Inflammation induction of Dickkopf-1 mediates chondrocyte apoptosis in osteoarthritic joint.
OBJECTIVE
Dysregulated Wnt signaling appears to modulate chondrocyte fate and joint disorders. Dickkopf-1 (DKK1) regulates the pathogenesis of skeletal tissue by inhibiting Wnt actions. This study examined whether DKK1 expression is linked to chondrocyte fate in osteoarthritis (OA).


METHODS
Articular cartilage specimens harvested from nine patients with knee OA and from six controls with femoral neck fracture were assessed for DKK1, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), Bad, Bax, Bcl2 and caspase-3 expression by real time-polymerase chain reaction (RT-PCR) and immunohistochemistry. Apoptotic chondrocytes were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labelling (TUNEL) and 4', 6-dianidino-2-phenylindole dihydrochloride (DAPI) staining. Human chondrocyte cultures were treated with recombinant IL-1beta and monoclonal DKK1 antibody to determine whether DKK1 impairs chondrocyte survival.


RESULTS
Expression of DKK1 correlated with inflammatory cytokine levels (IL-1beta and TNF-alpha expressions), proapoptosis regulators (Bad and caspase-3 expressions) and TUNEL staining in OA cartilage tissues. The IL-1beta induced expressions of DKK1, Bax, Bad and caspase-3-dependent apoptosis of chondrocyte cultures. Neutralization of DKK1 by monoclonal DKK1 antibody significantly abrogated IL-1beta-mediated caspase-3 cleavage and apoptosis and reversed chondrocyte proliferation. Recombinant DKK1 treatment impaired chondrocyte growth and promoted apoptosis. By suppressing nuclear beta-catenin accumulation and Akt phosphorylation, DKK1 mediated IL-1beta promotion of chondrocyte apoptosis.


CONCLUSIONS
Chondrocyte apoptosis correlates with joint OA. Expression of DKK1 contributes to cartilage deterioration and is a potent factor in OA pathogenesis. Attenuating DKK1 may reduce cartilage deterioration in OA.
Weng
L-H
LH
Department of Orthopedic Surgery, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Wang
C-J
CJ
Ko
J-Y
JY
Sun
Y-C
YC
Su
Y-S
YS
Wang
F-S
FS
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology*; D002358:Cartilage, Articular / Q000473:pathology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000494:pharmacology; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000473:pathology*; D010007:Osteochondritis / Q000473:pathology*
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta