G Kollias

Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-TNF in combination with OPG or PTH in TNF-mediated arthritis

Local bone erosion and systemic bone loss are hallmarks of rheumatoid arthritis and cause progressive disability. Tumour necrosis factor (TNF) is a key mediator of arthritis and acts catabolically on bone by stimulating bone resorption and inhibiting bone formation. We hypothesized that the concerted action of anti-TNF, which reduces inflammation, and of PTH, which stimulates bone formation, or of OPG, which blocks bone resorption, could lead to repair of local bone erosions and reversal of systemic bone loss. To test this, human TNF-transgenic (hTNFtg) mice with established erosive arthritis and systemic bone loss were treated with PTH, OPG and anti-TNF, alone or in combination. Local bone erosions almost fully regressed, upon combined treatment with anti-TNF and PTH and/or OPG, suggesting repair of inflammatory skeletal lesions. In contrast, OPG and anti-TNF alone led to arrest of bone erosions but did not achieve repair. Treatment with PTH alone had no influence on the progression of bone erosions. Local bone erosions showed all signs of new bone formation such as the presence of osteoblasts, osteoid formation and mineralization. Furthermore, systemic bone loss was completely reversed upon combined treatment and this effect was mediated by osteoblast stimulation and osteoclast blockade. In summary, we conclude that local joint destruction and systemic inflammatory bone loss due to TNF can regress, and that repair requires a combined approach by reducing inflammation, blocking bone resorption or stimulating bone formation.

Zoledronic acid protects from local and systemic bone loss in tumor necrosis factor-mediated arthritis

Increased osteoclast activity is a key factor for bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in RA. Zoledronic acid (ZA) is one of the most potent agents to block osteoclast function. We therefore investigated whether ZA can inhibit inflammatory bone loss. Human tumor necrosis factor transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with PBS, single or repeated doses of ZA, calcitonin or anti-tumor necrosis factor at the onset of arthritis. Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by single administration (-60%) and almost completely blocked by repeated administration (-95%) of ZA. Cartilage damage was partly inhibited (-40%), and synovial osteoclast counts were significantly reduced upon ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice upon ZA administration, which was due to an increase of trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after ZA. Calcitonin had no effect on synovial inflammation, bone erosions, cartilage damage or systemic bone mass. Anti-tumor necrosis factor entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation and cartilage damage, but had only minor effects on systemic bone mass. ZA appears as an effective tool to protect bone from arthritic damage. In addition to antiinflammatory drug therapy, modern bisphosphonates are promising candidates to maintain joint integrity and to reverse systemic bone loss in arthritis.

Isolated and combined inhibition of TNF-, IL-1 and RANKL-pathways in TNF-induced arthritis: effects on synovial inflammation, bone erosion and cartilage destruction

To investigate the efficacy of isolated and combined blockade of TNF-, IL-1- and RANKL-pathways on synovial inflammation, bone erosion and cartilage destruction in a TNF-driven arthritis model, human TNF transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra) or osteoprotegerin (OPG). In addition, each of three possible double combination therapies and a triple combination therapy was applied. Therapy was followed by histological assessment of synovial inflammation, bone erosion and cartilage damage. Synovial inflammation was inhibited by anti-TNF (-51%), but not IL-1Ra or OPG monotherapy. Combinations of anti-TNF with IL-1Ra (-91%) or OPG (-81%) were additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and also by OPG (-60%), but not by IL-1Ra monotherapy. Combination of anti-TNF and IL-1Ra, however, completely blocked bone erosion (-98%). The effects on inhibition of bone erosion were accompanied by reduction of osteoclast numbers within synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%), weakly, but not significantly by IL-1Ra, and not at all by OPG monotherapy. Combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, a triple combination of anti-TNF, IL-1Ra and OPG was not superior to double combination therapy with anti-TNF and IL-1Ra. Articular changes caused by chronic TNF overexpression are not completely blockable by monotherapies, which target TNF, IL-1 or RANKL. However, combined approaches that reduce TNF load and block IL-1 or RANKL as downstream mediators of TNF can lead to a complete remission. Differences in their efficacy to block synovial inflammation, bone erosion and cartilage destruction further strengthen the rationale for combined blockade of more than one proinflammatory pathway.