Background/Purpose: Synovial expression of CCR7 has been associated with inflammation and severity of symptoms in patients with meniscal tears and early osteoarthritis (OA). This receptor plays a role in trafficking of leukocytes and aids in the development of chronic inflammation. The current aim was to determine if CCR7 plays a mechanistic role in development of OA-related structural and functional manifestations after destabilization of the medial meniscus (DMM) in a murine model of knee OA.

Methods: To confirm expression of CCR7 in humans, knee synovial tissues from 15 patients with meniscal tears, and 9 asymptomatic organ donors were collected through IRB-approved biorepositories. Immunoperoxidase staining for CCR7 was evaluated by automated image analysis.  To investigate effects of CCR7 deficiency in vivo, genetically modified mice lacking expression of CCR7 (CCR7^-/-) and C57BL/6 congenic controls were obtained from Jackson Laboratory. Male mice were subjected to DMM surgery at 10-12 weeks of age.  Six weeks after surgery, groups of 5 mice were sacrificed and knee joints evaluated by histopathology for cartilage degeneration and osteophyte size using standard methods.  Synovial lining hyperplasia was scored on a scale of 0-3 with 0 = one cell layer thick, 1= 2-3 cell layers, 2 = 4-5 cell layers, and 3 = >6 cell layers thick. Changes in spontaneous climbing activity were measured longitudinally (up to 16 weeks) after DMM surgery in the two strains, using the LABORAS^®laboratory animal behavior analysis system (Metris B.V., Hoofdorp, The Netherlands).

Results: Synovial CCR7 staining was significantly higher in patients with meniscal tears (Mean % area +/- SEM = 12.26 +/- 2.4) compared to asymptomatic donors (3.55 +/- 2.7, p=0.01). Six-weeks after DMM surgery, CCR7^-/- mice exhibited reduced cartilage degeneration (Mean +/- SEM = 1.60+/-0.81) and osteophyte size (0.80+/-0.20) compared to their C57BL/6 controls (cartilage = 5.20+/-1.06, osteophyte = 1.40+/-0.24, p<0.0001).  Slight increases in synovial hyperplasia in response to DMM surgery occurred in both strains of mice (p=ns).  C57BL/6 mice decreased their climbing activity post-operatively starting at 4 weeks, and decreases were maximal at 8 weeks post-DMM surgery (46.87% lower than pre-DMM, p=0.012).  In contrast, at 4 weeks post-DMM CCR7^-/- mice maintained pre-operative climbing activity and climbing was significantly increased by 8 weeks post-DMM (25.64% higher than pre-DMM, p = 0.001).  At 8 weeks, time spent climbing was lower in C57BL/6 DMM mice compared to sham (p=0.0145) and naïve (p =0.00205) controls, while CCR7^-/- mice showed no significant differences between DMM-operated, sham and naïve control groups  

Conclusion: In the DMM model of OA, CCR7^-/- mice showed reduced cartilage degeneration and osteophyte size at 6 weeks post-surgery and improved function (measured by climbing activity) by 8 weeks post-surgery in contrast to their C57BL/6 counterparts. Based on these results, CCR7 may be a potential target for therapy with both structure- and symptom- modifying effects in OA.  Future studies will investigate the use of targeted treatments aimed at the blockade of CCR7 and its ligands in this model.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cc-chemokine-receptor-7-ccr7-deficiency-reduces-early-structural-and-functional-features-of-disease-in-a-murine-model-of-osteoarthritis/