Nf1 haploinsufficiency alters myeloid lineage commitment and function, leading to deranged skeletal homeostasis

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2015-10
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American English
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Wiley
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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.

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Rhodes, S. D., Yang, H., Dong, R., Menon, K., He, Y., Li, Z., … Yang, F.-C. (2015). Nf1 haploinsufficiency alters myeloid lineage commitment and function, leading to deranged skeletal homeostasis. Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research, 30(10), 1840–1851. http://doi.org/10.1002/jbmr.2538
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Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research
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