Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions

Feng Chun Yang, Shi Chen, Alexander Robling, Xijie Yu, Todd Nebesio, Jincheng Yan, Trent Morgan, Xiaohong Li, Jin Yuan, Janet Hock, David Ingram, D. Clapp

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Abstract

Individuals with neurofibromatosis type 1 (NF1) have a high incidence of osteoporosis and osteopenia. However, understanding of the cellular and molecular basis of these sequelae is incomplete. Osteoclasts are specialized myeloid cells that are the principal bone-resorbing cells of the skeleton. We found that Nf1+/- mice contain elevated numbers of multinucleated osteoclasts. Both osteoclasts and osteoclast progenitors from Nf1+/- mice were hyperresponsive to limiting concentrations of M-CSF and receptor activator of NF-κB ligand (RANKL) levels. M-CSF-stimulated p21 ras-GTP and Akt phosphorylation was elevated in Nf1+/- osteoclasts associated with gains of function in survival, proliferation, migration, adhesion, and lytic activity. These gains of function are associated with more severe bone loss following ovariectomy as compared with that in syngeneic WT mice. Intercrossing Nf1+/- mice and mice deficient in class 1A PI3K (p85α) restored elevated PI3K activity and Nf1+/- osteoclast functions to WT levels. Furthermore, in vitro-differentiated osteoclasts from NF1 patients also displayed elevated Ras/PI3K activity and increased lytic activity analogous to those in murine Nf1+/- osteoclasts. Collectively, our results identify a what we believe to be a novel cellular and biochemical NF1-haploinsufficient phenotype in osteoclasts that has potential implications for the pathogenesis of NF1 bone disease.

Original languageEnglish
Pages (from-to)2880-2891
Number of pages12
JournalJournal of Clinical Investigation
Volume116
Issue number11
DOIs
StatePublished - Nov 1 2006

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Neurofibromatosis 1
Osteoclasts
Phosphatidylinositol 3-Kinases
Macrophage Colony-Stimulating Factor Receptors
Proto-Oncogene Proteins p21(ras)
Bone and Bones
Macrophage Colony-Stimulating Factor
Metabolic Bone Diseases
Bone Diseases
Ovariectomy
Myeloid Cells
Guanosine Triphosphate
Skeleton
Osteoporosis
Phosphorylation
Ligands
Phenotype
Survival
Incidence

ASJC Scopus subject areas

  • Medicine(all)

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Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. / Yang, Feng Chun; Chen, Shi; Robling, Alexander; Yu, Xijie; Nebesio, Todd; Yan, Jincheng; Morgan, Trent; Li, Xiaohong; Yuan, Jin; Hock, Janet; Ingram, David; Clapp, D.

In: Journal of Clinical Investigation, Vol. 116, No. 11, 01.11.2006, p. 2880-2891.

Research output: Contribution to journalArticle

Yang, Feng Chun ; Chen, Shi ; Robling, Alexander ; Yu, Xijie ; Nebesio, Todd ; Yan, Jincheng ; Morgan, Trent ; Li, Xiaohong ; Yuan, Jin ; Hock, Janet ; Ingram, David ; Clapp, D. / Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1-haploinsufficient osteoclast functions. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 11. pp. 2880-2891.
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