Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis.
Although nullizygous loss of NF1 leads to myeloid malignancies, haploinsufficient loss of NF1 (Nf1) has been shown to contribute to osteopenia and osteoporosis which occurs in approximately 50% of neurofibromatosis type 1 (NF1) patients. Bone marrow mononuclear cells of haploinsufficient NF1 patients and Nf1(+/-) mice exhibit increased osteoclastogenesis and accelerated bone turnover; however, the culprit hematopoietic lineages responsible for perpetuating these osteolytic manifestations have yet to be elucidated. Here we demonstrate that conditional inactivation of a single Nf1 allele within the myeloid progenitor cell population (Nf1-LysM) is necessary and sufficient to promote multiple osteoclast gains-in-function, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to proresorptive challenge in vivo. Surprisingly, mice conditionally Nf1 heterozygous in mature, terminally differentiated osteoclasts (Nf1-Ctsk) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for Nf1 haploinsufficiency at a more primitive/progenitor stage of myeloid development in perpetuating osteolytic activity. We further identified p21Ras-dependent hyperphosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
Steven D
SD
Rhodes
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Hao
H
Yang
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Ruizhi
R
Dong
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Keshav
K
Menon
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Yongzheng
Y
He
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Zhaomin
Z
Li
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Shi
S
Chen
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Karl W
KW
Staser
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Li
L
Jiang
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Xiaohua
X
Wu
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Xianlin
X
Yang
Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Xianghong
X
Peng
Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Khalid S
KS
Mohammad
Endocrinology and Metabolism, Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Theresa A
TA
Guise
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Mingjiang
M
Xu
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Feng-Chun
FC
Yang
D000818:Animals; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D025542:Neurofibromin 1; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
GENETIC ANIMAL MODELS < ANIMAL MODELS; OSTEOCLASTS < CELLS OF BONE; OSTEOPOROSIS < DISEASES AND DISORDERS OF/RELATED TO BONE