Osteoarthritis Basic Science Studies
Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees
Version of Record online: 25 JAN 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 5, pages 1393–1402, May 2010
How to Cite
Weng, L.-H., Wang, C.-J., Ko, J.-Y., Sun, Y.-C. and Wang, F.-S. (2010), Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis & Rheumatism, 62: 1393–1402. doi: 10.1002/art.27357
- Issue online: 29 APR 2010
- Version of Record online: 25 JAN 2010
- Accepted manuscript online: 25 JAN 2010 12:00AM EST
- Manuscript Accepted: 11 JAN 2010
- Manuscript Received: 22 DEC 2008
- National Science Council, Taiwan. Grant Number: NSC-96-2314-B-182A-048
- National Health Research Institute, Taiwan. Grant Number: NHRI-EX98-9834EI
- Chang Gung Memorial Hospital–Kaohsiung Medical Center. Grant Numbers: CMRPG83038, CMRPG86053
Perturbation of Wnt signaling components reportedly regulates chondrocyte fate and joint disorders. The Wnt inhibitor Dkk-1 mediates remodeling of various tissue types. We undertook this study to examine whether control of Dkk-1 expression prevents joint deterioration in osteoarthritic (OA) knees.
Anterior cruciate ligament transection–and collagenase-induced OA in rat knees was treated with end-capped phosphorothioate Dkk-1 antisense oligonucleotide (Dkk-1–AS). Articular cartilage destruction, cartilage degradation markers, bone mineral density (BMD), and subchondral trabecular bone volume of injured knee joints were measured using Mankin scoring, enzyme-linked immunosorbent assay, dual x-ray absorptiometry, and histomorphometry. Dkk-1–responsive molecule expression and apoptotic cells in knee tissue were detected by quantitative reverse transcriptase–polymerase chain reaction, immunoblotting, and TUNEL staining.
Up-regulated Dkk-1 expression was associated with increased Mankin score and with increased serum levels of cartilage oligomeric matrix protein and C-telopeptide of type II collagen (CTX-II) during OA development. Dkk-1–AS treatment alleviated OA-associated increases in Dkk-1 expression, Mankin score, cartilage fibrillation, and serum cartilage degradation markers. Dkk-1–AS also alleviated epiphyseal BMD loss and subchondral bone exposure associated with altered serum levels of osteocalcin and CTX-I. The treatment abrogated chondrocyte/osteoblast apoptosis and subchondral trabecular bone remodeling in OA. Dkk-1 knockdown increased levels of nuclear β-catenin and phosphorylated Ser473-Akt but attenuated expression of inflammatory factors (Toll-like receptor 4 [TLR-4], TLR-9, interleukin-1β, and tumor necrosis factor α), the apoptosis regulator Bax, matrix metalloproteinase 3, and RANKL in OA knee joints.
Interference with the cartilage- and bone-deleterious actions of Dkk-1 provides therapeutic potential for alleviating cartilage destruction and subchondral bone damage in OA knee joints.