Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance

Liu, Zhaoyang; Ren, Yinshi; Mirando, Anthony J.; Wang, C.; Zuscik, Michael J.; O’Keefe, Regis J.; Hilton, Matthew J.

doi:10.1016/j.joca.2015.10.015

Cited by 28 publications

(27 citation statements)

References 46 publications

(56 reference statements)

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“…In one study, Rbpj knockout in limb mesenchymal progenitor cells using Prx1-Cre, or in adult chondrocytes using Col2a1-Cre ERT2 , promoted OA development within 8 months without surgical induction [26]. Similar results have been reported by the same group using Acan-Cre ERT2 and Rbpj-flox mice [27]. Interestingly, fibrotic cells and high levels of Mmp13 are observed in the superficial zone of Rbpj-knockout cartilage [27].…”

Section: Notch Signallingmentioning

confidence: 57%

Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB

2017

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Osteoarthritis (OA) is a multi-factorial and highly prevalent joint disorder worldwide. Since the establishment of murine surgical knee OA models in 2005, many of the key molecules and signalling pathways responsible for OA development have been identified. Here we review the roles of two multi-functional signalling pathways in OA development: Notch and nuclear factor kappa-light-chain-enhancer of activated B cells. Previous studies have identified various aspects of articular chondrocyte regulation by these pathways. However, comprehensive understanding of the molecular networks regulating articular cartilage homeostasis and OA pathogenesis is needed.

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Section: Notch Signallingmentioning

confidence: 57%

Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB

2017

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“…Numerous signaling pathways have been identified that regulate both cell cycle and chondrocyte hypertrophy, including BMP, TGF-β and Wnt. Recently, we identified the Notch signaling pathway as a critical regulator of chondrocyte hypertrophy, although it appears to regulate this process in an indirect manner 8 9 10 11 .…”

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confidence: 99%

Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest

Shang

Wang

Luo

et al. 2016

Sci Rep

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Cell cycle regulation is critical for chondrocyte differentiation and hypertrophy. Recently we identified the Notch signaling pathway as an important regulator of chondrocyte proliferation and differentiation during mouse cartilage development. To investigate the underlying mechanisms, we assessed the role for Notch signaling regulation of the cell cycle during chondrocyte differentiation. Real-time RT-PCR data showed that over-expression of the Notch Intracellular Domain (NICD) significantly induced the expression of p57, a cell cycle inhibitor, in chondrocytes. Flow cytometric analyses further confirmed that over-expression of NICD in chondrocytes enhances the G0/G1 cell cycle transition and cell cycle arrest. In contrast, treatment of chondrocytes with the Notch inhibitor, DAPT, decreased both endogenous and BMP2-induced SMAD 1/5/8 phosphorylation and knockdown of SMAD 1/5/8 impaired NICD-induced chondrocyte differentiation and p57 expression. Co-immunoprecipitation using p-SMAD 1/5/8 and NICD antibodies further showed a strong interaction of these proteins during chondrocyte maturation. Finally, RT-PCR and Western blot results revealed a significant reduction in the expression of the SMAD-related phosphatase, PPM1A, following NICD over-expression. Taken together, our results demonstrate that Notch signaling induces cell cycle arrest and thereby initiates chondrocyte hypertrophy via BMP/SMAD-mediated up-regulation of p57.

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“…While continuity of developmental programs may play a role in joint maintenance, there also appear to be factors with specific postnatal requirements at the joint, including Notch signaling, PRG4, and ERRFI1 . The Notch pathway has been implicated in progenitor maintenance in a variety of contexts, including a role for inhibiting cartilage differentiation in mice and zebrafish .…”

mentioning

confidence: 99%

“…The Notch pathway has been implicated in progenitor maintenance in a variety of contexts, including a role for inhibiting cartilage differentiation in mice and zebrafish . Notch1 is expressed at postnatal joints in mice, and conditional deletion of the essential Notch effector RBP‐Jk in either limb mesenchyme using Prx1 ‐Cre or postnatal chondrocytes using Col2a1 ‐CreER results in progressive joint cartilage degeneration and other osteoarthritic phenotypes . The miR‐140 is the major miRNA expressed in articular cartilage of murine joints, and deletion of miR‐140 predisposed mice to age‐related osteoarthritis of the knee without affecting joint specification .…”

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confidence: 99%

Building and maintaining joints by exquisite local control of cell fate

Smeeton

Askary

Crump

2016

WIREs Developmental Biology

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We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid-filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an “interzone” region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints.

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Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance

Cited by 28 publications

References 46 publications

Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB

Molecular mechanisms underlying osteoarthritis development: Notch and NF-κB

Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest

Building and maintaining joints by exquisite local control of cell fate

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