Indian hedgehog signaling pathway differences between swarm rat chondrosarcoma and native rat chondrocytes.

Indian Hedgehog (Ihh)--Parathyroid related protein (PTHrP) and Fibroblast Growth Factor 3 (FGFR3) signaling pathways are important in regulating endochondral bone formation. In the growth plate, Ihh and PTHrP are involved in a feedback loop to increase proliferation and delay differentiation of chondrocytes. Fibroblast Growth Factor Receptor 3 (FGFR3) conversely decreases proliferation and hastens differentiation with an agonist. Since proliferation is the hallmark of chondrosarcoma cells, we hypothesized that Ihh/PTHrP and FGF3R pathways may be dysfunctional on these cells. Therefore, we sought to investigate the role of these signaling pathways in the Swarm rat chondrosarcoma cells utilizing expression and functional studies. Semiquantitative RT-PCR analysis demonstrated difference in expression between normal growth plate chondrocytes and chondrosarcoma cells (JWS). JWS had an increased mRNA expression of FGF2 and FGFR3 suggesting a mechanism to reverse the proliferative rate of the cells. Immunohistochemical analysis showed increased staining for FGFR3 and patched-1 (Ihh receptor) in JWS compared to the rat tibia growth plate (p = 0.O004 and 0.02 respectively). In vitro functional experiments demonstrated that the use of FGF2, a FGFR3 receptor agonist, dramatically decreased the proliferative rate of Swarm chondrosarcoma cells (LTC). Cyclopamine, a hedgehog inhibitor, did not have a significant effect on their proliferative rate. However, when cyclopamine was used on normal chondrocytes, it effectively decreased the proliferative rate of these cells, suggesting abnormalities in this pathway in the chondrosarcoma cells. In conclusion, our investigation describes dissimilarity in the Indian Hedgehog and FGFR3 signaling pathways between the rat chondrosarcoma cells and native rat chondrocytes. Understanding the underlying mechanisms may provide a target for future therapy for chondrosarcoma.

Effect of chemotherapy on segmental bone healing enhanced by rhBMP-2.

Segmental bone defects are challenging clinical problems, and current surgical solutions are associated with high complication rates. In oncologic reconstructive surgery, bone healing will occur coincidently with the administration of chemotherapy to treat the underlying disease. Effective methods of graft modification or bone graft alternatives can be of great help clinically. A series of osteoinductive proteins (bone morphogenetic proteins or BMPs) has been described and shown to enhance bone formation in animal models. This study was designed to evaluate the effect of chemotherapy on bone healing enhanced by rhBMP-2. We used a critical-sized bone-defect rabbit model. Histological and radiological analysis showed that chemotherapy affects both the quantity and the quality of the bone enhanced by the addition of rhBMP-2. These results suggest that the effect of chemotherapy on bone formation could be related to inhibition in a specific pathway stimulated by the rhBMP-2.