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.