Nf1 Haploinsufficiency Alters Myeloid Lineage Commitment and Function, Leading to Deranged Skeletal Homeostasis. (21st May 2015)

• Record Type: Journal Article
• Authors: Rhodes, Steven D; Yang, Hao; Dong, Ruizhi; Menon, Keshav; He, Yongzheng; Li, Zhaomin; Chen, Shi; Staser, Karl W; Jiang, Li; Wu, Xiaohua; Yang, Xianlin; Peng, Xianghong; Mohammad, Khalid S; Guise, Theresa A; Xu, Mingjiang; Yang, Feng‐Chun
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 10(2015:Oct.)
• Page Start: 1840
• Page End: 1851
• Publication Date: 2015-05-21
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2538
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2538-sec-0001" sec-type="section"> <p>Although nullizygous loss of <italic>NF1</italic> leads to myeloid malignancies, haploinsufficient loss of <italic>NF1</italic> (<italic>Nf1</italic>) 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 <italic>Nf1<sup>+/–</sup></italic> 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 <italic>Nf1</italic> allele within the myeloid progenitor cell population (<italic>Nf1‐LysM</italic>) 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 <italic>Nf1</italic> heterozygous in mature, terminally differentiated osteoclasts (<italic>Nf1‐Ctsk</italic>) do not exhibit any of these skeletal phenotypes, indicating a critical requirement for <italic>Nf1</italic> 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 <italic>Nf1</italic> haploinsufficient myelomonocytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations. © 2015 American Society for Bone and Mineral Research</p> </sec> </abstract>