AMPA/kainate glutamate receptor antagonists prevent posttraumatic osteoarthritis
Cleo S. Bonnet, Sophie J. Gilbert, Emma J. Blain, Anwen S. Williams, Deborah J. Mason
Cleo S. Bonnet, Sophie J. Gilbert, Emma J. Blain, Anwen S. Williams, Deborah J. Mason
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Research Article Bone biology Therapeutics

AMPA/kainate glutamate receptor antagonists prevent posttraumatic osteoarthritis

Abstract

Musculoskeletal disorders represent the third greatest burden in terms of death and disability in the developed world. Osteoarthritis is the single greatest cause of chronic pain, has no cure, and affects 8.5 and 27 million people in the UK and US, respectively. Osteoarthritis is most prevalent in older people, but as it commonly occurs after joint injury, young people with such injuries are also susceptible. Painful joints are often treated with steroid or hyaluronic acid (HA) injections, but treatments to prevent subsequent joint degeneration remain elusive. In animals, joint injury increases glutamate release into the joint, acting on nerves to cause pain, and joint tissues to cause inflammation and degeneration. This study investigated synovial fluid glutamate concentrations and glutamate receptor (GluR) expression in injured human joints and compared the efficacy of GluR antagonists with current treatments in a mouse model of injury-induced osteoarthritis (ACL rupture). GluRs were expressed in the ligaments and meniscus after knee injury, and synovial fluid glutamate concentrations ranged from 19 to 129 μM. Intra-articular injection of NBQX (GluR antagonist) at the time of injury substantially reduced swelling and degeneration in the mouse ACL rupture model. HA had no effect, and Depo-Medrone reduced swelling for 1 day but increased degeneration by 50%. Intra-articular administration of NBQX modified both symptoms and disease to a greater extent than current treatments. There is an opportunity for repurposing related drugs, developed for CNS disorders and with proven safety in humans, to prevent injury-induced osteoarthritis. This could quickly reduce the substantial burden associated with osteoarthritis.

Authors

Cleo S. Bonnet, Sophie J. Gilbert, Emma J. Blain, Anwen S. Williams, Deborah J. Mason

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Figure 3

Histological knee joint severity in ACLr mice treated with 20 mM NBQX versus vehicle (water) and HA or Depo-Medrone versus vehicle (saline).

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Histological knee joint severity in ACLr mice treated with 20 mM NBQX ve...
(A) At day 21, NBQX treatment significantly reduced the joint severity score compared with vehicle (***P < 0.001, 2-sample t test). (B) Steroid (Depo-Medrone) treatment significantly increased joint degradation by approximately 50% compared with HA or saline vehicle treatment (*P < 0.05, 1-way ANOVA with Tukey’s post hoc). (C) When broken down into parameters, NBQX significantly reduced cartilage loss (OA damage, ***P < 0.001), proteoglycan loss (**P < 0.01), and bone changes (***P < 0.001, 2-sample t tests). (D) Significant reductions in joint severity score caused by NBQX treatment were seen in both the medial (*P < 0.05, Mann-Whitney test) and lateral (***P < 0.001, 2-sample t test) sides of the joint. (E) Healthy bone (b), covered by a smooth articular cartilage (c), was clearly present in knees with an intact ACL; however, following ACLr (with vehicle), severe cartilage loss is evident (red arrows), in conjunction with bone thickening and remodeling (black arrows) and chondrophyte formation (asterisks). Joint damage was sometimes so severe, cartilage and bone loss occurred down to the growth plate (black arrowhead). A single i.a. injection of NBQX reduced cartilage (red arrow) and bone changes (black arrow) and joints retained more structural integrity. Two injections of NBQX maintained joint structure similar to that seen in intact ACL samples. HA caused similar effects to vehicle, with severe cartilage loss (red arrows), bone thickening and remodeling (black arrows) and chondrophyte formation (asterisks). However, intra-articular Depo-Medrone was highly damaging to the joint, causing bone loss down through the growth plate (black arrowheads) in both the medial and lateral compartments and the formation of large chondrophytes (asterisk). FC, femoral condyle; TP, tibial plateaux; ACL, anterior cruciate ligament; m, meniscus. Scale bars: 50 μm. Data are presented as box plots (representing interquartile range, median, and all data points, including mean, which is indicated by a crossed circle). 20 mM NBQX (n = 10), vehicle (water, n = 15), HA (n = 8), Depo-Medrone (n = 7), vehicle (saline, n = 7).