Modulation of Hedgehog Signaling by Kappa Opioids to Attenuate Osteoarthritis

Authors

Alexander E Weber
Omid Jalali
Sean Limfat
Ruzanna Shkhyan
Robert Van Der Horst
Siyoung Lee
Yucheng Lin
Liangliang Li
Erik N Mayer
Liming Wang
Nancy Q Liu
Frank A Petrigliano
Jay R Lieberman
Denis Evseenko

Publication Date

8-1-2020

Journal

Arthritis & Rheumatology

DOI

10.1002/art.41250

PMID

32249508

PMCID

PMC7541630

PubMedCentral® Posted Date

8-1-2021

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Adult, Animals, Cartilage, Articular, Cell Culture Techniques, Chondrocytes, Cyclic AMP Response Element-Binding Protein, Disease Models, Animal, Female, Hedgehog Proteins, Humans, Injections, Intra-Articular, Knee Joint, Male, Meniscectomy, Middle Aged, Opioid Peptides, Osteoarthritis, Knee, Peptides, Rats, Receptors, Opioid, kappa, Signal Transduction, Swine

Abstract

OBJECTIVE: Inhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA.

METHODS: 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 (PMM) 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.

RESULTS: Inhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls).

CONCLUSION: The results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

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