title: Ras dependent paracrine secretion of osteopontin by Nf1+/- osteoblasts promote osteoclast activation in a neurofibromatosis type I murine model.
abstract: Neurofibromatosis type 1 (NF1) is a pandemic genetic disorder characterized by malignant and nonmalignant manifestations, including skeletal abnormalities, such as osteoporosis, scoliosis, short stature, and pseudarthrosis. Recent studies in genetically inbred mice and from human patients with NF1 have identified multiple gains in osteoclast (OCL) functions both in vitro and in vivo. Given that osteoblasts secrete cytokines that promote OCL maturation/activation, we sought to identify whether haploinsufficiency of Nf1 (Nf1+/-) osteoblasts and their precursors secrete cytokines that have a central role in this process. Osteoblast conditioned media (OBCM) from Nf1+/- osteoblasts promoted OCL migration and bone resorption compared with WT OBCM. Osteopontin (OPN), a matrix protein found in mineralized tissues and pivotal in modulating OCL functions, was present in increased concentrations in Nf1+/- osteoblasts. Addition of OPN neutralizing antibody to Nf1+/- OBCM diminished the gain in bioactivity on OCL functions, including OCL migration and bone resorption. Our study identifies an important paracrine loop whereby elevated secretion of OPN by osteoblasts activate Nf1+/- OCLs that already have an intrinsic propensity for bone resorption leading to osteopenia and osteoporosis.
authors.affiliation: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Huijie
authors.initials: H
authors.lastname: Li
authors.forename: Yaling
authors.initials: Y
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Jing
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Song
authors.forename: Jincheng
authors.initials: J
authors.lastname: Yan
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zhang
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jamie
authors.initials: J
authors.lastname: Case
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D000328:Adult; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D002648:Child; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D053495:Osteopontin / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D025542:Neurofibromin 1; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins