DESCRIPTION (provided by applicant): Acquisition and maintenance of normal bone mass requires an adequate number of proliferative osteogenic precursor cells as well as the differentiated functions of osteoblasts. A reduction in the osteoblast precursor cell population or under-performing osteoblasts has been associated with abnormal development of the skeleton, as well as impaired bone remodeling and fracture healing in aging patients. Increasingly, it is being recognized that local factors, including fibroblast growth factors (FGFs), are crucial regulators of the cellular events associated with the osteogenic process. The bone-inducing effects of FGFs are mediated through four high affinity receptors (FgfR1-4), with FgfR1 and 2 being the major receptors expressed in bone. However the mechanisms of FGF's bone inducing effect as well as specific functions of each FgfR in osteogenesis remain elusive. In this study, we will test the hypothesis that temporally expressed FgfR1 and FgfR2 coordinates osteogenic cell proliferation and differentiation to promote bone growth. In developing bones, expression of FgfR2 is mainly restricted to highly proliferative osteoblast precursor cells and decreases with maturation. Concomitant with FgfR2 down-regulation, cell proliferation decreases and FgfR1 expression increases in differentiating osteoblasts. Collective data from our preliminary transgenic mouse and in vitro cell culture studies suggest that FgfR1 and FgfR2 both positively contribute to bone formation but may have differential roles in the regulation of bone cell proliferation and differentiation. The loss of FgfR2 and FgfR1 function results in drastically reduced intramembranous and trabecular bone mass in mice, while gain of FgfR2 function appears to stimulate bone formation. Our in vitro preliminary data suggest that FgfR2 stimulates cell proliferation but inhibits late differentiation and that Rtmx2, BMP-2 and Stat1 may be downstream mediators of FgfR2 functions. Therefore, we propose that FgfR2 plays a significant role in expanding the differentiation-competent early osteogenic cell population, by stimulating both cell proliferation and early osteogenic differentiation via increases in Runx2 and/or BMP-2 and phosphorylation of Stat1. We propose further that late osteogenic differentiation requires down-regulation of FgfR2 and perhaps also up-regulation ofFgfR1. Our hypothesis will be tested in a complementary set of in vitro and in vivo studies, utilizing transgenic and gene knock out approaches to selectively modulate either FgfR1 or FgfR2 activity.