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CCN family member 3 precursor (Cellular communication network factor 3) (Insulin-like growth factor-binding protein 9) (IBP-9) (IGF-binding protein 9) (IGFBP-9) (Nephro blastoma-overexpressed gene protein homolog) (Protein NOV homolog) (NovH) [IGFBP9] [NOV] [NOVH]


CCN3 Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta.

An adequate development of the placenta includes trophoblast differentiation with the processes of trophoblast migration, invasion, cellular senescence and apoptosis which are all crucial to establishing a successful pregnancy. Altered placental development and function lead to placental diseases such as preeclampsia (PE) which is mainly characterized by insufficient trophoblast invasion and abnormally invasive placenta (AIP) disorders ([i]Placenta accreta[/i], [i]increta[/i], or [i]percreta)[/i] which are characterized by excessive trophoblast invasion. Both of them will cause maternal and fetal morbidity/mortality. However, the etiology of these diseases is still unclear. Our previous study has shown that the matricellular protein [i]nephroblastoma overexpressed[/i] (NOV, CCN3) induces G0/G1 cell cycle arrest, drives trophoblast cells into senescence and activates FAK and Akt kinases resulting in reduced cell proliferation and enhanced migration capability of the human trophoblast cell line SGHPL-5. The present study focuses on whether CCN3 can alter cell cycle-regulated pathways associated with trophoblast senescence and invasion activity in pathological versus gestational age-matched control placentas. Cell cycle regulator proteins were investigated by immunoblotting and qPCR. For localization of CCN3, p16, p21, and Cyclin D1 proteins, co-immunohistochemistry was performed. In early-onset PE placentas, CCN3 was expressed at a significantly lower level compared to gestational age-matched controls. The decrease of CCN3 level is associated with an increase in p53, Cyclin E1 and pRb protein expression, whereas the level of cleaved Notch-1, p21, Cyclin D1, pFAK, pAKT, and pmTOR protein decreased. In term AIP placentas, the expression of CCN3 was significantly increased compared to matched term controls. This increase was correlated to an increase in p53, p16, p21, Cyclin D1, cleaved Notch-1, pFAK, pAkt, and pmTOR whereas pRb was significantly decreased. However, in late PE and early AIP placentas, no significant differences in CCN3, p16, p21, Cyclin D1, p53, and cleaved Notch-1 expression were found when matched to appropriate controls. CCN3 expression levels are correlated to markers of cell cycle arrest oppositely in PE and AIP by activating the FAK/AKT pathway in AIP or down-regulating in PE. This may be one mechanism to explain the different pathological features of placental diseases, PE and AIP.


  • CCN3
  • abnormally invasive placenta
  • invasion
  • preeclampsia
  • senescence
  • trophoblast

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage.

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 [i]Ccn3[/i] mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with [i]p21[/i] and [i]p53[/i] mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 [i]in vitro[/i], either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H O caused a dose-dependent increase in [i]Ccn3[/i] gene and CCN3 protein expression, along with enhanced expression of [i]p21[/i] and [i]p53[/i] mRNA and proteins, as well as SA-β gal activity. Overexpression of CCN3 also enhanced [i]p21[/i] promoter activity via [i]p53[/i]. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of [i]p21[/i] and [i]p53[/i] 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.


  • CCN3
  • NOV
  • SASP
  • aging
  • cellular communication network factor 3
  • oxidative stress
  • p21
  • p53
  • primary chondrocytes
  • senescence

CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties.

During placental development, continuous invasion of trophoblasts into the maternal compartment depends on the support of proliferating extravillous trophoblasts (EVTs). Unlike tumor cells, EVTs escape from the cell cycle before invasion into the decidua and spiral arteries. This study focused on the regulation properties of glycosylated and non-glycosylated matricellular CCN1 and CCN3, primarily for proliferation control in the benign SGHPL-5 trophoblast cell line, which originates from the first-trimester placenta. Treating SGHPL-5 trophoblast cells with the glycosylated forms of recombinant CCN1 and CCN3 decreased cell proliferation by bringing about G0/G1 cell cycle arrest, which was accompanied by the upregulation of activated Notch-1 and its target gene p21. Interestingly, both CCN proteins increased senescence-associated β-galactosidase activity and the expression of the senescence marker p16. The migration capability of SGHPL-5 cells was mostly enhanced in response to CCN1 and CCN3, by the activation of FAK and Akt kinase but not by the activation of ERK1/2. In summary, both CCN proteins play a key role in regulating trophoblast cell differentiation by inducing senescence and enhancing migration properties. Reduced levels of CCN1 and CCN3, as found in early-onset preeclampsia, could contribute to a shift from invasive to proliferative EVTs and may explain their shallow invasion properties in this disease.

MeSH Terms

  • Biomarkers
  • Cell Cycle Checkpoints
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Cellular Senescence
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cysteine-Rich Protein 61
  • Extracellular Signal-Regulated MAP Kinases
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Models, Biological
  • Nephroblastoma Overexpressed Protein
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt
  • Receptors, Notch
  • Signal Transduction
  • Trophoblasts
  • Up-Regulation
  • beta-Galactosidase


  • CCN1
  • CCN3
  • migration
  • placenta
  • senescence
  • trophoblast

Impaired intervertebral disc development and premature disc degeneration in mice with notochord-specific deletion of CCN2.

Currently, our ability to treat intervertebral disc (IVD) degeneration is hampered by an incomplete understanding of disc development and aging. The specific function of matricellular proteins, including CCN2, during these processes remains an enigma. The aim of this study was to determine the tissue-specific localization of CCN proteins and to characterize their role in IVD tissues during embryonic development and age-related degeneration by using a mouse model of notochord-specific CCN2 deletion. Expression of CCN proteins was assessed in IVD tissues from wild-type mice beginning on embryonic day 15.5 to 17 months of age. Given the enrichment of CCN2 in notochord-derived tissues, we generated notochord-specific CCN2-null mice to assess the impact on the IVD structure and extracellular matrix composition. Using a combination of histologic evaluation and magnetic resonance imaging (MRI), IVD health was assessed. Loss of the CCN2 gene in notochord-derived cells disrupted the formation of IVDs in embryonic and newborn mice, resulting in decreased levels of aggrecan and type II collagen and concomitantly increased levels of type I collagen within the nucleus pulposus. CCN2-knockout mice also had altered expression of CCN1 (Cyr61) and CCN3 (Nov). Mirroring its role during early development, notochord-specific CCN2 deletion accelerated age-associated degeneration of IVDs. Using a notochord-specific gene targeting strategy, this study demonstrates that CCN2 expression by nucleus pulposus cells is essential to the regulation of IVD development and age-associated tissue maintenance. The ability of CCN2 to regulate the composition of the intervertebral disc suggests that it may represent an intriguing clinical target for the treatment of disc degeneration.

MeSH Terms

  • Aggrecans
  • Aging
  • Animals
  • Collagen Type I
  • Collagen Type II
  • Connective Tissue Growth Factor
  • Disease Models, Animal
  • Embryonic Development
  • Female
  • Intervertebral Disc
  • Intervertebral Disc Degeneration
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Notochord