and 2 other(s)
INTRODUCTION: Lubricin, one of the main lubricating constituents of synovial fluid, has been targeted as a prospective therapeutic option to inhibit the development and progression of osteoarthritis (OA) . Prior in vitro studies have shown lubricin to reduce frictional forces at articular cartilage surfaces by as much as 70% . Numerous analogues of this glycoprotein have been synthesized with the hopes of evoking similar biomechanical effects . The objective of the present study is to investigate the efficacy of intra-articular injections of several previously described lubricin mimetics in slowing or preventing the progression of post-traumatic OA using a rat anterior cruciate ligament (ACL) transection model . We hypothesized that a regimen of intra-articular injections of these lubricin mimetics would attenuate osteoarthritic progression in ACL transected knee joints. METHODS: Lubricin mimetics: Four lubricin mimetics were investigated. These mimetics were all structured around a polyacrylic acid (pAA) backbone with a thiol binding-terminus onto which hydrophilic polyethylene glycol (PEG) brushes were grafted. These mimetics differed from one another with regards to their respective binding orientations and steric interactions. Study design: Skeletally mature Sprague-Dawley rats (n=40) underwent bilateral ACL transections and were randomly allocated to receive intra-articular injections of one of the four mimetics. Beginning one week post-operatively for 3 weeks, the lubricin mimetics were injected (50µL) twice a week in the study knees, and an equal volume of saline was injected to the other side. Histological evaluation: All rats were euthanized at 8 weeks after surgery for histological evaluation (Safranin-O and Hematoxylin-Eosin). The degree of articular cartilage degradation and osteophyte formation were assessed with the OARSI scoring system and synovitis was evaluated semi-quantitatively . The medial femoral condyle and medial tibial plateau were evaluated and were further subdivided into 3 primary zones of interest (with zone #1 being adjacent to the cruciate ligaments and zone #3 on the periphery). Statistical analysis: 2-way ANOVA and Generalized estimating equations were used. The significance limit was set at p=0.05. RESULTS: Histomorphologcial evaluations: There was a statistically significant difference in articular cartilage degeneration of the medial femoral condyle observed between the lubricin mimetic-treated and contralateral control knees of the rats in group 3, with injection of the group 3 mimetic directly correlating with improved OARSI scores (p=0.041). Specifically, there was significantly less articular cartilage degenerative change in Group 3 treated animals in zone #1 of the medial tibial plateau (p=0.049) and in zone #2 of the medial femoral condyle (p=0.045). Lubricin mimetic injection did not significantly affect the presence or degree of synovitis across any of the four groups, and there was no evidence of an adverse synovial inflammatory response to the mimetics. There was a significant decrease in osteophyte formation in group 4 (p=0.002). DISCUSSION: This is the first study that evaluates the efficacy of intra-articular injections of lubricin glycoprotein analogues in a rat ACL transection model of post-traumatic OA. Although the in vitro lubricating efficacy of these mimetics has been established, no in vivo studies have been reported with these specific lubricin mimetics. This study supports the potential translational efficacy of these lubricin mimetics. Our data demonstrates that of the four mimetics examined in this study, the group 3 mimetic delivered the best results with regards to the femoral OARSI score of articular cartilage degeneration. Overall, the results of this study suggest that the tribosupplementation of a traumatically-injured knee joint with a certain structure of lubricin analogue may have an inhibitory effect on the development of post-traumatic osteoarthritis. SIGNIFICANCE: As efficacious, pragmatic clinical options are not yet readily available to counter the onset and subsequent development of OA, further investigation into the synthesis and behavior of lubricin analogues could yield novel translational applications in the future. REFERENCES:  Waller KA et al. Am J Sports Med. 2017,  Gleghorn JP et al. J Orthop Res. 2009,  Flannery CR, et al., Arthritis Rheum 2009,  Samaroo KJ et al. J Orthop Res. 2017,  Gerwin N et al. Osteoarthritis Cartilage. 2010,  Krenn V et al. Histopathology. 2006
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