Notch1 signaling regulates chondrogenic lineage determination through Sox9 activation

Haller, R; Schwanbeck, Ralf; Martini, Simone; Bernoth, Kristina; Kramer, Jan; Just, Ursula; Rohwedel, Jürgen

doi:10.1038/cdd.2011.114

Cited by 41 publications

(39 citation statements)

References 47 publications

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“…Furthermore, we have demonstrated here that sustained over-expression of NICD1 leads to suppression of Sox9, Col2a1 , and Acan in adult articular cartilage and chondrogenic cell cultures, while transient over-expression of NICD1 in adult joint cartilages promotes the expression of Sox9, Col2a1 and Acan in vivo . Interestingly, others have demonstrated that short-term or transient NOTCH signaling promotes chondrocyte anabolism by inducing Sox9 in vitro (52), although the mechanisms for this action remain unclear. Collectively, these data suggest that transient or physiological NOTCH signaling in chondrocytes favors a balanced anabolic and catabolic cartilage maintenance response, while sustained or high levels of NOTCH activity elicits a pathological response via the simultaneous suppression of chondrogenic genes and induction of catabolic factors.…”

Section: Discussionmentioning

confidence: 99%

A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis

et al. 2015

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Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis (OA), indicating a requirement for NOTCH during joint cartilage maintenance. Unexpectedly, NOTCH components are significantly up-regulated in human and murine post-traumatic OA, suggesting either a reparative or pathological role for NOTCH activation in OA. Here we investigated the potential dual role for NOTCH in joint maintenance and OA by generating two mouse models overexpressing the NOTCH1 intracellular domain within postnatal joint cartilage; one with sustained NOTCH activation that likely resembles pathological NOTCH signaling and one with transient NOTCH activation that more closely reflects physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage leads to an early and progressive OA pathology, while on the contrary, transient NOTCH activation enhances cartilage matrix synthesis and promotes joint maintenance under normal physiological conditions. Using RNA-seq, immunohistochemical, and biochemical approaches we identified several novel targets potentially responsible for NOTCH-mediated cartilage degradation, fibrosis, and OA progression, including components of the IL6/STAT3 and ERK/p38 MAPK pathways; factors that may also contribute to post-traumatic OA development. Collectively, these data demonstrate a dual role for the NOTCH pathway in joint cartilage and identify important downstream NOTCH effectors as potential targets for disease modifying osteoarthritis drugs (DMOADs).

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Section: Discussionmentioning

confidence: 99%

A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis

et al. 2015

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“…Different levels of Notch signaling have been shown to regulate dynamic biological events, including quiescence, proliferation and differentiation in various tissues [37, 39, 40]. Transient activation of Notch signaling can induce Sox9 expression in vitro [41], and we also found that intermittent Notch activation in articular cartilage promoted cartilage ECM synthesis and induced the expression of anabolic genes including Sox9 , Col2a1 and Acan in vivo [42]. On the contrary, when Notch signaling is hyper activated in the context of OA, it simultaneously suppresses the expression of chondrogenic genes and stimulates the expression of catabolic factors, such as MMP13 and ADAMTS5 [10, 35, 42].…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Ren

Mirando

et al. 2016

Osteoarthritis and Cartilage

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Objective 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. Methods Two loss-of-function mouse models were generated with tissue-specific knockout of the core Notch signaling component, RBPjκ. The AcanCreERT2 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, real-time qPCR, X-ray, and microCT imaging at multiple time-points. Results 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. Conclusions RBPjκ-dependent Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance.

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“…We then carried out SOX9 ChIP-seq in VCaP cells using these two anti-SOX9 antibodies in parallel. Peak calling by the model-based analysis for (-1 kb to +1 kb; -2 kb to +2 kb; -3 kb to +3 kb of TSSs); downstream elements (-1 kb to +1 kb; -2 kb to +2 kb; -3 kb to +3 kb of transcription stop sites); gene body ( 5′UTR, 3′UTR the strongest correlation in both the TCGA and MSKCC data sets, which may in part reflect the reported NOTCH regulation of SOX9 expression (29)(30)(31). The correlation with MAPK signaling may also reflect the reported SOX9 induction through activation of receptor tyrosine kinases, including FGFRs and MET (16,32).…”

Section: Sox9-binding Sites Identified By Chip-seq In Tmprss2:erg Fusmentioning

confidence: 99%

SOX9 drives WNT pathway activation in prostate cancer

Ma¹,

Ye²,

He³

et al. 2016

Journal of Clinical Investigation

149

126

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Notch1 signaling regulates chondrogenic lineage determination through Sox9 activation

Cited by 41 publications

References 47 publications

A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis

A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis

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

SOX9 drives WNT pathway activation in prostate cancer

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