Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis.
Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis.
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DOI：
10.1186/s13075-021-02477-z
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发表时间：
2021-04-08
影响因子：
4.9
通讯作者：
Rai MF
中科院分区：
文献类型：
--
作者：
Attur M;Duan X;Cai L;Han T;Zhang W;Tycksen ED;Samuels J;Brophy RH;Abramson SB;Rai MF
软骨和骨中骨膜蛋白（Postn）水平升高与骨关节炎（OA）相关。然而，目前尚不清楚Postn功能丧失是否可以延迟或预防OA的发展。在这项研究中，我们试图更好地了解Postn在OA发展中的作用，并评估Postn缺乏对小鼠创伤后和年龄相关OA的功能影响。使用Postn−/−（n = 32）和同窝野生型（wt）小鼠（n = 36）在两种小鼠实验性OA模型中研究了Postn缺乏的影响。在10周龄小鼠（n = 20）中通过内侧半月板（DMM）的不稳定性诱导创伤后OA;在24月龄小鼠（n = 13）中分析年龄相关OA。使用OARSI评分系统在组织学上评估软骨变性，并通过测量滑膜衬里细胞层和滑膜基质中的细胞密度来评估滑膜炎。通过μCT分析测量骨变化。通过ELISA测定血清Postn水平。免疫组化法检测Postn和胶原酶-3（MMP-13）的表达。在从21天大的Postn−/−（n = 3）和wt小鼠（n = 3）分离的软骨细胞上进行RNA-seq，以发现Postn敲除改变的基因和途径。在8周后的创伤后OA中，Postn−/−小鼠相对于wt小鼠表现出显著降低的软骨变性和OARSI评分（最大值：2.37 ± 0.74 vs. 4.00 ± 1.20，P = 0.011;总和：9.31 ± 2.52 vs. 21.44 ± 6.01，P = 0.0002）和自发性OA（最大值：1.93 ± 0.45 vs 3.58 ± 1.16，P = 0.014;总和：6.14 ± 1.57 vs 11.50 ± 3.02，P = 0.003）。在DMM模型中，Postn−/−小鼠的滑膜炎显著低于仅wt小鼠（1.88 ± 1.01 vs. 3.17 ± 0.63; P = 0.039）。Postn−/−小鼠还显示出较低的骨小梁参数，如BV/TV、vBMD、Tb.Th和Tb.N，以及较高的Tb。两种型号的Sp。Postn−/−小鼠与wt相比血清Postn水平可忽略不计。软骨的免疫荧光研究表明，Postn−/−小鼠表达的MMP-13水平低于野生型小鼠。RNA-seq显示，Postn−/−小鼠中细胞间粘附和细胞分化过程富集，而与细胞周期和DNA修复相关的过程在野生型小鼠中富集。Postn缺乏可预防DMM诱导的创伤后和年龄相关的自发性OA。RNA-seq研究结果需要进一步研究，以更好地了解Postn的机制作用及其作为OA治疗靶点的潜力。在线版本包含补充材料，可通过10.1186/s13075-021-02477-z获得。
Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice. The effects of Postn deficiency were studied in two murine experimental OA models using Postn−/− (n = 32) and littermate wild-type (wt) mice (n = 36). Post-traumatic OA was induced by destabilization of the medial meniscus (DMM) in 10-week-old mice (n = 20); age-related OA was analyzed in 24-month-old mice (n = 13). Cartilage degeneration was assessed histologically using the OARSI scoring system, and synovitis was evaluated by measuring the synovial lining cell layer and the cells density in the synovial stroma. Bone changes were measured by μCT analysis. Serum levels of Postn were determined by ELISA. Expression of Postn and collagenase-3 (MMP-13) was measured by immunostaining. RNA-seq was performed on chondrocytes isolated from 21-day old Postn−/− (n = 3) and wt mice (n = 3) to discover genes and pathways altered by Postn knockout. Postn−/− mice exhibited significantly reduced cartilage degeneration and OARSI score relative to wt mice in post-traumatic OA after 8 weeks (maximum: 2.37 ± 0.74 vs. 4.00 ± 1.20, P = 0.011; summed: 9.31 ± 2.52 vs. 21.44 ± 6.01, P = 0.0002) and spontaneous OA (maximum: 1.93 ± 0.45 vs. 3.58 ± 1.16, P = 0.014; summed: 6.14 ± 1.57 vs. 11.50 ± 3.02, P = 0.003). Synovitis was significantly lower in Postn−/− mice than wt only in the DMM model (1.88 ± 1.01 vs. 3.17 ± 0.63; P = 0.039). Postn−/− mice also showed lower trabecular bone parameters such as BV/TV, vBMD, Tb.Th, and Tb.N and high Tb. Sp in both models. Postn−/− mice had negligible levels of serum Postn compared with wt. Immunofluorescent studies of cartilage indicated that Postn−/− mice expressed lower MMP-13 levels than wt mice. RNA-seq revealed that cell-cell-adhesion and cell-differentiation processes were enriched in Postn−/− mice, while those related to cell-cycle and DNA-repair were enriched in wt mice. Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations to better understand the mechanistic role of Postn and its potential as a therapeutic target in OA. The online version contains supplementary material available at 10.1186/s13075-021-02477-z.
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DOI：
10.1006/bbrc.2001.5214
发表时间：
2001-07-20
影响因子：
3.1
作者：
Agarwala, KL;Ganesh, S;Yamakawa, K
通讯作者：
Yamakawa, K
影响因子：
3.7
作者：
Han, Tianzhen;Mignatti, Paolo;Attur, Mukundan
通讯作者：
Attur, Mukundan
影响因子：
8
作者：
Conway, Simon J.;Izuhara, Kenji;Kudo, Yasusei;Litvin, Judith;Markwald, Roger;Ouyang, Gaoliang;Arron, Joseph R.;Holweg, Cecile T. J.;Kudo, Akira
通讯作者：
Kudo, Akira
影响因子：
7
作者：
Glasson, S. S.;Blanchet, T. J.;Morris, E. A.
通讯作者：
Morris, E. A.
影响因子：
7
作者：
Duan, X.;Cai, L.;Rai, M. F.
通讯作者：
Rai, M. F.