Department of Clinical Research, Faculty of Health, University of Southern Denmark (SDU), Winsløwparken 19. 3, DK-5000 Odense C, Denmark; Steno Diabetes Center Odense, Odense University Hospital (OUH), J.B. Winsløws Vej 4, DK-5000 Odense C, Denmark; Department of Endocrinology, Molecular Endocrinology Unit, OUH, J.B. Winsløws Vej 4, DK-5000 Odense C, Denmark.
Department of Endocrinology, Molecular Endocrinology Unit, OUH, J.B. Winsløws Vej 4, DK-5000 Odense C, Denmark.
Bone. 2019 Apr;121:243-254. doi: 10.1016/j.bone.2019.01.014. Epub 2019 Jan 16.
NF-κB essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations.
We studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non-dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; μ-CT and histomorphometry of trans-iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of HpaII sites. NF-κB activity was quantitated in BM-MSCs using a luciferase NF-κB reporter assay.
Seven Caucasian women with IP (age: 24-67 years and BMI: 20.0-35.2 kg/m) and IKBKG mutation (del exon 4-10 (n = 4); c.460C>T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation (>90:10%) in blood, but not in BM-MSCs. NF-κB activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 ± 679 vs. 5422 ± 1038/μg protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, μ-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7-fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0-fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01).
Unlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT.
NF-κB 必需调节剂（NEMO），由 IKBKG 编码，是激活普遍转录因子核因子κB 轻链增强子激活 B 细胞（NF-κB）所必需的。动物研究表明，NEMO 是 NF-κB 介导的骨稳态所必需的，但在人类中尚未进行彻底研究。IKBKG 功能丧失性突变导致色素失禁症（IP），这是一种罕见的 X 连锁疾病，表现为线性色素减退、脱发、缺牙和免疫缺陷。单一病例报告描述了携带 IKBKG 功能低下突变的男孩发生骨质增生症（OPT）。
我们通过评估脊柱和非优势手臂和腿部的 X 光片、腰椎和股骨颈的 aBMD 使用 DXA、髂嵴活检标本的 μ-CT 和组织形态计量学、骨转换标志物以及骨髓骨骼（基质）干细胞（BM-MSCs）中的细胞表型，对患有 IP 的女性进行骨骼表型研究。使用 HpaII 位点甲基化的 PCR 方法测量血液白细胞和 BM-MSCs 中的 X 染色体失活。使用荧光素 NF-κB 报告基因测定法定量 BM-MSCs 中的 NF-κB 活性。
7 名患有 IP（年龄：24-67 岁，BMI：20.0-35.2 kg/m）和 IKBKG 突变（缺失外显子 4-10（n=4）；c.460C>T（n=3））的高加索女性与匹配的对照组进行了比较。血液中的 IKBKG 突变携带者存在极度偏倚的 X 染色体失活（>90:10%），但在 BM-MSCs 中则不然。与对照组相比，IKBKG 突变携带者的 BM-MSCs 中 NF-κB 活性较低（n=5）（3094±679 与 5422±1038/μg 蛋白，p<0.01）。然而，在骨骼 X 光片、aBMD、髂嵴 μ 结构或骨转换标志物方面未发现差异。IKBKG 突变携带者的侵蚀表面相对于类骨质表面的程度增加了 1.7 倍（p<0.01），并且静止逆转表面相对于活跃逆转表面的比例增加了 2.0 倍（p<0.01）。
与突变阳性男性不同，IKBKG 突变阳性女性未表现出 OPT。
