Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.
Progressive skeletal defects caused by Kindlin3 deficiency, a model of autosomal recessive osteopetrosis in humans.
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人类常染色体隐性遗传性骨化病模型--Kindlin3缺乏症引起的进行性骨骼缺陷。
DOI：
10.1016/j.bone.2022.116397
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发表时间：
2022-07
期刊：
影响因子：
4.1
通讯作者：
Byzova, Tatiana, V
中科院分区：
文献类型：
--
作者：
Dudiki, Tejasvi;Nascimento, Daniel W.;Childs, Lauren S.;Kareti, Swetha;Androjna, Charlie;Zhevlakova, Irina;Byzova, Tatiana, V
骨发育和稳态的细胞和分子机制在临床上很重要，但尚未完全理解。人类整合素和Kindlin 3的突变称为白细胞粘附缺陷（LAD），可引起广泛的并发症，包括骨硬化症。然而，罕见的，频繁的误诊，并致命的前降支排除机制分析骨骼异常，在这些患者。在这里，使用诱导型和组成型组织特异性Kindlin 3敲除（K3KO）小鼠，我们表明，骨髓谱系细胞中胚胎Kindlin 3的组成性缺乏导致生长迟缓，缺牙症和指示脑积水的颅骨畸形。显微CT分析显示颅缝早闭、后鼻孔狭窄、小颌沿着其他骨硬化症特征性骨骼异常。骨质疏松症的显著进展发生在成熟到中年的成年人中，导致颅神经孔和长骨的骨髓腔变窄。然而，出生后Kindlin 3对骨重建和结构不太重要。因此，髓样Kindlin 3对骨骼发育至关重要，其缺乏导致常染色体隐性骨硬化症（ARO）。该研究将有助于LADIII和ARO患者的诊断、管理和治疗选择。
The cellular and molecular mechanisms of bone development and homeostasis are clinically important, but not fully understood. Mutations in integrins and Kindlin3 in humans known as Leukocyte adhesion deficiencies (LAD) cause a wide spectrum of complications, including osteopetrosis. Yet, the rarity, frequent misdiagnosis, and lethality of LAD preclude mechanistic analysis of skeletal abnormalities in these patients. Here, using inducible and constitutive tissue-specific Kindlin3 knockout (K3KO) mice, we show that the constitutive lack of embryonic-Kindlin3 in myeloid lineage cells causes growth retardation, edentulism, and skull deformity indicative of hydrocephaly. Micro-CT analysis revealed craniosynostosis, choanal stenosis, and micrognathia along with other skeletal abnormalities characteristic of osteopetrosis. A marked progression of osteosclerosis occurs in mature to middle-aged adults, resulting in the narrowing of cranial nerve foramina and bone marrow cavities of long bones. However, postnatal-Kindlin3 is less critical for bone remodeling and architecture. Thus, myeloid Kindlin3 is essential for skeletal development and its deficiency leads to autosomal recessive osteopetrosis (ARO). The study will aid in the diagnosis, management, and treatment choices for patients with LADIII and ARO.
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影响因子：
2.8
作者：
Chen H;Zhou X;Fujita H;Onozuka M;Kubo KY
通讯作者：
Kubo KY
影响因子：
11.4
作者：
Blin-Wakkach, C;Wakkach, A;Carle, GF
通讯作者：
Carle, GF
DOI：
10.1016/0030-4220(72)90316-7
发表时间：
1972-01-01
影响因子：
--
作者：
DICK, HM;SIMPSON, WJ
通讯作者：
SIMPSON, WJ
影响因子：
0.7
作者：
Hwang, JM;Kim, IO;Wang, KC
通讯作者：
Wang, KC
影响因子：
19.7
作者：
Cure, JK;Key, LL;Gross, AJ
通讯作者：
Gross, AJ