Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis

Abstract

Objective. To investigate the effect of osteoclastogenesis inhibitory factor/osteoprotegerin (OPG) on chondrocytes in the development of osteoarthritis (OA) in vivo.Methods. To determine the role of endogenous OPG in the progression of OA, OA was surgically induced in OPG ؉/؊ mice and their wild-type (WT) littermates. To determine the role of exogenous OPG, knee joints of C57BL/6J mice with surgically induced OA were injected intraarticularly with recombinant human OPG (rHuOPG) or vehicle 5 times a week. All mice were euthanized 4 weeks after OA induction; joints were harvested and evaluated immunohistochemically.Results. Although OA changes were induced in both WT and OPG ؉/؊ mice, the degenerative changes in the articular cartilage were significantly enhanced in OPG ؉/؊ mice. In C57BL/6J mice with surgically induced OA, intraarticular OPG administration protected the articular cartilage from the progression of OA. The Mankin and cartilage destruction scores in OPGtreated animals were ϳ50% of those seen in the control group. Furthermore, OPG administration significantly protected articular cartilage thickness. Findings of the TUNEL assay indicated that rHuOPG prevented chondrocyte apoptosis in joints with surgically induced OA. Results of immunostaining indicated that OPG protein was detected in the synovium and in resident chondrocytes at higher levels in the OPG-treated group than in the control group.Conclusion. These data indicate that endogenous OPG had a protective effect against the cartilage destruction that occurs during OA progression. Furthermore, direct administration of rHuOPG to articular chondrocytes prevented cartilage destruction in an experimental murine model of OA via prevention of chondrocyte apoptosis.

New Perspective in Osteoarthritis: The OPG and RANKL System as a Potential Therapeutic Target?

“…Future therapeutic approaches could target reducing bone remodelling changes that take place in human OA subchondral bone, and data suggest that the modulation of OPG and RANKL could be an interesting target for such treatment. Since L-OA patients are in a remodelling/ resorptive phase, the inhibitory effect of OPG on bone resorption could therefore be proposed for this subpopulation; however, even though the administration of OPG in vivo in a murine OA model seems effective for the treatment of OA, 73 care should be taken since full-length OPG is known to be a survival factor for tumor cells. 9 1 Moreover, the anti-apoptotic effect of OPG via TRAIL can promote OA synovial membrane hyperplasia.…”

Targeting subchondral bone for treating osteoarthritis: what is the evidence?

“…A recent study carried out in an experimental mouse model of OA revealed, upon OPG administration, reduced cartilage degradation through an effect on trabecular bone [123]. In the same line of thought, data from an OPG transgenic mouse model of OA suggested that the in vivo beneficial effect of the administration of OPG could be due to its capacity to bind tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), an inducer of chondrocyte apoptosis [124]. However, data generated from an in vitro study in which treatment of human OA chondrocytes with OPG enhanced two catabolic factors involved in the pathophysiology of the disease [101] suggest that targeting the factor that mediates the effect of OPG, for example, by inhibiting RANKL, could lead to a new therapeutic approach against OA.…”

Accelerated development of aging‐associated and instability‐induced osteoarthritis in osteopontin‐deficient mice

“…The cartilage thickness was evaluated using Adobe Photoshop selection tools, which allowed us to select an area that spanned 450 m across the surface of the cartilage and extended down to the surface of the subchondral bone. The number of pixels within the area was converted to m 2 , and this converted value was divided by 450 m to estimate the mean cartilage thickness within the selected area (29,30).…”