title: Aberrant Myeloid Differentiation Contributes to the Development of Osteoporosis in Neurofibromatosis Type 1.
abstract: Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant genetic disorder affecting approximately 1 in 3000 individuals worldwide. NF1 results from heritable or spontaneous mutations of the NF1 tumor suppressor gene. NF1 encodes the protein neurofibromin, which functions to negatively regulate Ras-activity. Approximately 50 % of NF1 patients develop osteopenia or osteoporosis, resulting in significantly increased rates of long-bone fracture and morbidity. While defective osteoblast bone anabolism has been implicated as a central factor in the pathogenesis of NF1 associated skeletal deficits, recent data suggest that NF1 (Nf1) haploinsufficiency within the hematopoietic compartment, particularly in osteoclasts and myeloid progenitors, plays a pivotal role in engendering NF1 osseous manifestations. In this chapter, we review the latest data from clinical studies and murine models delineating a critical role for hematopoietic compartment, myeloid progenitors of NF1 (Nf1) haploinsufficient and their progeny-osteoclasts, in the pathogenesis of NF1 associated osteopenia/osteoporosis and discuss putative targets for future therapeutics.
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, R. Bunn Gautier Building, 417 1011 NW 15th street, Locator R-629, Miami, FL, 33136, USA. fxy37@med.miami.edu.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D057895:Haploinsufficiency; D006801:Humans; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics*; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism
chemical_list: D025542:Neurofibromin 1
keywords: Neurofibromatosis type 1; Osteoclasts; Osteoporosis; Therapies