Liu Z, Ren Y, Mirando A J, Wang C, Zuscik M J, O'Keefe R J, Hilton M J
Department of Orthopaedics and Rehabilitation, The Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Biology, University of Rochester, Rochester, NY 14642, USA.
Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA.
Osteoarthritis Cartilage. 2016 Apr;24(4):740-51. doi: 10.1016/j.joca.2015.10.015. Epub 2015 Oct 30.
Notch signaling has been identified as a critical regulator in cartilage development and joint maintenance, and loss of Notch signaling in all joint tissues results in an early and progressive osteoarthritis (OA)-like pathology. This study investigated the targeted cell population within the knee joint in which Notch signaling is required for normal cartilage and joint integrity.
Two loss-of-function mouse models were generated with tissue-specific knockout of the core Notch signaling component, RBPjκ. The AcanCre(ERT2) transgene specifically removed Rbpjκ floxed alleles in postnatal joint chondrocytes, while the Col1Cre(2.3kb) transgene deleted Rbpjκ in osteoblast populations, including subchondral osteoblasts. Mutant and control mice were analyzed via histology, immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (qPCR), X-ray, and microCT imaging at multiple time-points.
Loss of Notch signaling in postnatal joint chondrocytes results in a progressive OA-like pathology, and triggered the recruitment of non-targeted fibrotic cells into the articular cartilage potentially due to mis-regulated chemokine expression from within the cartilage. Upon recruitment, these fibrotic cells produced degenerative enzymes that may lead to the observed cartilage degradation and contribute to a significant portion of the age-related OA-like pathology. On the contrary, loss of Notch signaling in subchondral osteoblasts did not affect normal cartilage development or joint maintenance.
RBPjκ-dependent Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance.
Notch信号通路已被确定为软骨发育和关节维持的关键调节因子，所有关节组织中Notch信号通路的缺失会导致早期进行性骨关节炎（OA）样病理改变。本研究调查了膝关节内正常软骨和关节完整性所需Notch信号通路的靶向细胞群。
构建了两种功能丧失型小鼠模型，通过组织特异性敲除Notch信号通路的核心成分RBPjκ。AcanCre(ERT2)转基因特异性去除出生后关节软骨细胞中Rbpjκ的floxed等位基因，而Col1Cre(2.3kb)转基因则在成骨细胞群体（包括软骨下成骨细胞）中删除Rbpjκ。在多个时间点通过组织学、免疫组织化学（IHC）、实时定量聚合酶链反应（qPCR）、X射线和微计算机断层扫描（microCT）成像对突变小鼠和对照小鼠进行分析。
出生后关节软骨细胞中Notch信号通路的缺失导致进行性OA样病理改变，并可能由于软骨内趋化因子表达失调而引发非靶向纤维化细胞募集到关节软骨中。募集后，这些纤维化细胞产生降解酶，可能导致观察到的软骨降解，并导致很大一部分与年龄相关的OA样病理改变。相反，软骨下成骨细胞中Notch信号通路的缺失并不影响正常软骨发育或关节维持。
出生后关节软骨细胞而非软骨下成骨细胞中依赖RBPjκ的Notch信号通路是关节软骨和关节维持所必需的。
