Steven D. Rhodes, Hao Yang, Ruizhi Dong, Keshav Menon, Yongzheng He, Zhaomin Li, Shi Chen, Karl W. Staser, Li Jiang, Xiaohua Wu,Xianlin Yang, Xianghong Peng, Khalid S. Mohammad, Theresa A. Guise,Mingjiang Xu and Feng-Chun Yang
While 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 percent 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 gain-in-functions, resulting in enhanced osteoclastogenesis and accelerated osteoclast bone lytic activity in response to pro-resorptive 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 hyper-phosphorylation of Pu.1 within the nucleus of Nf1 haploinsufficent myelomoncytic osteoclast precursors, providing a novel therapeutic target for the potential treatment of NF1 associated osteolytic manifestations.