The osteoprotegerin/receptor activator of nuclear factor ?B/receptor activator of nuclear factor ?B ligand system in cartilage

Objective. Tumor necrosis factor ␣ (TNF␣) blockade provides substantive reduction of the symptoms of rheumatoid arthritis (RA). While the biologic actions of TNF␣ have been well characterized in immune and synovial cells, which are known to be major contributors to the progression of cartilage destruction in RA, the current studies were designed to assess the direct effects of TNF␣ on chondrocytes.Methods. We examined the expression of several groupings of messenger RNA (mRNA) that define key biologic pathways that have previously been associated with either the general actions of TNF␣ or cartilage destruction, in murine articular chondrocytes isolated from wild-type mice and TNF␣ receptor-null (p55/ p75 ؊/؊ ) mice. Results. TNF␣ induced the expression of multiple mRNA that facilitate apoptosis and lead to apoptosisinduced cell death. The induction of apoptosis was accompanied by the increased expression of several factors involved in the regulation of skeletal tissue proteolysis and resorption. Quantitative increases from 2-fold to >10-fold were seen for inducible nitric oxide synthase, matrix metalloproteinase 3, macrophage colony-stimulating factor, and osteoprotegerin mRNA expression. The dependence of the induction of these mRNA on TNF␣ was confirmed by comparison with the effects of TNF␣ on chondrocytes isolated from receptornull mice.Conclusion. These findings demonstrate that TNF␣ alters the expression of a complex array of genes within murine chondrocytes that contribute to the destruction of joint surfaces, independent of its actions on synovial and immune cells. Further studies are needed to clarify the biologic actions of TNF␣ in human cartilage cells.

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 62%

Tumor necrosis factor α activation of the apoptotic cascade in murine articular chondrocytes is associated with the induction of metalloproteinases and specific pro‐resorptive factors

Cho¹,

Lehmann²,

Edgar³

et al. 2003

“…The main target of OPG, however, remains bone erosion. This is underlined by its lack of effect on cartilage degradation, although RANKL and its receptor are expressed by chondrocytes (31).…”

Section: Discussionmentioning

confidence: 99%

Single and combined inhibition of tumor necrosis factor, interleukin‐1, and RANKL pathways in tumor necrosis factor–induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction

Zwerina

Hayer

Tohidast‐Akrad³

et al. 2004

293

212

Objective. To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model.Methods. Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically.Results. Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra.Conclusion. Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.

“…Cartilage from patients with OA contains increased levels of OPG mRNA, and the expression of these 3 proteins extends into the midzone of the cartilage (18,19). OPG is expressed in the synovial tissues of patients with rheumatoid arthritis, spondylarthropathies, and OA (19).…”

mentioning

confidence: 99%

“…OPG is expressed in the synovial tissues of patients with rheumatoid arthritis, spondylarthropathies, and OA (19). OPG expression by chondrocytes is increased in response to in vitro stimulation with interleukin-1␤, the proinflammatory cytokine expressed in OA joints (18), implying the existence of OPG targets within the joint space, in addition to the subchondral area.…”

mentioning

confidence: 99%

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

Shimizu¹,

Asou²,

Itoh³

et al. 2007

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.