Bone Resorption, Osteoclastogenesis and Adalimumab

Osteoclasts (OCs) are cells specialized in bone degradation that participate in bone and joint destruction in Rheumatoid Arthritis (RA). Experimental models have clearly demonstrated that OCs are essential for local bone resorption in arthritis. In RANKL knockout mice(1; 2), in rats receiving OPG(3-6) or in c-fos(-/-) hTNF transgenic mice(7) induction of arthritis leads to inflammation but not to bone erosion. Systemic osteoporosis is an important comorbidity in RA(8; 9). Increased systemic bone resorption due to OC activation occurs even in early (< 2 years) RA and correlates with disease activity(10). Bisphosphonates are effective in preventing systemic bone loss in inflammatory diseases, but for unknown reasons do not seem to influence periarticular bone erosion and joint destruction. Finally, a systemic factor affecting osteoclastogenesis seems to be present in RA, as shown by an increased formation of OCs from bone marrow of patients with severe arthritis when compared to controls(11).

TNF-alpha is a major pathologic mediator in RA. It may induce bone resorption either directly, stimulating osteoclastogenesis(12; 13) or indirectly, by influencing RANKL, OPG and prostaglandin production by osteoblasts(14; 15). These pathways may be important for the pathophysiology of several diseases such as periodontitis, Rheumatoid arthritis and osteoporosis(16; 17). In mice, TNF-alpha increases the number of osteoclast precursors in vivo but its role may, however, be more complex and implicate also osteoclastogenesis-inhibiting mechanisms(18; 19); in fact, in certain conditions, TNF-alpha may decrease osteoclastogenesis(20), so the in vivo effect of blocking TNF may be difficult to predict from these models.

Anti-TNF agents reduce bone destruction in RA but it is not clear how this effect is achieved since, as described in the preceding paragraph, TNF has been shown to have antagonistic effects in osteoclast formation and activity. Moreover, little is known of the effect of anti-TNF therapy on osteoclast biology in humans.

Working hypothesis

This project is based on two different but closely related hypothesis: