Browsing by Author "Yang, Feng- Chun"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions
    (Public Library of Science, 2012) He, Yongzheng; Rhodes, Steven D.; Chen, Shi; Wu, Xiaohua; Yuan, Jin; Yang, Xianlin; Jiang, Li; Li, Xianqi; Takahashi, Naoyuki; Xu, Mingjiang; Mohammad, Khalid S.; Guise, Theresa A.; Yang, Feng- Chun; Pediatrics, School of Medicine
    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 p21(Ras) 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.