Our laboratory is interested in identifying and elucidating the molecular mechanism of action of regulators of bone remodeling. This interest led us to study the role of neurofibronin, a GTPase activating protein encoded by the NF1 gene in bone remodeling. Mutation in NF1 causes Neurofibromatosis Type 1 (NF1), a syndrome characterized, among other manifestations, by disabling skeletal abnormalities, whose origin is unknown. To characterize the role of Nf1 in bone biology and to overcome the embryonic lethality of Nf1-/- mice, we generated mice deficient for Nf1 specifically in osteoblasts (Nf1ob-/- mice). In preliminary data, we show that Nf1 deficiency in osteoblasts leads to a high bone mass caused by an increase in bone formation. We also present evidence that the kinases ERK and RSK2 as well as ATF4, a transcription factor required for osteoblast differentiation, may be a target of Nf1 signaling involved in the high bone mass of Nf1ob-/- mice. Surprisingly, Nf1 deficiency in osteoblasts also increases osteoclast differentiation and bone resorption through yet unknown mechanisms. These data, along with our recent findings related to the role of ATF4 in bone resorption therefore suggest that, in osteoblasts, an increase in ATF4 activity may be responsible for most of the NF1 skeletal manifestations, including the increase in bone resorption observed in Nf1ob-/- mice and humans. ? In this application, we propose to use WT and Nf1-/- osteoblast/osteoclast co-cultures and cell signaling studies to characterize the signaling pathways whereby Nf1 in osteoblasts regulate osteoclastogenesis, bone resorption, collagen synthesis and bone formation. To confirm that ATF4 is a target of Nf1 signaling in osteoblasts and to demonstrate the in vivo relevance of these findings, we will attempt to rescue the bone phenotypes of Nf1ob-/- mice, genetically by removing one copy of Atf4 in Nf1ob-/- mice and pharmacologically by blocking Ras and MARK in Nf1ob-/- mice and osteoblasts. ? ? Relevance: Neurofibromatosis (NF1) is characterized by debilitating skeletal abnormalities that are often progressive and difficult to treat. This project aims at understanding the origin of these bony abnormalities and to test pharmacological candidates that could ameliorate the skeletal manifestations of the syndrome using a mouse model of NF1. It also aims at characterizing novel signaling pathways and target genes regulating bone remodeling, with the long-term goal to better understand diseases affecting the skeleton and to propose rationale therapies. ? ? ?
| Elefteriou, Florent; Benson, M Douglas; Sowa, Hideaki et al. (2006) ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab 4:441-51 |
