Recent studies have demonstrated that the global or osteoblast-specific deletion of neuropeptide Y Y1 receptor (Y1R), as well as the pharmacological blockade of Y1R, leads to pronounced anabolic effects in bone metabolism. This suggests that anti-Y1R drug therapy might have clinical applications for the prevention/recovery of bone loss occurring in osteoporosis. Given the high fracture incidence in this target population, it remained important to evaluate Y1R roles in bone regeneration/healing.
Therefore, we investigated the effects of germline (Y1R−/−) or osteoblast-specific (Y1lox/lox;Cre/+) deletion of Y1R in bone fracture healing, using a murine model of tibial fracture. Closed fractures stabilized by intramedullary fixation were generated in 11-week-old mice, and the process of fracture repair was monitored by X-ray, micro-CT and histomorphometric analyses.
At 3-weeks post-fracture, Y1R−/− mice already exhibited a smaller callus when compared to their WT littermates. In fact, Y1R−/− fracture calluses were still not bridged, in comparison to the 89% of bridged fractures in WT (P=0.002). Structural analysis detected a 27% decrease in callus tissue volume (P<0.001) and a 9% reduction in bone volume density (BV/TV; P<0.001), which together resulted in a decrease of polar moment of inertia (callus strength; P<0.05). Moreover, histologically Y1R-/- fracture callus presented a reduced vascular area (P<0.05) and a trend towards increased cartilage content (≈5%; P=0.07). Importantly, by 6-weeks post-fracture all Y1R−/− fracture calluses were radiologically bridged. Interestingly at 6-weeks Y1R−/− calluses exhibited an increase of 31% in BV/TV (P<0.05). Importantly, no structural or histological changes were detected on fracture calluses from Y1lox/lox;Cre/+ and WT at 3-weeks post-fracture.
In conclusion, our findings suggest that Y1R global deletion delays the early stages of bone fracture bridging, without inhibiting the completion of healing to union. This delay was independent from osteoblast-specific Y1R. The knowledge acquired is important for the design of new Y1R-based therapeutic approaches.
17 May 2014 - 20 May 2014