Two‐Phase Change in Cartilage Metabolism Indicated by Serum Biomarkers at Onset of Posttraumatic Osteoarthritis in a Medial Meniscus Destabilization Rat Model
Authors: Howell Megan M. , Gunn Brady L. , Goldenstein Allison J. , Permyakov Roman A. , Memar Shayan , Abeyrathna Prasanna , Cramberg Michael , Brechue William , Kondrashov Peter 
Published: April 2020

Purpose

Osteoarthritis (OA) is a chronic degeneration of articular cartilage from a deficit of supporting proteins. Surgical destabilization of the medial meniscus (DMM) experimentally leads to trauma‐induced knee OA in rats. Changes in cartilage function or joint remodeling associated with joint instability or disease may be reflected by changes in synthesis or degradation of extracellular matrix, assessed by measuring metabolites, serving as biomarkers, of cartilage synthesis/degradation. Aggrecan chondroitin sulfate 846 epitope (CS846) is associated with synthesis of cartilage ground substance and is elevated in patients with OA. Degradation of type I and II collagen is related to increased serum concentration of C‐terminus of 3/4 peptide, measured as C1,2C.

Methods

Female Lewis rats (n=40) were randomly assigned to DMM (n=20) or sham (n=20) surgery groups. Surgical intervention followed a 2‐week acclimation. The joint capsule was opened and the medial meniscotibial ligament was transected for DMM; no ligaments were cut for sham. Blood samples were collected by tail clipping 1 week prior (baseline) and 2‐weeks (acute phase, surgery effect) and 6‐weeks (late phase, OA effect) postsurgery. Clotted blood was centrifuged (3000 rpm, 30 minutes) and aliquots of serum stored (−80ºC) until analysis. CS846 and C1,2C were analyzed by enzyme‐linked immunosorbent assay kits.

Results

CS846 and C1,2C serum level changes were significant over time (mean [SD] ng/ml) in both groups, but the dynamics were different. CS846 was elevated 2‐weeks postsurgery (1334.7 [1786.6]) compared to baseline (417.8 [591], P=.012), but decreased 6‐weeks postsurgery (610 [1213.4], P=.066) in DMM. CS846 did not change from baseline to 2‐weeks or 6‐weeks postsurgery (P=.16 and .35) in sham. C1,2C decreased 2‐weeks postsurgery in DMM (4211 [1176], P<.001) and sham (4580 [1238], P<.001) compared to baseline (sham 6817 [1348], DMM 5918 [1211]), but the decrease was slightly less in DMM (P=.076). C1,2C continued to decrease between 2‐weeks and 6‐weeks postsurgery in sham (3447 [897], P<.001), but not DMM (4111 [485], P=.360); the between‐groups difference was significant (P<.001).

Conclusions

Biomarker dynamics suggested a 2‐phase progression of OA in the posttraumatic model. During the acute phase (2 weeks after trauma), altered joint configuration resulted in increased pressure on articular cartilage causing destruction of ground substance, indicated by increased CS846. Surgical intervention caused collagen type I fiber damage in both groups. Wound healing caused products of collagen breakdown (C1,2C) to rapidly decrease in sham and to a lesser extent in DMM. In the late phase of OA (6 weeks after trauma), erosion of cartilage resulted in collagen type II breakdown, indicated by a lesser decrease in C1,2C in DMM than sham. Continued damage to articular cartilage in DMM caused C1,2C to remain relatively constant between 2‐weeks and 6‐weeks postsurgery. These data indicate that CS846, but not C1,2C, is more useful in the diagnosis of early stages of OA and that the opposite is true in the later phase.