Tremendous unmet clinical needs exist in musculoskeletal medicine. Novel strategies are urgently needed to promote bone formation and function safely in patients with severe osteoporosis or experiencing delayed-union or nonunion in fracture repair. A fundamental understanding of mechanisms governing osteoblast differentiation is critical for the development of such bone-enhancing strategies. Work from our laboratory and others has firmly established Indian hedgehog (Ihh), a member of the Hedgehog (Hh) family, as an essential regulator for osteoblast differentiation, chondrocyte development and cartilage vascularization during endochondral bone formation - the osteogenic process that directs both skeletal growth and bone fracture repair. However, although it is known that the Gli family (Gli1-Gli3) of transcriptional activators and repressors collectively mediate Hh signaling in mammals, it is not clear which Gli or what form (activator versus repressor) is responsible for each of the diverse functions of Ihh in the skeleton. Moreover, the role of Hh signaling in bone homeostasis and regeneration in the adult has not been elucidated. In the previous funding cycle of this project, by employing murine genetics we established the critical role of Gli3 - predominantly a repressor antagonized by Ihh signaling - in control of chondrocyte proliferation and maturation. Intriguingly, we uncovered that Ihh regulates both osteoblast and skeletal vascular development via mechanisms independent of the Gli3 repressor;this finding prompted us to hypothesize that an additional effector, most probably the activator form of Gli2, is required for mediating the role of Ihh in osteoblastogenesis and in cartilage vascularization. In the current proposal we will test the role of Gli2 activator in Ihh-mediated osteoblast differentiation and skeletal vascularization. In addition, we will test the potential roles of Hh signaling in bone homeostasis and fracture healing in adult mice.
Tremendous unmet clinical needs exist in musculoskeletal medicine. Novel strategies are required to safely promote bone formation in osteoporosis and bone fracture repair. Hedgehog (Hh) signaling has been established to be a key pathway controlling osteoblast development in the embryo, providing a promising target pathway for development of bone anabolic agents. This proposal is designed to elucidate the molecular mechanism through which Hh controls osteoblast differentiation, as well as the potential roles of Hh signaling in bone homeostasis and fracture repair in the adult. Research results from this study will provide a molecular framework for developing novel bone-enhancing pharmaceutics.
|Shi, Yu; Chen, Jianquan; Karner, Courtney M et al. (2015) Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation. Proc Natl Acad Sci U S A 112:4678-83|
|Lim, Joohyun; Tu, Xiaolin; Choi, Kyunghee et al. (2015) BMP-Smad4 signaling is required for precartilaginous mesenchymal condensation independent of Sox9 in the mouse. Dev Biol 400:132-8|
|Kazmers, Nikolas H; McKenzie, Jennifer A; Shen, Tony S et al. (2015) Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing. Bone 81:524-32|
|Karner, Courtney M; Esen, Emel; Okunade, Adewole L et al. (2015) Increased glutamine catabolism mediates bone anabolism in response to WNT signaling. J Clin Invest 125:551-62|
|Schwartz, Andrea G; Long, Fanxin; Thomopoulos, Stavros (2015) Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment. Development 142:196-206|
|Huang, Alice H; Riordan, Timothy J; Pryce, Brian et al. (2015) Musculoskeletal integration at the wrist underlies the modular development of limb tendons. Development 142:2431-41|
|Karner, Courtney M; Long, Fanxin; Solnica-Krezel, Lilianna et al. (2015) Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice. Hum Mol Genet 24:4365-73|
|Tang, Chao; Pan, Yibin; Luo, Huan et al. (2015) Hedgehog signaling stimulates the conversion of cholesterol to steroids. Cell Signal 27:487-97|
|Joeng, Kyu Sang; Long, Fanxin (2014) Wnt7b can replace Ihh to induce hypertrophic cartilage vascularization but not osteoblast differentiation during endochondral bone development. Bone Res 2:14004|
|Chen, Jianquan; Long, Fanxin (2014) mTORC1 signaling controls mammalian skeletal growth through stimulation of protein synthesis. Development 141:2848-54|
Showing the most recent 10 out of 30 publications