Abstract
Summary Statement
Increased Dkk-1 signaling is associated with OA occurrence and joint microenvironment damage. Interruption of Dkk1 action is beneficial to improve OA knees.
Introduction
Osteoarthritis (OA) is a leading cause of disability and healthcare financial burden for total knee arthroplasty, rehabilitation, and disability. Inappropriate mechanical stress, immunological, or biochemical regulation reportedly disturbs homeostasis among cartilage, synovium and subchondral bone microstructure that contributes to OA pathogenesis. Control of joint-deleterious factor action is an emerging strategy to ameliorate OA-induced joint deterioration. Dickkopf-1 (Dkk-1) is a potent inhibitor for Wnt/β-catenin signaling regulation of tissue development and remodeling in physiological or pathological contexts. Dkk-1 also acts as a master deleterious factor that represses osteoblast differentiation capacity and bone repair. Associations among Dkk-1 expression, chondrocyte fate, synovial fibroblast behavior or OA incidence are merit of characterization.
Patients & Methods
Cartilage, synovial tissue and fluid were harvested from informed consent OA patients underwent arthroplasty and patient with knee injuries without OA changes as controls. Primary chondrocyte cultures and synovial fibroblasts were treated with inflammatory cytokines or Dkk-1 antisense oligonucleotide or monoclonal antibodies. Knees in experimental animals were subjected to anterior cruciate ligament transection- or intra-articular collagenase injection to induce OA. Joint inflammation, integrity and subchondral bone microstructure in knees as well gait profiles were quantified using 2-deoxyglucose-probed near-infrared in vivo image, µCT, catwalk and histomorphometric analyses.
Results
In clinical vignettes, patients with end-stage OA knee had higher abundances of Dkk-1 in cartilage, synovial tissue, and synovial fluid compared to control patients. Disruption of DKk-1 signaling ameliorated the promoting effects of inflammatory cytokines on the survival and cartilage matrix synthesis in primary cartilage chondrocyte cultures. Of interest, Dkk-1 neutralization attenuated the excessive angiogenic activities and matrix metalloproteinase secretion in primary synovial fibroblasts of OA knees. Dkk-1 modulation of survival or metabolic activities in chondrocytes and synovial fibroblasts were through β-catenin-dependent and -independent signaling pathways. Moreover, increased Dkk-1 expression in lesion sites and sera was associated with the incidence of femoral head osteonecrosis. Loss of Dkk-1 action alleviated bone cell apoptosis in osteonecrotic bone microenvironments. In experimental OA knee models, knockdown of Dkk-1 alleviated articular cartilage damage as evidenced by improved Mankin score in OA knees. Dkk-1 disruption also alleviated the adverse effects of OA on subchondral bone exposure and loss of trabecular bone volume and mineral acquisition in injured joints. Loss of Dkk-1 function reduced joint inflammation, vessel number, leukocyte infiltration in synovium compartment of OA joint and improved gait profiles of affected limbs.
Conclusion
Dkk-1 signaling is associated with the OA knee occurrence and accelerates apoptosis, matrix degradation and angiogenic activities in chondrocytes and synovial fibroblasts of OA joint. Dkk-1 interference alleviates the promoting effects of OA on cartilage, synovial and subchondral bone remodeling. Blocking the deleterious actions of Dkk-1 in joint microenvironment will be a prospective molecular regime beneficial for retarding excessive joint deterioration in OA knees.
