Why TNF-α inhibition is not sufficient to avoid juxta-articular erosions in chronic arthritis?

There is an emerging interest in the role of anti-TNF-α therapy in reducing bone damage in chronic arthritis with special regard to rheumatoid arthritis. Accumulation of osteoclasts in rheumatoid synovial tissues, and their activation due to osteoclastogenic cytokines and chemokines at cartilage erosion sites suggest that they may advantageously be considered as therapeutic targets. Given that the primary role of TNF-α in osteoclastogenesis, the inhibition of TNF-α represents an important strategy for reducing bone damage in rheumatoid arthritis. In point of fact, there is evidence that treatment with anti-TNF-α agents may avoid or reduce bone damage in rheumatoid arthritis, even if further studies are required to provide a biological explanation and a link for the observation of the advantageous effects of TNF-α inhibitors on the progression of bone damage in chronic arthritis. The existence of factors involved in osteoclast activation, including IL-1, IL-6, IL-7, IL-11, IL-17, M-CSF, TGF-β, MIP-1α, MIP-1β, IP-10, MIG, and OSCAR, indicates that TNF-α is only a single player in the great molecular cauldron of osteoclastogenesis. The presence of mediators behind the TNF-α and RANK-RANKL complex that may be independent in inducing osteoclastogenesis, such as NFATc1, suggests that the anti-TNF-α therapy will not provide a complete reduction of bone damage in chronic arthritis.