Kappa opioids modulate hedgehog signaling to attenuate osteoarthritis

Abstract

Purpose: Osteoarthritis (OA) affects 50 million Americans, at an annual cost of $100 billion. Pain management is currently a hallmark of OA treatment. One of the most frequently employed treatment strategies involves opioid analgesics. Opioids are highly addictive and have led to an opioid epidemic. One strategy to reduce opioid addiction is to implement kappa-opioid receptor (KOR) agonist medications which have been documented to provide pain-relief without the addictive potential of commonly used opioid medications (which target the mu-opioid receptor). Our previous work showed that KOR is expressed in chondrocytes and synovial cells. Previous studies have also shown that inhibition of the Hedgehog (Hh) signaling pathway prevents cartilage degeneration and promotes repair in animal models of OA. Current study was designed to explore if modulation of kappa opioid receptor (KOR) signaling may have a therapeutic potential for achieving disease-modifying activity in OA models through Hh modulation. Methods: Normal human primary tissues were obtained from the National Disease Research Interchange (NDRI). Human OA samples were collected from patients with severe osteoarthritis undergoing total joint replacements. Normal porcine articular cartilage tissue was used for explant studies. For in vivo studies a partial medial meniscectomy (PMM) rat model was used. A novel automated 3D indentation mapping mechanical tester (Mach-1) was used to quantify articular cartilage thickness and stiffness properties. Results: We have demonstrated that activation of KOR by a selective peptide agonist JT09 inhibits Hh signaling in normal and osteoarthritic human chondrocytes via cAMP/CREB pathway. JT09 has also markedly decreased matrix degeneration in porcine explants induced by a Hh agonist SAG. Moreover, in vivo application of JT09 via intra-articular injection significantly attenuated rat articular cartilage degeneration after PMM. In JT09 treated rats, cartilage content and structure were largely maintained, and osteophyte formation was greatly reduced. In addition, treatment with JT09 prevented functional compressive tissue degeneration following PMM. Conclusions: Current study defines a novel molecular 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 in cartilage and/or synovial tissue can improve outcomes in patients with arthritis.