RBP-Jκ-dependent Notch signaling is required for murine articular cartilage and joint maintenance.
RBP-Jκ-dependent Notch signaling is required for murine articular cartilage and joint maintenance.
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DOI：
10.1002/art.38076
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发表时间：
2013-10
影响因子：
--
通讯作者：
Hilton, Matthew J.
中科院分区：
文献类型：
--
作者：
Mirando, Anthony J.;Liu, Zhaoyang;Moore, Tyler;Lang, Alexandra;Kohn, Anat;Osinski, Alana M.;O'Keefe, Regis J.;Mooney, Robert A.;Zuscik, Michael J.;Hilton, Matthew J.
骨关节炎（OA）是一种退行性疾病，导致严重的关节软骨破坏和残疾。虽然对OA发生和进展的机制知之甚少，但已在软骨相关信号分子中鉴定出基因突变，其涉及OA和关节疾病中受损的细胞信号传导。Notch通路最近被鉴定为生长板软骨发育的关键调节因子，并且其组分在关节组织中表达。因此，我们着手研究Notch信号在关节软骨发育、维持和关节疾病发病机制中的新作用。我们进行了第一次小鼠遗传研究，其中核心Notch信号传导组分RBPjκ在关节内被组织特异性删除。Prx1Cre转基因去除了间充质关节前体细胞中的Rbpjκ floxed等位基因，而Col2CreERT2转基因特异性地删除了出生后软骨细胞中的Rbpjκ。还利用关节软骨细胞培养物来检查Notch对基因表达的调节。间充质关节前体细胞中Notch信号传导的丧失不影响胚胎关节发育，而是导致早期进行性OA样病理。此外，出生后软骨中Notch信号传导的部分丧失导致进行性关节软骨退化和年龄相关的OA样病理。Notch信号的抑制改变ECM相关因子的表达：COL2A1、PRG4、COL10A1、MMP 13和ADAMTS。这些数据已经将RBPjκ依赖性Notch途径鉴定为：1）参与关节维持和关节软骨稳态的新途径，2）关节软骨ECM相关分子的关键调节剂，和3）OA样关节疾病的潜在重要治疗靶标。
Osteoarthritis (OA) is a degenerative disease resulting in severe joint cartilage destruction and disability. While the mechanisms underlying the development and progression of OA are poorly understood, gene mutations have been identified within cartilage-related signaling molecules implicating impaired cell signaling in OA and joint disease. The Notch pathway has recently been identified as a crucial regulator of growth plate cartilage development and components are expressed in joint tissues. Therefore, we set out to investigate a novel role for Notch signaling in joint cartilage development, maintenance, and the pathogenesis of joint disease. We performed the first mouse genetic studies in which the core Notch signaling component, RBPjκ, was tissue-specifically deleted within joints. The Prx1Cre transgene removed Rbpjκ floxed alleles in mesenchymal joint precursor cells, while the Col2CreERT2 transgene specifically deleted Rbpjκ in postnatal chondrocytes. Articular chondrocyte cultures were also utilized to examine Notch regulation of gene expression. Loss of Notch signaling in mesenchymal joint precursor cells does not affect embryonic joint development, but rather results in an early, progressive OA-like pathology. Additionally, partial loss of Notch signaling in postnatal cartilage results in progressive joint cartilage degeneration and an age-related OA-like pathology. Inhibition of Notch signaling alters expression of the ECM-related factors: COL2A1, PRG4, COL10A1, MMP13, and ADAMTSs. These data have identified the RBPjκ-dependent Notch pathway as: 1) a novel pathway involved in joint maintenance and articular cartilage homeostasis, 2) a critical regulator of articular cartilage ECM-related molecules, and 3) a potentially important therapeutic target for OA-like joint disease.
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影响因子：
--
作者：
Grogan, Shawn P.;Olee, Tsaiwei;Hiraoka, Koji;Lotz, Martin K.
通讯作者：
Lotz, Martin K.
影响因子：
3.9
作者：
Majewski, Jacek;Schwartzentruber, Jeremy A.;Samuels, Mark E.
通讯作者：
Samuels, Mark E.
影响因子：
12.4
作者：
Haller, R.;Schwanbeck, R.;Rohwedel, J.
通讯作者：
Rohwedel, J.
影响因子：
4.6
作者：
Hilton, MJ;Tu, XL;Long, FX
通讯作者：
Long, FX
影响因子：
2.1
作者：
Pacifici, Maurizio;Koyama, Eiki;Iwamoto, Masahiro
通讯作者：
Iwamoto, Masahiro