TY - JOUR
T1 - Ccn3 (Nov) drives degradative changes in aging articular cartilage
AU - Kuwahara, Miho
AU - Kadoya, Koichi
AU - Kondo, Sei
AU - Fu, Shanqi
AU - Miyake, Yoshiko
AU - Ogo, Ayako
AU - Ono, Mitsuaki
AU - Furumatsu, Takayuki
AU - Nakata, Eiji
AU - Sasaki, Takako
AU - Minagi, Shogo
AU - Takigawa, Masaharu
AU - Kubota, Satoshi
AU - Hattori, Takako
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers 16K11476 and 25462888 to T.H.,19K22716 to S.K. (Satoshi Kubota), and 20K18601 to M.K., as well as funding from the Foundation for Growth Science to T.H., a Ryobi Teien Foundation award to T.H., and a SHISEIKAI Scholarship Fund for basic medical science researchers (Keiko Watanabe Award) to T.H.
Funding Information:
Funding: This work was supported by JSPS KAKENHI Grant Numbers 16K11476 and 25462888 to T.H.,19K22716 to S.K. (Satoshi Kubota), and 20K18601 to M.K., as well as funding from the Foundation for Growth Science to T.H., a Ryobi Teien Foundation award to T.H., and a SHISEIKAI Scholarship Fund for basic medical science researchers (Keiko Watanabe Award) to T.H.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/10/2
Y1 - 2020/10/2
N2 - 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.
AB - 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.
KW - Aging
KW - CCN3
KW - Cellular communication network factor 3
KW - NOV
KW - Oxidative stress
KW - P21
KW - P53
KW - Primary chondrocytes
KW - SASP
KW - Senescence
UR - http://www.scopus.com/inward/record.url?scp=85092441374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092441374&partnerID=8YFLogxK
U2 - 10.3390/ijms21207556
DO - 10.3390/ijms21207556
M3 - Article
C2 - 33066270
AN - SCOPUS:85092441374
SN - 1661-6596
VL - 21
SP - 1
EP - 18
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 20
M1 - 7556
ER -