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Inhibition of GAB2 expression has a protective effect on osteoarthritis:An in vitro and in vivo study
Haokun Mo1, Siying Yang1, An-Min Chen1
1Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Osteoarthritis is a chronic age-related degenerative disease associated with varying degrees of pain and joint mobility disorders. Grb2-associated-Binding protein-2 (GAB2) is an intermediate molecule that plays a role downstream in a variety of signaling pathways, such as inflammatory signaling pathways. The role of GAB2 in the pathogenesis of OA has not been fully studied. In this study, we found that GAB2 expression was elevated in chondrocytes after constructing in vivo and in vitro models of OA. Inhibition of GAB2 by siRNA decreased the expression of MMP3, MMP13, iNOS, COX2, p62, and increased the expression of COL2, SOX9, ATG7, Beclin-1 and LC3II/LC3I. Furthermore, inhibition of GAB2 expression inhibited interleukin-1β (IL-1β) -induced mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling. In vivo studies, we found that reduced GAB2 expression effectively delayed cartilage destruction in a mouse model of OA induced by destabilisation of the medial meniscus (DMM). In conclusion, our study demonstrates that GAB2 is a potential therapeutic target for OA.
Insights
Grb2-associated-Binding protein-2 (GAB2) is elevated in osteoarthritis and drives disease progression. Inhibiting GAB2 in preclinical models reduced cartilage damage and inflammation, suggesting GAB2 as a therapeutic target for osteoarthritis.
Area of Science:
- Biomedical Science
- Molecular Biology
- Pathology
Background:
- Osteoarthritis (OA) is a degenerative joint disease causing pain and mobility loss.
- The role of Grb2-associated-Binding protein-2 (GAB2) in OA pathogenesis is not fully understood.
- GAB2 is an intermediate signaling molecule involved in inflammatory pathways.
Purpose of the Study:
- To investigate the role of GAB2 in osteoarthritis.
- To determine if GAB2 is a potential therapeutic target for OA.
Main Methods:
- Constructed in vivo and in vitro OA models.
- Utilized small interfering RNA (siRNA) to inhibit GAB2 expression.
- Analyzed gene and protein expression, including matrix metalloproteinases (MMPs), inflammatory markers, and autophagy-related proteins.
- Assessed signaling pathways like MAPK and NF-κB.
- Evaluated cartilage destruction in a destabilization of the medial meniscus (DMM) mouse model.
Main Results:
- GAB2 expression was upregulated in OA chondrocytes.
- GAB2 inhibition decreased pro-inflammatory and catabolic markers (MMP3, MMP13, iNOS, COX2) and increased anabolic markers (COL2, SOX9).
- GAB2 inhibition promoted autophagy (ATG7, Beclin-1, LC3II/LC3I) and suppressed IL-1β-induced MAPK and NF-κB signaling.
- Reduced GAB2 expression attenuated cartilage destruction in the DMM mouse model.
Conclusions:
- GAB2 plays a significant role in osteoarthritis pathogenesis.
- Inhibiting GAB2 demonstrates therapeutic potential for osteoarthritis by reducing inflammation and cartilage degradation.
- GAB2 represents a promising therapeutic target for osteoarthritis treatment.
