He, YongzhengRhodes, Steven D.Chen, ShiWu, XiaohuaYuan, JinYang, XianlinJiang, LiLi, XianqiTakahashi, NaoyukiXu, MingjiangMohammad, Khalid S.Guise, Theresa A.Yang, Feng- Chun2025-06-092025-06-092012He Y, Rhodes SD, Chen S, et al. c-Fms signaling mediates neurofibromatosis Type-1 osteoclast gain-in-functions. PLoS One. 2012;7(11):e46900. doi:10.1371/journal.pone.0046900https://hdl.handle.net/1805/48574Skeletal 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.en-USAttribution 4.0 InternationalBone resorptionOsteoclastsOsteoporosisArticle