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Published on: January 7, 2019
SHP2-mediated ROS activation induces chondrocyte paraptosis in osteoarthritis and is attenuated by low-intensity
Wenjie Hou1, Xingru Shang1,2, Xiaoxia Hao1
1Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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.
Insights
SHP2 promotes osteoarthritis (OA) progression by exacerbating chondrocyte paraptosis. Low-intensity pulsed ultrasound (LIPUS) inhibits this process by targeting SHP2, offering a potential treatment for OA.
Area of Science:
- Cell Biology
- Biochemistry
- Orthopedics
Background:
- Paraptosis, a programmed cell death pathway, is implicated in osteoarthritis (OA) pathogenesis, but its mechanisms remain unclear.
- Disrupted proteostasis and altered redox homeostasis are common triggers for paraptosis.
- The specific role of SHP2 in chondrocyte paraptosis and its link to OA require further investigation.
Purpose of the Study:
- To investigate the role of SHP2 in chondrocyte paraptosis.
- To elucidate the regulatory mechanism of SHP2 in OA.
- To examine the therapeutic effects of low-intensity pulsed ultrasound (LIPUS) on SHP2-mediated paraptosis and OA progression.
Main Methods:
- SHP2 expression was modulated using siRNA knockdown and plasmid overexpression in IL-1β-induced chondrocytes.
- Adeno-associated viruses were used to study SHP2 in a rat OA model.
- The effects of LIPUS on paraptosis, oxidative stress, ER stress, and MAPK activation were assessed in vitro and in vivo.
Main Results:
- IL-1β induces chondrocyte paraptosis via reactive oxygen species (ROS)-mediated ER stress and MAPK activation, with SHP2 exacerbating ROS production.
- SHP2 knockdown and ROS inhibition significantly reduced paraptosis, inflammation, and cartilage degeneration.
- LIPUS treatment downregulated SHP2 expression, inhibiting MAPK activation, ER stress, and ER-derived vacuoles, thereby delaying OA progression in both cellular and animal models.
Conclusions:
- SHP2 plays a critical role in promoting IL-1β-induced oxidative stress and paraptosis in chondrocytes, contributing to OA progression.
- LIPUS effectively mitigates OA by downregulating SHP2 and inhibiting paraptosis.
- SHP2 is a potential therapeutic target, and LIPUS presents a promising non-invasive treatment for trauma-related OA.
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