Related Experiment Video
Updated: Jun 8, 2025
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
TRPM2-mediated feed-forward loop promotes chondrocyte damage in osteoarthritis via calcium-cGAS-STING-NF-κB pathway
Kai Sun1, Xiong Zhang1, Liangcai Hou1
1Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Introductions:
Osteoarthritis (OA) is a significant contributor to disability in the elderly population. However, current therapeutic options are limited. The transient receptor potential melastatin 2 (TRPM2) is involved in a range of disease processes, yet its role in OA remains unclear.
Objectives:
To investigate the role of TRPM2 in OA.
Methods:
Cartilage samples were collected from patients with osteoarthritis (OA) and mice with OA to examine TRPM2 expression levels. To investigate the effects of TRPM2 modulation on the destabilization of the medial meniscus (DMM) induced knee OA in mice, we utilized TRPM2 knockout mice and employed adenovirus-mediated overexpression of TRPM2. Furthermore, siRNA-mediated TRPM2 knockdown or plasmid-mediated TRPM2 overexpression was conducted to explore the role of TRPM2 in IL-1β-induced chondrocytes. The regulatory mechanism of IL-1β on TRPM2 expression was screened by signaling pathway inhibitors, and the transcription factors and binding sites of TRPM2 were predicted using the database. The binding of RELA (NF-κB-p65) to the Trpm2 promoter was verified by chip-PCR and ChIP-qPCR. The therapeutic potential of Ca2+ chelation with BAPTA-AM for the treatment of osteoarthritis (OA) was investigated.
Results:
An increased expression of TRPM2 was observed in the cartilage of OA patients and OA mice. Furthermore, mice deficient in Trpm2 exhibited a protective effect against DMM-induced OA progression. In contrast, TRPM2 overexpression resulted in exacerbation of DMM-induced OA and thepromotion of an OA-like phenotype of chondrocytes. TRPM2 was upregulated by IL-1β in an NF-κB-p65-dependent manner. Subsequently, the TRPM2-Ca2+-mtDNA-cGAS-STING-NF-κB axis in the progression of OA was validated. Furthermore, inhibition of the TRPM2-Ca2+ axis with BAPTA-AM effectively attenuated established OA.
Conclusions:
Our data collectively revealed a pathological feedback loop involving TRPM2, Ca2+, mtDNA, cGAS, STING, and NF-κB in OA chondrocytes. This suggests that disrupting this loop could be a viable therapeutic approach for OA.
Insights
Transient receptor potential melastatin 2 (TRPM2) exacerbates osteoarthritis (OA) by promoting a pathological feedback loop involving calcium (Ca2+), mitochondrial DNA (mtDNA), and NF-κB signaling. Inhibiting this TRPM2-Ca2+ axis offers a potential therapeutic strategy for OA.
Area of Science:
- Biomedical Science
- Molecular Biology
- Immunology
Background:
- Osteoarthritis (OA) is a leading cause of disability in older adults, with limited effective treatments.
- The role of the Transient Receptor Potential Melastatin 2 (TRPM2) ion channel in OA pathogenesis is not well understood.
Purpose of the Study:
- To elucidate the function of TRPM2 in osteoarthritis.
- To investigate the molecular mechanisms underlying TRPM2-mediated OA progression.
- To evaluate TRPM2 as a potential therapeutic target for OA.
Main Methods:
- TRPM2 expression was analyzed in human and mouse OA cartilage.
- TRPM2 knockout and overexpression models were used in mice with destabilization of the medial meniscus (DMM)-induced OA.
- In vitro studies involved siRNA/plasmid-mediated TRPM2 modulation in IL-1β-stimulated chondrocytes.
- Signaling pathways, transcription factors, and the therapeutic effect of Ca2+ chelation were investigated.
Main Results:
- TRPM2 expression is elevated in OA cartilage from patients and mice.
- TRPM2 deficiency protects against DMM-induced OA, while overexpression exacerbates it.
- IL-1β upregulates TRPM2 via the NF-κB-p65 pathway, activating the TRPM2-Ca2+-mtDNA-cGAS-STING-NF-κB axis.
- Ca2+ chelation with BAPTA-AM attenuated established OA.
Conclusions:
- TRPM2 plays a critical role in OA pathogenesis by mediating a pathological feedback loop.
- The identified TRPM2-Ca2+-mtDNA-cGAS-STING-NF-κB axis represents a novel pathway in OA.
- Targeting this axis, particularly the TRPM2-Ca2+ interaction, holds promise for developing new OA therapies.
More Related Videos
Related Concept Videos
01:24T Cell Types and Functions
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:28Inflammatory Response
Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...