Enzyme is Promising Path to Degenerative Joint Diseases Cure

Degenerative joint diseases like osteoarthritis and intervertebral disc degeneration are conditions that affect millions of people worldwide, leading to pain and reduced mobility. These diseases remain incurable because current treatments manage symptoms rather than addressing the root cause.

A Yale study in the journal Nature Bone Research found that cytosolic phospholipase A2 (cPLA2) is an important enzyme. It plays a key role in inflammation and cartilage breakdown. The study suggests that cPLA2 could be a possible target for treating joint diseases.

Osteoarthritis and intervertebral disc degeneration are conditions that slowly break down cartilage in joints and discs in the spine. This leads to pain, inflammation, and impaired function that worsens over time.

“cPLA2 is an important enzyme in inflammation,” says Chuan-Ju Liu, PhD, Charles W. Ohse Professor of Orthopaedics & Rehabilitation and the principal investigator and author. “This enzyme produces arachidonic acid, which creates various inflammatory mediators. Although cPLA2 is known to play a role in inflammation, its direct effect on cartilage cells, called chondrocytes, and cartilage damage was not clear.”

Members of the Liu Lab for Translational Orthopaedic Research used advanced methods to examine the relationship between cPLA2 and joint degeneration. Notably, they investigated a common antihistamine, fexofenadine, as a potential cPLA2 inhibitor.

The study revealed several critical insights:

1. Role in damaged cartilage cells: cPLA2 is the main driver of cartilage decay. This enzyme becomes too active in certain cartilage cells. These cells are already likely to break down and show signs of aging.
2. Keeping cartilage healthy: Removing cPLA2 through genetics and blocking it with drugs greatly lowered inflammation. This also stopped cartilage cells from breaking down and aging. This means this gene is crucial for keeping cartilage cells healthy, and stopping its action could protect the cartilage from damage.
3. Potential of fexofenadine: Fexofenadine blocked cPLA2 effectively by reducing inflammation and prevented cartilage cells from aging.

These findings underscore the potential of targeting cPLA2 as a disease-modifying treatment strategy for degenerative joint diseases. The researchers believe that blocking cPLA2 can help with inflammation and chondrocyte aging—the main causes of cartilage damage.

"To learn what cPLA2 does and its treatment potential, our team looked at its expression in chondrocytes and used single-cell RNA sequencing," Liu says. “We analyzed human osteoarthritis and normal cartilage samples, identifying eight distinct chondrocyte populations. Degenerative chondrocytes, including prehypertrophic chondrocytes and fibrochondrocytes, showed significant enrichment of cPLA2. This pattern was consistent in both humans and preclinical trial data, emphasizing the enzyme’s association with cartilage degradation.”

Preclinical trial investigations showed that deleting the cPLA2 gene led to remarkable reductions in cartilage loss and joint inflammation. Observations showed less thickening of the bone layer under cartilage in joints.

Also, less inflammation occurred in the thin membrane that lines the joints. This membrane makes fluid that lubricates and cushions the joints. Additionally, there were fewer bony growths. Pain and functional impairments significantly improved, suggesting a direct link between cPLA2 activity and joint health.

Pharmacological studies using fexofenadine further supported the genetic findings. Fexofenadine treatment reduced cartilage degradation as well as both inflammation and age-related deterioration. Removing cPLA2 did not cause these effects to happen. This shows that the drug's protective abilities came from cPLA2 inhibition.

Degenerative joint diseases, such as osteoarthritis and disc degeneration, cause pain and serious problems. Their complexity makes them hard to treat, and current treatments often do not work well.

The study shows strong evidence of cPLA2's role in joint degeneration. It also opens new opportunities for other uses. The authors encourage more research on cPLA2's role in other inflammatory and degenerative diseases. This could expand the use of drugs like fexofenadine beyond just joint diseases.

“Future research should look more closely at the specific molecular pathways affected by cPLA2," Liu adds. "It is important to study how blocking cPLA2 affects other cell types in the joint. This includes synoviocytes and immune cells. Studying how well cPLA2 inhibitors work and their safety in real-life settings will help turn these findings into useful treatments."

This study highlights the importance of a holistic approach to treating degenerative joint diseases. By studying the molecular processes behind these conditions, researchers can create better treatments. These treatments do more than ease symptoms; they can change the course of the disease.

Other authors include: Guiwu Huang; Chaopeng He; Wenyu Fu; Jingwei Bi, MD; Jianji Wang; and Daniel Wiznia, MD.