c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions |
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Authors: | Yongzheng He Steven D Rhodes Shi Chen Xiaohua Wu Jin Yuan Xianlin Yang Li Jiang Xianqi Li Naoyuki Takahashi Mingjiang Xu Khalid S Mohammad Theresa A Guise Feng-Chun Yang |
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Institution: | 1. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.; 2. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.; 3. Division of Hard Tissue Research, Matsumoto Dental University, Shiojiri, Nagano, Japan.; 4. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.; University of Toronto, Canada, |
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Abstract: | Skeletal abnormalities including osteoporosis and osteopenia occur frequently in both pediatric and adult neurofibromatosis type 1 (NF1) patients. NF1 (Nf1) haploinsufficient osteoclasts and osteoclast progenitors derived from both NF1 patients and Nf1+/− mice exhibit increased differentiation, migration, and bone resorptive capacity in vitro, mediated by hyperactivation of p21Ras in response to limiting concentrations of macrophage-colony stimulating factor (M-CSF). Here, we show that M-CSF binding to its receptor, c-Fms, results in increased c-Fms activation in Nf1+/
− osteoclast progenitors, mediating multiple gain-in-functions through the downstream effectors Erk1/2 and p90RSK. PLX3397, a potent and selective c-Fms inhibitor, attenuated M-CSF mediated Nf1+/− osteoclast migration by 50%, adhesion by 70%, and pit formation by 60%. In vivo, we administered PLX3397 to Nf1
+/− osteoporotic mice induced by ovariectomy (OVX) and evaluated changes in bone mass and skeletal architecture. We found that PLX3397 prevented bone loss in Nf1+/−-OVX mice by reducing osteoclast differentiation and bone resorptive activity in vivo. Collectively, these results implicate the M-CSF/c-Fms signaling axis as a critical pathway underlying the aberrant functioning of Nf1 haploinsufficient osteoclasts and may provide a potential therapeutic target for treating NF1 associated osteoporosis and osteopenia. |
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