Local Drug-Induced Modulation of gp130 Receptor Signaling Delays Disease Progression in a Pig Model of Temporo-Mandibular Joint Osteoarthritis

Nancy Q. Liu; Shuo Chen; Shuo Chen; Dawei Geng; Dawei Geng; Jie Lei; Jie Lei; Jiankang Zhang; Jiankang Zhang; Liangliang Li; Liangliang Li; Yucheng Lin; Yucheng Lin; Yuxin Ouyang; Ruzanna Shkhyan; Ben Van Handel; Fangzhou Bian; Tadiwanashe Mkaratigwa; Yang Chai; Yang Chai; Denis Evseenko; Denis Evseenko

doi:10.3389/fdmed.2022.937819

Frontiers in Dental Medicine (Jul 2022)

Local Drug-Induced Modulation of gp130 Receptor Signaling Delays Disease Progression in a Pig Model of Temporo-Mandibular Joint Osteoarthritis

Nancy Q. Liu,
Shuo Chen,
Shuo Chen,
Dawei Geng,
Dawei Geng,
Jie Lei,
Jie Lei,
Jiankang Zhang,
Jiankang Zhang,
Liangliang Li,
Liangliang Li,
Yucheng Lin,
Yucheng Lin,
Yuxin Ouyang,
Ruzanna Shkhyan,
Ben Van Handel,
Fangzhou Bian,
Tadiwanashe Mkaratigwa,
Yang Chai,
Yang Chai,
Denis Evseenko,
Denis Evseenko

Affiliations

Nancy Q. Liu: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Shuo Chen: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry of University of Southern California (USC), Los Angeles, CA, United States
Shuo Chen: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterial and Digital Medical Devices, Beijing, China
Dawei Geng: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Dawei Geng: Department of Orthopaedic Surgery, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
Jie Lei: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry of University of Southern California (USC), Los Angeles, CA, United States
Jie Lei: Center for Temporomandibular Disorders and Orofacial Pain, Peking University School and Hospital of Stomatology, National Center of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Research Center of Oral Biomaterial and Digital Medical Devices, Beijing, China
Jiankang Zhang: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Jiankang Zhang: State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China
Liangliang Li: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Liangliang Li: Department of Orthopaedics, The Affiliated Jiangning Hospital With Nanjing Medical University, Nanjing, China
Yucheng Lin: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Yucheng Lin: Department of Orthopaedic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
Yuxin Ouyang: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Ruzanna Shkhyan: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Ben Van Handel: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Fangzhou Bian: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Tadiwanashe Mkaratigwa: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Yang Chai: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry of University of Southern California (USC), Los Angeles, CA, United States
Yang Chai: Broad Center for Stem Cell Research and Regenerative Medicine Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Denis Evseenko: Department of Orthopaedic Surgery, Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States
Denis Evseenko: Broad Center for Stem Cell Research and Regenerative Medicine Keck School of Medicine of USC, University of Southern California (USC), Los Angeles, CA, United States

DOI: https://doi.org/10.3389/fdmed.2022.937819
Journal volume & issue: Vol. 3

Abstract

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Temporomandibular joint disorders (TMJs) are a multifaceted group of chronic disorders characterized by stiffness in the jaw, limited jaw mobility and pain when opening or closing the mouth. TMJs are relatively common, with incidence rates in the range of 5–12%, with nearly twice as many women as men being affected. One of the primary causes of TMJs is a degenerative disease of joints, such as osteoarthritis (OA), characterized by progressive loss of cartilage, which causes stiffness, swelling, and pain. Currently, there are no disease-modifying agents on the market for OA. We have recently discovered a small molecule, R805, acting as a modulator of glycoprotein 130 (gp130) receptor for the IL-6 family of cytokines. R805 enables regenerative outputs of endogenous joint stem and progenitor cells through immunomodulation in the joint microenvironment by reducing the levels of destructive cytokines and supporting chondrocyte survival and anabolism. Extensive testing has shown R805 to be safe at doses far above the therapeutic level. Here, we have conducted a pivotal efficacy study in our newly established pig model of TMJ post-traumatic OA. IA injection of R805 has shown a highly significant reduction of articular cartilage degeneration, reduced synovitis and reduced degenerative changes in subchondral bone in the mandibular condyle compared to the vehicle-treated group. These data will support additional preclinical development of R805 as a first-in-class injectable therapeutic for TMJ osteoarthritis.

Published in Frontiers in Dental Medicine

ISSN: 2673-4915 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Dentistry
Website: https://www.frontiersin.org/journals/dental-medicine#

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