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Updated: Dec 9, 2025
Destabilization of the Medial Meniscus and Cartilage Scratch Murine Model of Accelerated Osteoarthritis
Published on: July 6, 2022
TRIM24-RIP3 axis perturbation accelerates osteoarthritis pathogenesis
Jimin Jeon1,2,3, Hyun-Jin Noh2,4, Hyemi Lee1,2,3
1Department of Pharmacology, Ajou University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea.
Objectives:
Recently, necroptosis has attracted increasing attention in arthritis research; however, it remains unclear whether its regulation is involved in osteoarthritis (OA) pathogenesis. Since receptor-interacting protein kinase-3 (RIP3) plays a pivotal role in necroptosis and its dysregulation is involved in various pathological processes, we investigated the role of the RIP3 axis in OA pathogenesis.
Methods:
Experimental OA was induced in wild-type or Rip3 knockout mice by surgery to destabilise the medial meniscus (DMM) or the intra-articular injection of adenovirus carrying a target gene (Ad-Rip3 and Ad-Trim24 shRNA). RIP3 expression was examined in OA cartilage from human patients; Trim24, a negative regulator of RIP3, was identified by microarray and in silico analysis. Connectivity map (CMap) and in silico binding approaches were used to identify RIP3 inhibitors and to examine their direct regulation of RIP3 activation in OA pathogenesis.
Results:
RIP3 expression was markedly higher in damaged cartilage from patients with OA than in undamaged cartilage. In the mouse model, adenoviral RIP3 overexpression accelerated cartilage disruption, whereas Rip3 depletion reduced DMM-induced OA pathogenesis. Additionally, TRIM24 knockdown upregulated RIP3 expression; its downregulation promoted OA pathogenesis in knee joint tissues. The CMap approach and in silico binding assay identified AZ-628 as a potent RIP3 inhibitor and demonstrated that it abolished RIP3-mediated OA pathogenesis by inhibiting RIP3 kinase activity.
Conclusions:
TRIM24-RIP3 axis perturbation promotes OA chronicity by activating RIP3 kinase, suggesting that the therapeutic manipulation of this pathway could provide new avenues for treating OA.
Insights
Necroptosis, regulated by receptor-interacting protein kinase-3 (RIP3), is implicated in osteoarthritis (OA). Inhibiting the TRIM24-RIP3 axis with AZ-628 shows promise for treating OA by blocking RIP3 kinase activity.
Area of Science:
- Cellular biology
- Molecular mechanisms of disease
- Rheumatology
Background:
- Necroptosis, a programmed cell death pathway, is increasingly studied in arthritis.
- The role of receptor-interacting protein kinase-3 (RIP3) in necroptosis and its potential involvement in osteoarthritis (OA) pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the role of the RIP3 signaling axis in the pathogenesis of osteoarthritis.
- To identify potential therapeutic targets within the RIP3 pathway for OA treatment.
Main Methods:
- Experimental osteoarthritis (OA) was induced in wild-type and Rip3 knockout mice.
- RIP3 expression was analyzed in human OA cartilage.
- TRIM24, a negative regulator of RIP3, was identified.
- RIP3 inhibitors were identified using Connectivity Map (CMap) and in silico binding assays.
Main Results:
- RIP3 expression was significantly elevated in OA cartilage from human patients.
- RIP3 overexpression exacerbated OA, while Rip3 depletion attenuated OA pathogenesis in mice.
- TRIM24 knockdown upregulated RIP3, promoting OA, whereas TRIM24 downregulation protected against OA.
- AZ-628 was identified as a potent RIP3 inhibitor that abrogated OA pathogenesis by inhibiting RIP3 kinase activity.
Conclusions:
- Perturbation of the TRIM24-RIP3 axis promotes OA chronicity through RIP3 kinase activation.
- Targeting the TRIM24-RIP3 pathway offers a potential therapeutic strategy for osteoarthritis.
