Effect of Lubricin Mimetics on the Inhibition of Osteoarthritis in a Rat Anterior Cruciate Ligament Transection Model

Daniel Nemirov, Yusuke Nakagawa, Zhexun Sun, Amir Lebaschi, Susumu Wada, Camila Carballo, Xiang Hua Deng, David Putnam, Lawrence J. Bonassar, Scott A. Rodeo

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Background: Lubricin, a mucinous glycoprotein, plays a chondroprotective role as a constituent of synovial fluid. Structural analogs have been synthesized to mimic the structure and function of native lubricin in an effort to recapitulate this effect with the goal of delaying progression of osteoarthritis (OA). Purpose: To investigate the efficacy of intra-articular injections of lubricin mimetics in slowing or preventing the progression of posttraumatic OA by using a rat anterior cruciate ligament transection model. Study Design: Controlled laboratory design. Methods: Four lubricin mimetics were investigated, differing from one another in their binding orientations and steric interactions. Eighty skeletally mature Sprague-Dawley rats underwent bilateral anterior cruciate ligament transections and were randomly allocated to receive intra-articular injections (50 µL/injection) of 1 of the 4 mimetics in the right knee and equal volumes of saline injection in the contralateral knee (control). All rats were euthanized 8 weeks postoperatively and assessed via biomechanical analysis, which evaluated comparative friction coefficients across the 4 groups, and histological evaluation of articular cartilage, osteophytes, and synovitis. The Osteoarthritis Research Society International (OARSI) histopathological assessment system was used to evaluate the degree of articular cartilage degeneration and osteophytes, while synovitis was assessed through a semiquantitative scoring system. Binding efficacy of the 4 mimetics was assessed in vitro and in vivo through the immunohistochemical localization of polyethylene glycol. Articular cartilage degeneration and synovitis scoring data analyses were performed with generalized estimating equation modeling. Results: Injection of the group 3 mimetic (random 24 + 400 + 30) directly correlated with improved OARSI scores for femoral articular cartilage degeneration when compared with saline-injected contralateral control knees (P =.0410). No lubricin mimetic group demonstrated statistically significant differences in OARSI scores for tibial articular cartilage degeneration. Injection of the group 4 mimetic (AB 24 + 400 + 30) led to a statistically significant difference in osteophyte OARSI score (P =.0019). None of the 4 lubricin mimetics injections incited an additive synovial inflammatory response. Immunohistochemical staining substantiated the binding capacity of all 4 mimetics, while in vivo experimentation revealed that the group 1 and 3 mimetics were still retained within the joint 4 weeks after injection. There were no differences in friction coefficients between any pair of groups and no significant trends based on lubricin mimetic structure. Conclusion: We demonstrated that the tribosupplementation of a traumatically injured knee with a specific lubricin structural analog may attenuate the natural progression of OA. Clinical Relevance: The current lack of efficacious clinical options to counter the onset and subsequent development of OA suggests that further investigation into the synthesis and behavior of lubricin analogs could yield novel translational applications.

Original languageEnglish
Pages (from-to)624-634
Number of pages11
JournalAmerican Journal of Sports Medicine
Volume48
Issue number3
DOIs
Publication statusPublished - Mar 1 2020

Bibliographical note

Publisher Copyright:
© 2020 The Author(s).

Funding

One or more of the authors has declared the following potential conflict of interest or source of funding: This work was financially supported by a grant from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Disease. S.A.R. has received consulting fees from Flexion Therapeutics, research support from Angiocrine Biosciences, honoraria from Fidia Pharma, compensation for services other than consulting from Smith & Nephew, royalties from Zimmer Biomet (Cayenne), and is a paid associate editor for AJSM. D.P. is listed as an inventor on a patent filed by Cornell. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

FundersFunder number
National Institutes of Health
National Institute of Arthritis and Musculoskeletal and Skin Diseases

    ASJC Scopus Subject Areas

    • Orthopedics and Sports Medicine
    • Physical Therapy, Sports Therapy and Rehabilitation

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