Ras dependent paracrine secretion of osteopontin by Nf1+/- osteoblasts promote osteoclast activation in a neurofibromatosis type I murine model.
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.
Li
Huijie
H
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Liu
Yaling
Y
Zhang
Qi
Q
Jing
Yongmin
Y
Chen
Shi
S
Song
Zhaohui
Z
Yan
Jincheng
J
Li
Yan
Y
Wu
Xiaohua
X
Zhang
Xianghong
X
Zhang
Yingze
Y
Case
Jamie
J
Yu
Menggang
M
Ingram
David A
DA
Yang
Feng-Chun
FC
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*
D017077:Culture Media, Conditioned; D025542:Neurofibromin 1; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins