Dmp1 Null Mice Develop a Unique Osteoarthritis-like Phenotype.
Dmp1 Null Mice Develop a Unique Osteoarthritis-like Phenotype.
复制标题
Dmp1 缺失小鼠形成独特的骨关节炎样表型
DOI：
10.7150/ijbs.15833
复制
发表时间：
2016
影响因子：
9.2
通讯作者：
Feng JQ
中科院分区：
文献类型：
--
作者：
Zhang Q;Lin S;Liu Y;Yuan B;Harris SE;Feng JQ
患有低磷血症佝偻病（包括DMP 1突变）的患者会发生严重的骨关节炎（OA），尽管其机制在很大程度上尚不清楚。在这项研究中，我们首先确定了DMP 1的表达在肥大的软骨细胞使用免疫组织化学（IHC）和X-gal分析的DMP 1敲除-lacZ-敲入杂合子小鼠。接下来，我们采用多种技术，包括X射线，micro-CT，H&E染色，Goldner染色，扫描电子显微镜，免疫组化检测等，对7周龄至1岁的Dmp 1基因敲除小鼠的OA样表型进行了表征。我们发现Dmp 1基因敲除小鼠具有经典的OA样表型，如关节软骨降解，骨赘形成和软骨下骨赘。这些Dmp 1基因敲除小鼠还出现了独特的病理变化，包括关节软骨的双相变化，从1个月龄时肥大软骨细胞的初始扩张到3个月龄时关节软骨层的快速减少。此外，这些无效小鼠表现出严重的膝关节肿大和骨形成不良，类骨质面积扩大。为了解决DMP 1是否在关节软骨中起直接作用，我们通过将Dmp 1-loxP小鼠与Col X Cre小鼠杂交来特异性地在肥大软骨细胞中缺失DMP 1。有趣的是，这些条件性基因敲除小鼠在关节软骨或生长板上都没有表现出明显的缺陷。由于低磷酸盐血症在Dmp 1基因敲除小鼠的整个生命周期中一直存在，我们还研究了高磷酸盐饮食是否会改善OA样表型。8周的高磷酸盐饮食治疗显著挽救了Dmp 1缺失小鼠的OA样缺陷，支持磷酸盐稳态在维持健康关节形态和功能方面的关键作用。总之，这项研究表明，在DMP 1敲除小鼠中存在独特的OA样表型，但缺乏DMP 1对软骨形成的直接影响。相反，DMP 1通过“FGF 23-肾磷重吸收”轴调节磷酸盐稳态对于维持健康的关节至关重要。
Patients with hypophosphatemia rickets (including DMP1 mutations) develop severe osteoarthritis (OA), although the mechanism is largely unknown. In this study, we first identified the expression of DMP1 in hypertrophic chondrocytes using immunohistochemistry (IHC) and X-gal analysis of Dmp1-knockout-lacZ-knockin heterozygous mice. Next, we characterized the OA-like phenotype in Dmp1 null mice from 7-week-old to one-year-old using multiple techniques, including X-ray, micro-CT, H&E staining, Goldner staining, scanning electronic microscopy, IHC assays, etc. We found a classical OA-like phenotype in Dmp1 null mice such as articular cartilage degradation, osteophyte formation, and subchondral osteosclerosis. These Dmp1 null mice also developed unique pathological changes, including a biphasic change in their articular cartilage from the initial expansion of hypertrophic chondrocytes at the age of 1-month to a quick diminished articular cartilage layer at the age of 3-months. Further, these null mice displayed severe enlarged knees and poorly formed bone with an expanded osteoid area. To address whether DMP1 plays a direct role in the articular cartilage, we deleted Dmp1 specifically in hypertrophic chondrocytes by crossing the Dmp1-loxP mice with Col X Cre mice. Interestingly, these conditional knockout mice didn't display notable defects in either the articular cartilage or the growth plate. Because of the hypophosphatemia remained in the entire life span of the Dmp1 null mice, we also investigated whether a high phosphate diet would improve the OA-like phenotype. A 8-week treatment of a high phosphate diet significantly rescued the OA-like defect in Dmp1 null mice, supporting the critical role of phosphate homeostasis in maintaining the healthy joint morphology and function. Taken together, this study demonstrates a unique OA-like phenotype in Dmp1 null mice, but a lack of the direct impact of DMP1 on chondrogenesis. Instead, the regulation of phosphate homeostasis by DMP1 via the axis of “FGF23-renal phosphorus reabsorption” is vital for maintaining a healthy joint.
登录
查看更多内容
影响因子：
19.7
作者：
HARDY, DC;MURPHY, WA;WHYTE, MP
通讯作者：
WHYTE, MP
影响因子：
--
作者：
Lawrence, Reva C.;Felson, David T.;Wolfe, Frederick
通讯作者：
Wolfe, Frederick
影响因子：
30.8
作者：
Lorenz-Depiereux, Bettina;Bastepe, Murat;Strom, Tim M.
通讯作者：
Strom, Tim M.
影响因子：
1.5
作者：
Feng, Jian Q.;Scott, Greg;Mishina, Yuji
通讯作者：
Mishina, Yuji
影响因子：
7.6
作者：
Feng, JQ;Huang, H;Mishina, Y
通讯作者：
Mishina, Y