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.
Highlights
Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases with an incidence of 1 out of 3000 individuals [1]
Nf1+/2 osteoclasts and osteoclast progenitors are hyperresponsive to limiting doses of macrophage-colony stimulating factor (M-CSF), the molecular mechanisms mediating this phenotype remain unclear
We reported an increased frequency of osteoclast progenitors in Nf1+/2 bone marrow induced by M-CSF as assessed by the colony forming unit-macrophage (CFU-M) assay [18]
Summary
Neurofibromatosis type 1 (NF1) is one of the most common genetic diseases with an incidence of 1 out of 3000 individuals [1]. Clinical studies have reported that NF1 patients are at a significant risk for both generalized osteoporotic abnormalities [5,6,7] and focal skeletal abnormalities including dystrophic kyphoscoliosis and pseudarthrosis [8,9]. NF1 patients have an increased prevalence of osteoporosis beginning from childhood and adolescence [10,11,12], leading to greater risk of fracture later in life [13]. Given that osteoporosis occurs in a younger patient population and the predisposition to pseudarthrosis is 2–5% in individuals with NF1 [3,14,15], the ultimate health costs and sequelae of this condition in NF1 patients may be significantly greater. Despite evidence of low serum Vitamin D levels in some NF1 patients, clinical studies involving Vitamin D supplementation have yielded conflicting results on whether improvements in bone mineral density (BMD) can be achieved [10,16,17]
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