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Updated: May 23, 2026
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice
Hwanhee Oh1, Churl-Hong Chun, Jang-Soo Chun
1Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Dickkopf-1 (Dkk1) inhibits osteoarthritis (OA) cartilage destruction by blocking Wnt signaling, while Dkk2 does not. This suggests Dkk1 is a potential therapeutic target for OA treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Rheumatology
Background:
- Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage destruction.
- Dickkopf (Dkk) proteins are antagonists of the canonical Wnt signaling pathway.
- The specific roles of Dkk-1 and Dkk-2 in OA pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the differential roles of Dkk-1 and Dkk-2 in the context of osteoarthritic cartilage destruction in a mouse model.
- To explore the potential of Dkk-1 as a therapeutic target for OA.
Main Methods:
- Assessed Dkk and catabolic factor expression in human and mouse OA cartilage at mRNA and protein levels.
- Induced experimental OA in mice using destabilization of the medial meniscus (DMM) or Epas1 adenovirus.
- Examined Dkk's role by intraarticular injection of AdDkk-1 and using chondrocyte-specific Col2a1-Dkk1 and Col2a1-Dkk2 transgenic mice.
- Treated primary mouse chondrocytes with recombinant Dkk proteins.
Main Results:
- Dkk1 expression was upregulated, while Dkk2 expression was downregulated in OA cartilage.
- Overexpression of Dkk1 significantly inhibited DMM-induced OA in mice.
- Col2a1-Dkk1 transgenic mice showed significantly reduced OA compared to wild-type controls.
- Col2a1-Dkk2 transgenic mice did not exhibit significant differences in OA.
- Dkk-1 pretreatment inhibited Wnt-3a-induced expression of catabolic factors (Mmp13, Adamts4) in chondrocytes.
Conclusions:
- Dkk1, but not Dkk2, expression in chondrocytes plays a protective role against OA cartilage destruction.
- Dkk-1's therapeutic potential in OA is linked to its ability to inhibit Wnt-mediated catabolic factor expression.
- Dkk-1 represents a promising therapeutic target for osteoarthritis treatment.
