Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease

Roddy, Karen A.; Boulter, Catherine A.

doi:10.1016/j.joca.2014.12.012

Cited by 20 publications

(21 citation statements)

References 42 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our finding that both treatment with recombinant CCN3 and CCN3 overexpression significantly increased the p53 expression indicates that p53 regulation by CCN3 also occurs in chondrocytes. The other CCN3-deficient mice caused by deletion of exon 3 showed skeletal abnormalities in some joints and heart defects [ 30 ]; 12-month-old male knee joints showed some degenerative changes, but female joints did not [ 31 ]. Since these CCN3-deficient mice were able to express the first 1 and 2 domains coded by exon 1 and 2, the phenotypes of these mice must be interpreted with care.…”

Section: Discussionmentioning

confidence: 99%

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

Kuwahara

Kadoya

Kondo

et al. 2020

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

Kuwahara

Kadoya

Kondo

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Using the targeted mutation mice model of CCN3, Roddy K.A. et al have also reported that CCN3 is required for maintenance of articular cartilage and for joint homeostasis [24]. …”

Section: Discussionmentioning

confidence: 99%

CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function

Yoshioka

Ono

Maeda

et al. 2016

Bone

View full text Add to dashboard Cite

The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-β3 (TGF-β3). Overexpression of CCN4 enhanced TGF-β3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-β3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs. Immunoprecipitation–western blot analysis revealed that CCN4 bound to TGF-β3 and regulated the ability of TGF-β3 to bind to hBMSCs. In vivo analysis confirmed there was a significant decrease in the gene expression levels of chondrocyte markers in cartilage samples from Ccn4-knock out (KO) mice, compared to those from wild type (WT) control. In order to investigate the regenerative properties of the articular cartilage in Ccn4-KO mice, articular cartilage defects were surgically performed in the knee joints of young mice, and the results showed that the cartilage was partially repaired in WT mice, but not in Ccn4-KO mice. In conclusion, these results show, for the first time, that CCN4 has a positive influence on chondrogenic differentiation by modulating the effects of TGF-β3.

show abstract

“…CCN3 is essential for maintaining HSC long term repopulating activity and bone marrow engraftment (Gupta et al, 2007). Finally, CCN3 is also known to participate in chondrogenesis (Heath et al, 2008;Hoshijima et al, 2012;Janune et al, 2017Janune et al, , 2011Kawaki et al, 2008;Lafont et al, 2005;Roddy and Boulter, 2015), osteogenesis (Heath et al, 2008;Matsushita et al, 2013;Minamizato et al, 2007;Ouellet and Siegel, 2012;Rydziel et al, 2007) and dentin regeneration .…”

Section: Roles Of Ccn3 In Tissue Regenerationmentioning

confidence: 99%

Regenerating CNS myelin: Emerging roles of regulatory T cells and CCN proteins

Gallardo

Dittmer

Dombrowski

et al. 2019

Neurochemistry International

View full text Add to dashboard Cite

Efficient myelin regeneration in the central nervous system (CNS) requires the migration, proliferation and differentiation of oligodendrocyte progenitor cells (OPC) into myelinating oligodendrocytes. In demyelinating diseases such as multiple sclerosis (MS), this regenerative process can fail, and therapies targeting myelin repair are currently completely lacking in the clinic.The immune system is emerging as a key regenerative player in many tissues, such as muscle and heart. We recently reported that regulatory T cells (Treg) are required for efficient CNS remyelination. Furthermore, Treg secrete CCN3, a matricellular protein from the CCN family, implicated in regeneration of other tissues. Treg-derived CCN3 promoted oligodendrocyte differentiation and myelination. In contrast, previous studies showed that CCN2 inhibited myelination. These studies highlight the need for further scrutiny of the roles that CCN proteins play in myelin development and regeneration. Collectively, these findings open up exciting avenues of research to uncover the regenerative potential of the adaptive immune system. Highlights• Adaptive immune cells are emerging as key regulators of tissue regneration • Treg support oligodendrocyte differentiation and remyelination • CCN3 enhances oligodendrocyte differentiation and myelination • CCN family of proteins may hold therapeutic potential for neurological dieases Keywords (up to 6)Treg, CCN3, remyelination, oligodendrocyte, regeneration Abbreviations ALSAmyotrophic Lateral Sclerosis AR amphiregulin AT2 type II alveolar epithelial cellIn the field of regenerative immunology, influences of innate immune responses are perhaps better understood at this point, though several recent discoveries have shone a light on the adaptive immune system in tissue regeneration (Aurora and Olson, 2014). In particular, T lymphocytes have emerged as key cellular players that can influence tissue regeneration, both positively and negatively. This review will focus on an anti-inflammatory subset of CD4 + T cells that has gained much attention in regenerative biology, regulatory T cells.

show abstract

Targeted mutation of NOV/CCN3 in mice disrupts joint homeostasis and causes osteoarthritis-like disease

Cited by 20 publications

References 42 publications

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function

Regenerating CNS myelin: Emerging roles of regulatory T cells and CCN proteins

Contact Info

Product

Resources

About