CPII and C2C Biomarkers Favor Cartilage Degradation During Initial Progression of Osteoarthritis in Rats That Have Undergone Destabilization of the Medial Meniscus Surgery

Abstract

PurposeMeniscal tears can be simulated in animal models using destabilization of the medial meniscus (DMM) surgery, which has been shown to lead to the progression of knee osteoarthritis (OA). Previous studies on DMM‐induced knees have noted damage to the articular cartilage as soon as 2 weeks post‐surgery. By 10 weeks, severe OA was observed in the DMM‐induced knees. While histological markers for OA have been established, no prior study has examined OA serum biomarker changes during the progression from trauma to cartilage degradation. Cartilage turnover can be assessed by measuring metabolites produced during synthesis and degradation of cartilage. These metabolites can serve as biomarkers for cartilage remodeling. Due to the abundance of type II collagen in articular cartilage, CPII and C2C serum biomarkers involved in the synthesis and degradation of type II collagen were selected for this study. Degradation of type II collagen results in increased levels of fragment epitopes (Col2‐3/4long mono), which can be measured as collagen type II cleavage product (C2C). Whereas, synthesis of type II collagen can be detected from circulating levels of procollagen IIC propeptide (CPII), the cleaved C‐terminal globular domain of the pre‐propeptide. Both CPII and C2C have been suggested as early indicators of cartilage injury. Thus, the focus of this study was to document changes in these biomarkers over 2 months in rats that have undergone DMM surgery.MethodsFemale Lewis rats (n=35) underwent a unilateral DMM surgery, in which the medial meniscotibial ligament was transected. Five rats were sacrificed weekly for 7 weeks. Blood from the tail of each rat was collected prior to DMM surgery and euthanasia, for a total of 2 blood samples per rat. Serum from each blood sample was analyzed for C2C and CPII using ELISA kits.ResultsPrior to surgery, C2C and CPII averaged 260 ± 12 ng/mL and 780 ± 47 ng/mL, respectively. Subsequent to DMM surgery, C2C and CPII levels increased to 356 ± 31 ng/mL and 2502 ± 807 ng/mL, respectively, resulting in a degradation‐synthesis ratio (C2C:CPII) of 0.142 during the first week. C2C:CPII increased to 0.462 at 2 weeks post‐surgery, and decreased to 0.093 after 3 weeks. C2C:CPII again increased 4 weeks post‐surgery to 0.393, where it plateaued throughout the remaining 3 weeks. By 7 weeks post‐surgery C2C:CPII was 0.323.ConclusionsThese results lead to the suggestion that collagen type II degradation increased within 2 weeks following the DMM surgery, and collagen type II synthesis was highest 3 weeks after the surgery. An explanation for this may be the physiological and biochemical need to compensate for articular cartilage deterioration after onset of trauma‐induced OA. As OA progressed throughout the remaining weeks (4–7), degradation of type II collagen increased relative to the rate of synthesis and remained above the pre‐surgery ratio. This indicates there is substantial articular cartilage degeneration and remodeling occurring within the first 4 weeks of DMM‐induced knee OA and may represent the optimal period for therapeutic intervention.