Early ablation of Ccr2 in aggrecan-expressing cells following knee injury ameliorates joint damage and pain during post-traumatic osteoarthritis.

OBJECTIVE: To investigate whether Ccr2 inactivation in aggrecan-expressing cells induced before post-traumatic OA (PTOA) onset or during progression, improves joint structures, synovial thickness and pain. DESIGN: We induced a Ccr2 deletion in aggrecan-expressing cells (CCR2-AggKO) in skeletally mature mice using a tamoxifen-inducible Ccr2 inactivation. We stimulated PTOA changes (destabilization of medial meniscus, DMM) in CCR2-AggKO and CCR2+/+ mice, inducing recombination before DMM or 4 wks after DMM (early-vs late-inactivation). Joint damage was evaluated 2, 4, 8, 12 wks post-DMM using multiple scores: articular-cartilage structure (ACS), Safranin-O, histomorphometry, osteophyte size/maturity, subchondral bone thickness and synovial hyperplasia. Spontaneous (incapacitance meter) and evoked pain (von-Frey filaments) were assessed up to 20 wks. RESULTS: Early aggrecan-Ccr2 inactivation in CCR2-AggKO mice (N=8) resulted in improved ACS score (8-12wk, P=0.002), AC area (4-12wk, P<0.05) and Saf-O score (2wks P=0.004, 4wks P=0.02, 8-12wks P=0.002) compared to CCR2+/+. Increased subchondral bone thickness was delayed only at 2 wks and exclusively following early recombination. Osteophyte size was not affected, but osteophyte maturation (cartilage-to-bone) was delayed (4wks P=0.04; 8 wks P=0.03). Although late aggrecan-Ccr2 deletion led to some cartilage improvement, most data did not reach statistical significance; osteophyte maturity was delayed at 12wks. Early aggrecan-Ccr2 deletion led to improved pain measures of weight bearing compared to CCR2+/+ mice (N = 9, 12wks diff 0.13 [0.01, 0.26], 16wks diff 0.15 [0.05, 0.26], 20wks diff 0.23 [0.14, 0.31]). Improved mechanosensitivity in evoked pain, although less noticeable, was detected. CONCLUSIONS: We demonstrated that deletion of Ccr2 in aggrecan expressing cells reduces the initiation but not progression of OA.