manifested as endoplasmic reticulum (ER)-derived vacuolization, was mediated by ROS-mediated ER stress and MAPK activation. SHP2 facilitates ROS production, thereby exacerbating the chondrocytes paraptosis. SHP2 knockdown and ROS inhibition effectively reduced this process and significantly mitigated inflammation and cartilage degeneration. Furthermore, we discovered that LIPUS delayed OA progression by inhibiting the activation of the MAPK pathway, ER stress, and ER-derived vacuoles in chondrocytes, all of which play critical roles in paraptosis, through the downregulation of SHP2 expression. Results on animals showed that LIPUS inhibited cartilage degeneration and alleviated OA progression.

Conclusion

SHP2 exacerbates IL-1β-induced oxidative stress and the subsequent paraptosis in chondrocytes, promoting OA progression. LIPUS mitigates paraptosis by modulating SHP2, which in turn slows OA progression.

The translational potential of this article

This study indicates that a novel SHP2-mediated cell death mechanism, paraptosis, plays a role in post-traumatic OA progression. LIPUS helps maintain cartilage-subchondral bone unit integrity by targeting SHP2 inhibition. SHP2 emerges as a potential therapeutic target, while LIPUS provides a promising non-invasive approach for treating trauma-related OA.