A fundamental understanding of the molecular mechanism governing adult osteoprogenitors and their differentiation is essential for developing novel bone anabolic therapeutics. We have recently discovered that Hh signaling induces expression of Igf signaling components and activates Igf signaling, thus engaging in a Hh-Igf positive feedabck loop in osteoblast-lineage cells. In addition, we have identified a Hh-responsive population as critical osteoprogenitors in adult bones. In the current proposal, we will further elucidate the biochemical basis for the Hh-Igf feedback mechanism, and explore the physiological relevance of the regulatory loop in postnatal osteoprogenitors and adult bone formation. Overall, successful completion of this project will provide novel mechanistic insights about Hh-Igf signaling in adult bones, and may open new avenues for developing effective bone anabolic therapeutics.
There continues to be a pressing need for safe and effective therapeutics that stimulates bone formation in various medical conditions. Hedgehog signaling is indispensable for osteoblast differentiation in the long bones durign embryogenesis. However, the molecular mechanisms mediating the bone-promoting function of Hh is not well understood. Moreover, the contribution of Hh signaling to adult bone homeostasis is not well defined. The current proposal explores the biochemical and functional interaction between Hh and Igf signaling, and investigates the relavance of Hh-responsive osteoprogenitors to adult bone formation. These studies are expected to provide novel insights about the mechanism and function of Hh signaling in the postnatal skeleton. Such new knowledge may provide additional avenues for developing novel bone anabolic therapeutics.
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| Shi, Yu; He, Guangxu; Lee, Wen-Chih et al. (2017) Gli1 identifies osteogenic progenitors for bone formation and fracture repair. Nat Commun 8:2043 |
| Shi, Yu; Long, Fanxin (2017) Hedgehog signaling via Gli2 prevents obesity induced by high-fat diet in adult mice. Elife 6: |
