Multiple Increased Osteoclast Functions in Individuals with ieurofibromatosis Type 1

摘要

Skeletal abnormalities including scoliosis, tibial dysplasia, sphenoid wing dysplasia, and decreased bone mineral density (BMD) are associated with neurofibromatosis' type 1 (NF1), We report the cellular phenotype of NF1 human-derived osteoclasts and compare the in vitro findings with the clinical phenotype. Functional characteristics (e.g., osteociast formation, migration, adhesion, resorptive capacity) and cellular mechanistic alterations (e.g., F-actin polymerizations MAPK phosphorylation, RhoGT-Pase activity) from osteoclasts cultured from peripheral blood of individuals with NF1 (N - 75) were assessed, Osteociast formation was compared to phenotypic, radiologic, and biochemical data. NF1 osteoprogenitor cells demonstrated increased osteociast forming capacity. Human NF1-derived osteoclasts demonstrated increased migration, adhesion, and in vitro bone resorption. These activities coincided with increased actin belt formation and hyperactivity in MAPK and RhoGTPase pathways. Although osteociast formation was increased, no direct correlation of osteociast formation with BMD, markers of bone resorption, or the clinical skeletal phenotype was observed suggesting that osteociast formation in vitro cannot directly predict. NF1 skeletal phenotypes. While NF1 haploinsufnciency produces a generalized osteociast gai-n-in-function and may contribute to increased bone resorption, reduced BMD, and focal skeletal defects associated with NF1, additional and perhaps local modifiers are likely required for the development of skeletal abnormalities in NF1.