Abstract
IntroductionThe receptor activator nuclear factor-kappaB ligand (RANKL) diffuses from articular cartilage to subchondral bone. However, the role of chondrocyte-synthesized RANKL in rheumatoid arthritis-associated juxta-articular bone loss has not yet been explored. This study aimed to determine whether RANKL produced by chondrocytes induces osteoclastogenesis and juxta-articular bone loss associated with chronic arthritis.MethodsChronic antigen-induced arthritis (AIA) was induced in New Zealand (NZ) rabbits. Osteoarthritis (OA) and control groups were simultaneously studied. Dual X-ray absorptiometry of subchondral knee bone was performed before sacrifice. Histological analysis and protein expression of RANKL and osteoprotegerin (OPG) were evaluated in joint tissues. Co-cultures of human OA articular chondrocytes with peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with macrophage-colony stimulating factor (M-CSF) and prostaglandin E2 (PGE2), then further stained with tartrate-resistant acid phosphatase.ResultsSubchondral bone loss was confirmed in AIA rabbits when compared with controls. The expression of RANKL, OPG and RANKL/OPG ratio in cartilage were increased in AIA compared to control animals, although this pattern was not seen in synovium. Furthermore, RANKL expression and RANKL/OPG ratio were inversely related to subchondral bone mineral density. RANKL expression was observed throughout all cartilage zones of rabbits and was specially increased in the calcified cartilage of AIA animals. Co-cultures demonstrated that PGE2-stimulated human chondrocytes, which produce RANKL, also induce osteoclasts differentiation from PBMCs.ConclusionsChondrocyte-synthesized RANKL may contribute to the development of juxta-articular osteoporosis associated with chronic arthritis, by enhancing osteoclastogenesis. These results point out a new mechanism of bone loss in patients with rheumatoid arthritis.
Highlights
The receptor activator nuclear factor-kappaB ligand (RANKL) diffuses from articular cartilage to subchondral bone
The resorptive signal measured by the RANKL/OPG ratio was increased in the articular cartilage of antigen-induced arthritis (AIA) rabbits, and this increase was simultaneous to a significant bone loss in the subchondral plate that was homogeneous along the femoral condyle surface
We have demonstrated an increase in RANKL immunostaining in AIA cartilage as compared to OA and healthy cartilage, and remarkably the increase of RANKL/OPG ratio in the cartilage of AIA rabbits was simultaneous to subchondral bone loss
Summary
The receptor activator nuclear factor-kappaB ligand (RANKL) diffuses from articular cartilage to subchondral bone. This study aimed to determine whether RANKL produced by chondrocytes induces osteoclastogenesis and juxta-articular bone loss associated with chronic arthritis. Juxta-articular bone loss is related to the intensity of inflammatory response in the affected joint [2,3,4,5,6,7]. This fact is observed in RA, and in other arthritides associated with a high degree of inflammation [8,9]. Macrophages differentiate into bone-resorbing osteoclasts in zones of contact between the inflamed synovium and subchondral bone in RA in the presence of a crucial factor, the receptor activator of nuclear factor-B ligand (RANKL) [10,11]
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