A friend in knee: CCN3 may inhibit osteoarthritis progression

Peidl, Alex

doi:10.1007/s12079-017-0446-y

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…In addition, CCN3 was previously shown to be induced by glucose starvation [ 37 ]. Another report suggests that recombinant CCN3 ameliorates 1L-1β induced metalloproteinases in cultured chondrocytes by the activation of PI3K/AKT/mTOR pathway [ 38 , 39 ]. Taking these facts into consideration, it is assumed that the observed CCN3 induction may be a protective response against multiple stimuli such as age-related oxidative stress and nutrition shortages.…”

Section: Discussionmentioning

confidence: 99%

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

Kuwahara

Kadoya

Kondo

et al. 2020

IJMS

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Aging is a major risk factor of osteoarthritis, which is characterized by the degeneration of articular cartilage. CCN3, a member of the CCN family, is expressed in cartilage and has various physiological functions during chondrocyte development, differentiation, and regeneration. Here, we examine the role of CCN3 in cartilage maintenance. During aging, the expression of Ccn3 mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with p21 and p53 mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 in vitro, either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H2O2 caused a dose-dependent increase in Ccn3 gene and CCN3 protein expression, along with enhanced expression of p21 and p53 mRNA and proteins, as well as SA-β gal activity. Overexpression of CCN3 also enhanced p21 promoter activity via p53. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of p21 and p53 mRNAs. We have produced cartilage-specific CCN3-overexpressing transgenic mice, and found degradative changes in knee joints within two months. Inflammatory gene expression was found even in the rib chondrocytes of three-month-old transgenic mice. Similar results were observed in human knee articular chondrocytes from patients at both mRNA and protein levels. These results indicate that CCN3 is a new senescence marker of chondrocytes, and the overexpression of CCN3 in cartilage may in part promote chondrocyte senescence, leading to the degeneration of articular cartilage through the induction of p53 and p21.

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Section: Discussionmentioning

confidence: 99%

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

Kuwahara

Kadoya

Kondo

et al. 2020

IJMS

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“…CCN3 also modulates the expression of inflammatory molecules in astrocyte . Recently, emerging evidence have indicated that CCN3 may act as a therapeutic target in OA . Mice lacking CCN3 protein have been shown to display osteoarthritic changes in knee articular cartilage .…”

Section: Introductionmentioning

confidence: 99%

“…16 Recently, emerging evidence have indicated that CCN3 may act as a therapeutic target in OA. 17 Mice lacking CCN3 protein have been shown to display osteoarthritic changes in knee articular cartilage. 18 CCN3 may inhibit osteoarthritis progression by maintaining the differentiated phenotype of articular cartilage.…”

Section: Introductionmentioning

confidence: 99%

NOV/CCN3 induces cartilage protection by inhibiting PI3K/AKT/mTOR pathway

Huang

Mao

et al. 2019

J Cellular Molecular Medi

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Osteoarthritis (OA), an age‐related degenerative joint disease, is pathologically characterized by articular cartilage degeneration and synovial inflammation. Nephroblastoma overexpressed (NOV or CCN3), a matricellular protein, is a primary member of the CCN family (Cyr61, Ctgf, NOV) of proteins and is involved in various inflammatory disorders. Previous studies reported that CCN3 might play a therapeutic role in OA. However, the underlying mechanism remains unclear. In this study, we confirmed the expression of CCN3 was decreased in human and rat OA articular cartilage. Recombinant CCN3 ameliorated the IL‐1β‐induced matrix catabolism, as demonstrated by MMP1, MMP3, MMP13, ADAMTS5 and iNOS expression, in vitro. In addition, the degradation of cartilage matrix such as collagen 2 and aggrecan could be reversed by CCN3. Furthermore, we found CCN3 promoted autophagy as Atg5, Beclin1 and LC3‐II expression were increased. High‐mobility group box 1 was negatively correlated with CCN3 in IL‐1β‐induced osteoarthritis responses, and HMGB1 is involved in the protective effect of CCN3 in OA. Moreover, CCN3 overexpression decreased the expression of HMGB1 and reversed the IL‐1β induced MMPs production. Additionally, recombinant CCN3 or CCN3 overexpression attenuated the activation of PI3K/AKT/mTOR pathway induced by IL‐1β. Our study presents new mechanisms of CCN3 in osteoarthritis and indicates that CCN3 can serve as a novel potential therapeutic target for osteoarthritis.

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“…Since CCN3 was found to direct immature chondrocytes towards articular chondrocytic differentiation (Janune et al 2011), the utility of CCN3 in OA treatment was challenged. In fact, several reports from independent laboratories reported the favorable effects of CCN3 in vitro and in vivo (Janune et al 2017; Peidl 2018; Huang et al 2019). Nevertheless, a recent report indicated that long‐term overexpression of CCN3 in cartilage enhanced age‐related articular cartilage degeneration (Kuwahara et al 2020).…”

Section: Ccn3 In Osteoarthritis and Agingmentioning

confidence: 99%

Cellular communication network factor 3 in cartilage development and maintenance

Kubota

Kawaki

Perbal³

et al. 2021

J. Cell Commun. Signal.

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Cellular communication network factor (CCN) 3 is one of the classical members of the CCN family, which are characterized by common molecular structures and multiple functionalities. Although this protein was discovered as a gene product overexpressed in a truncated form in nephroblastoma, recent studies have revealed its physiological roles in the development and homeostasis of mammalian species, in addition to its pathological association with a number of diseases. Cartilage is a tissue that creates most of the bony parts and cartilaginous tissues that constitute the human skeleton, in which CCN3 is also differentially produced to exert its molecular missions therein. In this review article, after the summary of the molecular structure and function of CCN3, recent findings on the regulation of ccn3 expression and the roles of CCN3 in endochondral ossification, cartilage development, maintenance and disorders are introduced with an emphasis on the metabolic regulation and function of this matricellular multifunctional molecule.

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A friend in knee: CCN3 may inhibit osteoarthritis progression

Cited by 5 publications

References 7 publications

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

NOV/CCN3 induces cartilage protection by inhibiting PI3K/AKT/mTOR pathway

Cellular communication network factor 3 in cartilage development and maintenance

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