Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice.
Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice.
复制标题
DOI：
10.1371/journal.pone.0035979
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mbalaviele G
中科院分区：
文献类型：
--
作者：
Bonar SL;Brydges SD;Mueller JL;McGeough MD;Pena C;Chen D;Grimston SK;Hickman-Brecks CL;Ravindran S;McAlinden A;Novack DV;Kastner DL;Civitelli R;Hoffman HM;Mbalaviele G
NLRP3炎症体复合体负责促炎症细胞因子IL-1β的成熟。NLRP3的突变是导致低温肾炎的原因，这是一系列疾病，包括新生儿起病的多系统炎症性疾病(NOMID)。虽然IL-1β的过度产生和全身炎症是所有低温尿路疾病的共同特征，但骨骼异常，尤其是膝关节的显著异常和低骨量是NOMID患者的独特特征。为了深入了解NOMID骨骼异常的机制，我们产生了全局表达D301N NLRP3突变(人类NLRP3中D303N的同源)的敲入小鼠。NOMID小鼠表现出血液和许多组织中的中性粒细胞增多，包括膝关节，以及高水平的血清炎症介质。它们还表现出生长迟缓和出生后严重的骨量减少，至少部分原因是异常加速的骨吸收，伴随着破骨细胞生成的增加。膝关节的组织学分析显示异常生长板，软骨细胞丢失，骨痂中央区域生长停滞。最引人注目的是，在所有NOMID小鼠的长骨中观察到生长板中部区域的组织“尖峰”，这可能是更严重变形的先兆，类似于在NOMID患者中观察到的。这些发现提供了直接证据，将NOMID相关的NLRP3激活突变与出生后骨骼生长和骨骼重塑的异常联系起来。
The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID). While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3). NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue “spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling.
登录
查看更多内容
影响因子：
3.7
作者：
Rajamäki K;Lappalainen J;Oörni K;Välimäki E;Matikainen S;Kovanen PT;Eklund KK
通讯作者：
Eklund KK
DOI：
10.1073/pnas.86.7.2398
发表时间：
1989-04-01
影响因子：
11.1
作者：
PACIFICI, R;RIFAS, L;PECK, WA
通讯作者：
PECK, WA
DOI：
10.1073/pnas.0708576105
发表时间：
2008-03-11
影响因子：
11.1
作者：
Vaira, Sergio;Johnson, Trevor;Novack, Deborah Veis
通讯作者：
Novack, Deborah Veis
影响因子：
6.2
作者：
Ford-Hutchinson, Alice Fiona;Ali, Zenobia;Jirik, Frank Robert
通讯作者：
Jirik, Frank Robert
影响因子：
4
作者：
Di Benedetto, Adriana;Watkins, Marcus;Civitelli, Roberto
通讯作者：
Civitelli, Roberto