CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

International Journal of Molecular Sciences - Tập 21 Số 20 - Trang 7556
Miho Kuwahara1,2,3, Koichi Kadoya1,4, Sei Kondo1,2, Shanqi Fu1,2, Yoshiko Miyake1,2, Ayako Ogo1,2, Mitsuaki Ono1,5, Takayuki Furumatsu1,6, Eiji Nakata1,6, Takako Sasaki7, Shogo Minagi3, Masaharu Takigawa8, Satoshi Kubota1,2, Takako Hattori1,2
1Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
2Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine,
3Department of Occlusal and Oral Functional Rehabilitation, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;
4Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine,
5Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine,
6Department of Orthopedic Surgery, Okayama University Graduate School of Medicine,
7Department of Biochemistry, Faculty of Medicine, Oita University, Oita 879-5593, Japan;
8Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Dental School/Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8525, Japan;

Tóm tắt

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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International Journal of Molecular Sciences

Tập 21 Số 20

7556

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