Session VIII - Basic Science
Effect of IGF-1 on Chondrocyte Apoptosis in a Rabbit Intra-articular Fracture Model
Purpose: Intra-articular fracture has been shown to induce chondrocyte apoptosis, a process considered to correlate with posttraumatic osteoarthritis severity. The induction of apoptosis has also been shown to be time-dependent, potentially offering a therapeutic window during which apoptosis may be inhibited. The expression of insulin-like growth factor-1 (IGF-1) has been shown to protect chondrocytes from apoptosis in vitro, as well as maintain a fully differentiated chondrocyte phenotype. Chondrocytes involved in intra-articular fracture undergo dedifferentiation to more primitive mesenchymal tissue resulting in biomechanically inferior fibrocartilage. Theoretically, posttraumatic administration of IGF-1 may inhibit chondrocyte apoptosis and protect chondrocytes from dedifferentiation, preserving a more viable articular surface. Our hypothesis states that intra-articular administration of IGF-1 after fracture will inhibit chondrocyte apoptosis in vivo.
Methods: Protocol was approved by Institutional Animal Care and Use Committee. 24 skeletally mature New Zealand white rabbits were randomized to control and IGF-1 groups. All subjects underwent standardized medial femoral condyle intra-articular fracture in a single hind limb. Fractures were repaired with a 1.5-mm lag screw. 1.5 cc fibrin clot was administered intra-articular in all subjects, with 25 mcg/ml IGF-1 in half of the subjects. Subjects were permitted cage activity ad lib. Half of the animals in each group were sacrificed at 2 weeks and half at 4 weeks. At necropsy, specimens were fixed and embedded in paraffin followed by H&E, safranin O, TUNEL, BCL-x, MIB-1 immunohistochemical staining.
Results: Data were analyzed using an analysis of variance followed by a Newman-Keuls multiple comparison test. Significance was defined as alpha of 0.05. 2-week control showed significantly higher rate of apoptosis than 2-week IGF-1 (21 ± 6 vs. 12 ± 6, P = 0.04). Likewise, 4-week control showed significantly higher rate of apoptosis than 4-week IGF-1 (23 ± 7 vs. 10 ± 2, P =0.01). There was no significant difference between 2-week control and 4-week control, or between 2 week IGF and 4-week IGF. Pathologic characterization with BCL-x, MIB-1, Type II collagen is pending at this time.
Conclusion/Significance: Intra-articular administration of IGF-1 at the time of fracture repair appears to inhibit chondrocyte apoptosis in vivo, when compared to controls, in this animal model. If intra-articular administration of IGF-1 acutely inhibits chondrocyte apoptosis, this may ultimately lead to interventions to reduce posttraumatic arthritis after fracture.