Preclinical studies demonstrate reduced inflammation, senescence, and pain in mice models for osteoarthritis and intervertebral disc degeneration.

CHENGDU, SICHUAN, CHINA, November 24, 2025 /EINPresswire.com/ -- Researchers at Yale University have identified cytosolic phospholipase A2 (cPLA2) as a key driver of cartilage degeneration and chondrocyte senescence in osteoarthritis and intervertebral disc degeneration. Through genetic deletion and pharmacological inhibition using fexofenadine, they effectively suppressed inflammation, preserved cartilage integrity, and alleviated pain in preclinical models. The study positions cPLA2 as a promising therapeutic target and highlights fexofenadine, a widely available, FDA-approved drug, as a potential repurposed treatment for debilitating musculoskeletal disorders.

Musculoskeletal disorders, such as osteoarthritis (OA) and intervertebral disc degeneration (IVDD), are chronic debilitating conditions characterized by progressive joint pain, stiffness, and loss of mobility. Despite their growing global burden, effective disease-modifying therapies remain elusive. Increasing evidence suggests chronic inflammation and chondrocyte senescence as central drivers of cartilage degeneration, characterized by accelerated extracellular matrix breakdown and impaired tissue repair. However, the molecular mediators linking inflammatory signaling to cartilage degeneration and chondrocyte dysfunction remain poorly understood.

Among potential mediators, cytosolic phospholipase A2 (cPLA2) has emerged as a molecule of particular interest. cPLA2 is a key enzyme that catalyzes the hydrolysis of membrane phospholipids to release arachidonic acid, a precursor for bioactive lipid mediators, such as prostaglandins and leukotrienes, that orchestrate inflammatory responses. While cPLA2’s role in systemic inflammation is well established, its specific contribution to cartilage homeostasis and degeneration has not been thoroughly explored.

Addressing this gap, a research team from the Yale University School of Medicine, led by Prof. Chuanju Liu, investigated the role of cPLA2 in chondrocytes and its contribution to the pathogenesis of these musculoskeletal disorders. Their study, published in the journal Bone Research on 15 October 2025 and reported in a recent news article by Yale School of Medicine, also assessed whether pharmacological inhibition of cPLA2 could offer therapeutic benefits. Of particular interest was fexofenadine (FFD), a widely available over-the-counter antihistamine recently identified as a cPLA2 inhibitor, highlighting a promising avenue for drug repurposing in degenerative cartilage diseases.

The study used in vivo, in vitro, and single-cell analyses to explore cPLA2’s role in cartilage degeneration. cPLA2 knockout and wild-type mice model were studied in aging-associated and surgically induced OA and IVDD models, with treatments using FFD and AACOCF3. Single-cell RNA sequencing revealed that cPLA2 is enriched in pre-hypertrophic and fibrocartilage-like chondrocytes, pinpointing the cell populations driving degeneration. The team used cell-based assays with human chondrocytes to examine inflammatory and senescence responses, while molecular, histological, and behavioral assessments, including qRT-PCR, western blotting, micro-CT, and immunohistochemistry, confirmed cPLA2’s central role in inflammation, senescence, and cartilage breakdown.

The findings were striking. “We found that both genetic deletion and pharmacological inhibition of cPLA2 significantly reduced cartilage degradation, inflammation, and markers of cellular senescence,” highlights Prof. Liu. Notably, treatment with FFD preserved cartilage structure and improved behavioral outcomes, including reduced pain-associated responses and improved mobility in mouse models, highlighting its potential as a repurposed therapeutic agent.

Histological and molecular analyses supported these observations. Cartilage tissues from cPLA2-deficient or FFD-treated mice showed better matrix integrity, higher levels of anabolic markers, such as type II collagen and aggrecan, and lower levels of degenerative enzymes like MMP13. Furthermore, markers of cellular senescence, including p16 and p21, were markedly reduced following cPLA2 inhibition.

Prof. Liu says, “Fexofenadine, an FDA-approved and widely used antihistamine, demonstrated strong potential as a repurposed drug for treating degenerative cartilage diseases. Its ability to inhibit cPLA2 offers a cost-effective, accessible, and well-tolerated therapeutic strategy that could be translated into clinical applications more rapidly than developing novel drugs from scratch.”

In conclusion, this study provides compelling evidence that targeting cPLA2 can simultaneously suppress inflammation and senescence, thereby preserving cartilage integrity and delaying the progression of degenerative musculoskeletal disorders such as OA and IVDD. Its findings can not only advance our understanding of the molecular mechanisms underlying cartilage degeneration but could also open doors to the development of disease-modifying therapies.

Future research focusing on clinical validation and optimization of cPLA2 inhibitors like fexofenadine could revolutionize the management of osteoarthritis and intervertebral disc degeneration, offering renewed hope to patients suffering from these chronic, debilitating conditions.

***

Reference
Title of original paper: Cytosolic phospholipase A2 as a therapeutic target for degenerative joint diseases
Journal: Bone Research
DOI: https://doi.org/10.1038/s41413-025-00470-9

Yini Bao
International Journal of Oral Science
2885546461 ext.
[email protected]
Visit us on social media:
X

Legal Disclaimer:

EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.

Information contained on this page is provided by an independent third-party content provider. Frankly and this Site make no warranties or representations in connection therewith. If you are affiliated with this page and would like it removed please contact [email protected]