Dkk‐1–Mediated Inhibition of Wnt Signaling in Bone Ameliorates Osteoarthritis in Mice

Abstract

Objective. Wnt signaling is a master regulator of joint homeostasis, but its role in osteoarthritis (OA) remains unclear. This study was undertaken to characterize the activation of Wnt/␤-catenin in knee joints of mice with OA and to assess how inhibiting this pathway in bone could affect cartilage.Methods. OA was induced by partial meniscectomy in Topgal mice and in transgenic mice overexpressing Dkk-1 under the control of the 2.3-kb Col1a1 promoter (Col1a1-Dkk-1-Tg mice). Wnt/␤-catenin activation was assessed by X-Gal staining at baseline and at weeks 4, 6, and 9. Cartilage and bone damage was analyzed in Col1a1-Dkk-1-Tg mice with OA at week 6. Primary chondrocytes and cartilage explants were used to assess the effect of Dkk-1 on cartilage catabolism.Results. In meniscectomized Topgal mice, Wnt was mainly activated in osteocytes from the subchondral bone at week 6 after OA induction, as well as in osteophytes and synovium at week 4. Chondrocytes from damaged zones expressed X-Gal from week 4. Dkk-1 expression was high in chondrocytes in control mouse knees (mean ؎ SEM 84.2 ؎ 3.1%) but decreased greatly in knees of meniscectomized mice from week 4 (mean ؎ SEM 14.4 ؎ 3.8%). The OA score was lower in meniscectomized Col1a1-Dkk-1-Tg mice at week 6 compared with wild-type mice (5.1 ؎ 0.6 versus 8.4 ؎ 0.6; P ‫؍‬ 0.002). Subchondral bone fraction and osteophyte volume were decreased. However, cartilage explants from Col1a1-Dkk-1-Tg mice showed proteoglycan loss and increased NITEGE expression. Expression of vascular endothelial growth factor (VEGF) was reduced in osteoblasts from Col1a1-Dkk-1-Tg mice, thereby decreasing expression of messenger RNA for matrix metalloproteinases in chondrocytes.Conclusion. Wnt activation in OA affects the whole joint, particularly bone. Selective inhibition of this pathway in bone by Dkk-1 decreased OA severity through VEGF inhibition.

Lithium Chloride Modulates Adipogenesis and Osteogenesis of Human Bone Marrow-Derived Mesenchymal Stem Cells

“…Furthermore, DKK1 is a canonical upstream inhibitor of Wnt signaling [33,34]; this study showed that LiCl can counteract the DKK1 inhibition of Wnt signaling. These findings indicate that LiCl regulated BMSC differentiation in a Wnt signaling-dependent manner.…”

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…Altered activity of Wnt signaling in chondrocytes may involve osteoclastic activity in subchondral bone growth plates leading to sclerosis or osteophyte formation at the edges of joints (165,166). In addition, Dickkopf-1 (Dkk1) is an inhibitor of this pathway, and its overexpression in bone leads to thicker and stiffer bones, retarding cartilage degradation (167). Moreover, the deletion of sclerostin, another Wnt antagonist, increased the severity of OA, although no changes in cartilage were observed (168).…”

Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice

“…Indeed, chondrocyte-specific deletion of MMP13 alleviated OA in mice; the Wnt family members were candidates for the regulation of MMP13 expression in chondrocytes because its expression was increased in chondrocytes from mice with conditional activation of β-catenin (12). Cumulative data showed that Wnt activity is low under physiological conditions, and activation of Wnt signaling contributes to cartilage breakdown in OA (13,14). The modulation of Wnt inhibitors had significant effects on chondrocyte catabolism of mice.…”

“…The modulation of Wnt inhibitors had significant effects on chondrocyte catabolism of mice. Indeed, loss of sclerostin enhanced cartilage degradation (15) and the overexpression of Dkk-1 alleviated OA (14). Despite the hypoxic status of cartilage (16), the involvement of hypoxia in regulating Wnt signaling and MMP13 expression in cartilage is still unclear.…”