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

• DOI: 10.1172/jci29092
• Publication Date: 2006-10-19T21:40:03Z
• Authors: Feng-Chun Yang; Shi Chen; Alexander G. Robling; Xijie Yu; Todd D. Nebesio; Jincheng Yan; Trent Morgan; Xiaohong Li; Jin Yuan; Janet Hock; David A. Ingram; D. Wade Clapp
• Keywords: Neurofibromin 1; Multinucleate; Osteolysis

Individuals with neurofibromatosis type 1 (NF1) have a high incidence of osteoporosis and osteopenia. However, understanding the cellular molecular basis these sequelae is incomplete. Osteoclasts are specialized myeloid cells that principal bone-resorbing skeleton. We found Nf1(+/-) mice contain elevated numbers multinucleated osteoclasts. Both osteoclasts osteoclast progenitors from were hyperresponsive to limiting concentrations M-CSF receptor activator NF-kappaB ligand (RANKL) levels. M-CSF-stimulated p21(ras)-GTP Akt phosphorylation was in associated gains function survival, proliferation, migration, adhesion, lytic activity. These more severe bone loss following ovariectomy as compared syngeneic WT mice. Intercrossing deficient class 1(A) PI3K (p85alpha) restored activity functions Furthermore, vitro-differentiated NF1 patients also displayed Ras/PI3K increased analogous those murine Collectively, our results identify what we believe be novel biochemical NF1-haploinsufficient phenotype has potential implications for pathogenesis disease.