The Hedgehog signaling (Hh) pathway is essential for normal embryonic development and plays critical roles in adult tissue maintenance, renewal and regeneration.1 A multicenter team of researchers wondered whether inhibiting this Hedgehog signaling pathway could prevent cartilage degeneration and/or promote knee repair by way of kappa opioid receptors.
Their work, “Modulation of Hedgehog Signaling by Kappa Opioids to Attenuate Osteoarthritis,” was published in the April 5, 2020 edition of Arthritis and Rheumatology.
Co-author Alexander Weber, M.D., with the department of orthopedic surgery at USC’s Keck School of Medicine explained the genesis of the research to OTW. “Orthopaedic surgeons are always looking for new ways to treat osteoarthritis. Dr. Denis Evseenko had done some very preliminary work with kappa opioids as a way of treating osteoarthritis and he and I recognized the tremendous potential that this class of medication has. We collaborated for this animal-model test to further our understanding of how kappa opioids might be used for osteoarthritis treatment.”
The authors wrote, “Primary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy model of knee OA in rats was used. A novel automated 3‐dimensional indentation tester (Mach‐1) was used to quantify the thickness and stiffness properties of the articular cartilage.”
They found that kappa opioid receptor activation inhibited Hedgehog signaling via a selective peptide agonist named JT09. This peptide “markedly” decreased matrix degeneration induced by an Hedgehog agonist in pig articular chondrocytes and cartilage explants.
In this work, an intra-articular injection into the rat knee after partial medial meniscectomy “significantly” lessened articular cartilage degeneration (60% improvement in the tibial plateau versus vehicle‐treated controls). In rats treated with JT09, found the authors, “cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% treated controls).”
Dr. Weber commented to OTW “This study has tremendous potential to change clinical practice. We are a few iterations away from that, if a large animal model confirms these results , then a clinical trial is the next step. The amazing contribution of this line of work and this drug class is that they have the ability to protect the cartilage in joints from damage while also providing pain relief in a less addictive way. This may play a role for fighting the opioid epidemic in this country and while minimizing the burden that osteoarthritis puts on our workforce and health care system.”
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