Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice
Article first published online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2568–2578, August 2012
How to Cite
Oh, H., Chun, C.-H. and Chun, J.-S. (2012), Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis & Rheumatism, 64: 2568–2578. doi: 10.1002/art.34481
- Issue published online: 27 JUL 2012
- Article first published online: 27 JUL 2012
- Accepted manuscript online: 5 APR 2012 11:47AM EST
- Manuscript Accepted: 20 MAR 2012
- Manuscript Received: 23 JUL 2011
- National Research Foundation of Korea. Grant Numbers: 2011-0001158, 2010-0026293
- Korea Healthcare Technology Research and Development project. Grant Numbers: A101793, A110274
Dkk is a family of canonical Wnt antagonists with 4 members (Dkk-1, Dkk-2, Dkk-3, and Dkk-4). We undertook this study to explore the roles of Dkk-1 and Dkk-2 in osteoarthritic (OA) cartilage destruction in mice.
Expression of Dkk and other catabolic factors was determined at the messenger RNA and protein levels in human and mouse OA cartilage. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM) or by intraarticular injection of Epas1 adenovirus (AdEPAS-1). The role of Dkk in OA pathogenesis was examined by intraarticular injection of AdDkk-1 or by using chondrocyte-specific Dkk1 (Col2a1-Dkk1)–transgenic mice and Dkk2 (Col2a1-Dkk2)–transgenic mice. Primary culture mouse chondrocytes were also treated with recombinant Dkk proteins.
We found opposite patterns of Dkk1 and Dkk2 expression in human and mouse experimental OA cartilage: Dkk1 was up-regulated and Dkk2 was down-regulated. Overexpression of Dkk1 by intraarticular injection of AdDkk-1 significantly inhibited DMM-induced experimental OA. DMM-induced OA was also significantly inhibited in Col2a1-Dkk1–transgenic mice compared with their wild-type littermates. However, Col2a1-Dkk2–transgenic mice showed no significant difference in OA pathogenesis. Wnt-3a, which activates the canonical Wnt pathway, induced Mmp13 and Adamts4 expression in primary culture chondrocytes, an effect that was significantly inhibited by Dkk-1 pretreatment or Dkk1 overexpression.
Our findings indicate that expression of Dkk1, but not Dkk2, in chondrocytes inhibits OA cartilage destruction. The protective effect of Dkk-1 appears to be associated with its capacity to inhibit Wnt-mediated expression of catabolic factors, such as Mmp13, providing evidence that Dkk-1 might serve as a therapeutic target for OA treatment.