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ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies
Lejian Jiang1,2, Jiachen Lin3,4,5, Sen Zhao3,4,5
1Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
ADAMTS5 is involved in the pathogenesis of OA. As the major aggrecanase-degrading articular cartilage matrix, ADAMTS5, has been regarded as a potential target for OA treatment. We here provide an updated insight on the regulation of ADAMTS5 and newly discovered therapeutic strategies for OA. Pathophysiological and molecular mechanisms underlying articular inflammation and mechanotransduction, as well as chondrocyte hypertrophy were discussed, and the role of ADAMTS5 in each biological process was reviewed, respectively. Senescence, inheritance, inflammation, and mechanical stress are involved in the overactivation of ADAMTS5, contributing to the pathogenesis of OA. Multiple molecular signaling pathways were observed to modulate ADAMTS5 expression, namely, Runx2, Fgf2, Notch, Wnt, NF-κB, YAP/TAZ, and the other inflammatory signaling pathways. Based on the fundamental understanding of ADAMTS5 in OA pathogenesis, monoclonal antibodies and small molecule inhibitors against ADAMTS5 were developed and proved to be beneficial pre-clinically both in vitro and in vivo. Recent novel RNA therapies demonstrated potentials in OA animal models. To sum up, ADAMTS5 inhibition and its signaling pathway-based modulations showed great potential in future therapeutic strategies for OA.
Insights
ADAMTS5 enzyme overactivation drives osteoarthritis (OA) pathogenesis. Inhibiting ADAMTS5 and its signaling pathways offers promising therapeutic strategies for treating OA, with new antibody and RNA-based treatments showing potential.
Area of Science:
- Biochemistry and Molecular Biology
- Rheumatology and Orthopedics
Background:
- ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) is a key enzyme in articular cartilage degradation.
- Its overactivation is implicated in the pathogenesis of osteoarthritis (OA), a prevalent joint disease.
Purpose of the Study:
- To provide an updated review on the regulation of ADAMTS5 in OA.
- To explore novel therapeutic strategies targeting ADAMTS5 for OA treatment.
Main Methods:
- Review of pathophysiological and molecular mechanisms in OA, focusing on inflammation, mechanotransduction, and chondrocyte hypertrophy.
- Analysis of signaling pathways modulating ADAMTS5 expression, including Runx2, Fgf2, Notch, Wnt, NF-κB, and YAP/TAZ.
- Evaluation of pre-clinical data for ADAMTS5 inhibitors (monoclonal antibodies, small molecules) and RNA therapies in OA models.
Main Results:
- Factors like senescence, inheritance, inflammation, and mechanical stress contribute to ADAMTS5 overactivation in OA.
- Multiple signaling pathways significantly influence ADAMTS5 expression and activity.
- Pre-clinical studies demonstrate the efficacy of ADAMTS5 inhibitors and novel RNA therapies in OA models.
Conclusions:
- Targeting ADAMTS5 and its associated signaling pathways presents a promising therapeutic avenue for OA.
- Inhibition of ADAMTS5 activity holds significant potential for developing effective OA treatments.
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