Purpose

Osteoarthritis affects 12% of the population, yet no disease-modifying treatments exist. Cartilage breakdown is the hallmark of osteoarthritis, and patients suffer from pain and loss of joint function/independence, severely affecting quality of life.

Receptor tyrosine kinase–like orphan receptor 2 (ROR2) is a WNT receptor regulating limb outgrowth during development. Chondrocytes require ROR2 to undergo hypertrophy throughout the process of endochondral bone formation. Loss-of-function mutations in humans causes Recessive Robinow Syndrome, characterised by limb shortening and brachydactyly.

Although absent from healthy adult articular cartilage, our studies identified high ROR2 signalling in patients with osteoarthritis, suggesting a role in the disease process.

Aim: To test ROR2 blockade as a novel disease-modifying treatment for osteoarthritis.

Methods and Materials

Human cartilage organoid model, menisco-ligament injury model of osteoarthritis in mice, behavioural studies, in vitro experiments.

Results

ROR2/WNT5A signalling was increased in osteoarthritic cartilage. Blocking ROR2 induced articular chondrogenesis, with anabolic and anti-catabolic effects in a cell line. Human cartilage formation increased in an organoid model in nude mice using primary chondrocytes from patients with osteoarthritis, a clinically validated model that predicts long-term outcome of cartilage repair.

In therapeutic regime, ROR2-siRNA reduced cartilage destruction and provided rapid and sustained pain relief in a murine model of osteoarthritis. Given the limited expression pattern of ROR2 in adulthood, no systemic or local toxicity were expected, nor were any observed (1).

Conclusion

ROR2 blockade has potential as a disease-modifying treatment for osteoarthritis, providing cartilage protection and rapid and sustained pain relief. This will be crucial for clinical success of any treatment for osteoarthritis and promote patient compliance.

Our current approach requires too frequent injections to be acceptable for patients. We are developing longer acting/systemic ROR2 blockers, and researching biomarkers to identify patients with osteoarthritis who are predicted to respond to ROR2-blockade therapy, for patient stratification and individualised therapy.

1. Thorup et al., STM (2020).