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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.

c-Fms Signaling Mediates Neurofibromatosis Type-1 Osteoclast Gain-In-Functions