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

  • Author Footnotes
    a HW and HO contributed equally to this work.
    H. Willcockson
    Footnotes
    a HW and HO contributed equally to this work.
    Affiliations
    Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA
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  • Author Footnotes
    a HW and HO contributed equally to this work.
    H. Ozkan
    Footnotes
    a HW and HO contributed equally to this work.
    Affiliations
    Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA
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  • L. Arbeeva
    Affiliations
    Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA
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  • E. Mucahit
    Affiliations
    Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA
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  • L. Musawwir
    Affiliations
    Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA
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  • L. Longobardi
    Correspondence
    Address correspondence and reprint requests to: L. Longobardi, Division of Rheumatology, Allergy and Immunology, University of North Carolina at Chapel Hill, 3300 Thurston Bowles Bldg, Campus Box 7280, Chapel Hill, NC 27599, USA. Tel: 1-919-843-4727; fax: 1-919-966-1739.
    Affiliations
    Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina-Chapel Hill, NC, USA
    Search for articles by this author
  • Author Footnotes
    a HW and HO contributed equally to this work.
Published:September 05, 2022DOI:https://doi.org/10.1016/j.joca.2022.08.015

      Summary

      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.

      Keywords

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