Open AccessEnhanced Activation of Rac1/Cdc42 and MITF Leads to Augmented Osteoclastogenesis in Autosomal Dominant Osteopetrosis Type II
Author(s) -
Jung YounKwan,
Kwon KiTae,
Jang JiAe,
Han MinSu,
Kim GunWoo,
Han Seungwoo
Publication year - 2019
Publication title -
jbmr plus
Language(s) - English
Resource type - Journals
ISSN - 2473-4039
DOI - 10.1002/jbm4.10070
Subject(s) - microphthalmia associated transcription factor , osteoclast , osteopetrosis , peripheral blood mononuclear cell , bone resorption , cancer research , exon , activator (genetics) , gene knockdown , medicine , chemistry , biology , endocrinology , immunology , transcription factor , gene , genetics , receptor , in vitro
The autosomal dominant osteopetrosis type II (ADOII) caused by the mutation of chloride channel 7 (ClC‐7) gene is the most common form of adult‐onset osteopetrosis. Despite dysfunctional bone resorption, an augmented osteoclast differentiation was reported recently in ADOII patients. DNA sequencing analysis of the ADOII patient's ClC‐7 gene identified a known heterozygous mutation, c.643G>A in exon 7, encoding p.Gly215Arg. In vitro osteoclast differentiation from the ADOII patient's peripheral blood mononuclear cells (PBMCs) increased compared with control despite their dysfunctional bone resorbing capacity. Osteoclasts from the ADOII patient's PBMCs and ClC‐7 knockdown bone marrow monocytes (BMMs) showed an enhanced Ser‐71 phosphorylation of Rac1/Cdc42 and increase of the microphthalmia‐associated transcription factor (MITF) and receptor activator of NF‐κB (RANK) that can be responsible for the enhanced osteoclast differentiation. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.