Kappa opioids modulate hedgehog signaling to attenuate osteoarthritis

Inhibition of Hedgehog (Hh) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). Current study was designed to explore if modulation of kappa opioid receptor (KOR) signaling may have therapeutic potential for achieving disease‐modifying activity in OA models through Hh modulation.

Normal human primary tissues were obtained from the NDRI. Human OA samples were collected from patients with osteoarthritis undergoing total joint replacements. For in vivo studies, a partial medial meniscectomy (PMM) rat model was used. A novel automated 3D indentation tester (Mach‐1) was used to quantify articular cartilage thickness and stiffness properties.

We have demonstrated that activation of KOR by a selective peptide agonist JT09 inhibits Hh signaling (p=0.002) in normal and osteoarthritic human articular chondrocytes via cAMP/CREB pathway. JT09 markedly decreased matrix degeneration in articular chondrocytes and cartilage explants induced by a Hh agonist, SAG (p=0.026). Moreover, in vivo application of JT09 via intra‐articular injection significantly (60% improvement, p=0.021 for the tibial plateau) attenuated articular cartilage degeneration after PMM. In JT09 treated rats, cartilage content, structure and functional properties were largely maintained, and osteophyte formation was reduced (by 70%, p=0.005).

Current study defines a novel mechanism for the role of the KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in processes and pathologies shown to involve opioid and Hh signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with arthritis.