Bone loss is one of the major pathological symptoms of inflammatory arthritis, and is the consequence of osteoclast induction, differentiation and activation. Tumor necrosis factor-a (TNF-a) is one of the key components of inflammatory. It plays a crucial role in the bone and joint destruction that occurs in chronic inflammation. To gain better understanding of the role of TNF-a in osteoclastogenesis, we have investigated direct effects of TNF-a on osteoclast differentiation by M-CSF and RANKL from bone marrow derived macrophages in vitro. Although, at low concentrations, TNF-a acted as a co stimulator with RANKL, at high concentration (10 ng/ml) it significantly suppressed the proliferation of osteoclast precursors (p <0.01). In high concentration it significantly down regulated the RANKL-induced osteoclastic genes expression, CTR and Cath K, as measured by Q-PCR (p< 0.05). As shown previously, TGF- is able to inhibit RANKL-induced osteoclast differentiation by a direct action on osteoclast precursors (Lari et al., 2006). TGF-b also inhibits osteoclast differentiation of either TNF- or TNF-and RANKL. Therefore, the data suggests that TGF-b is acting as a direct inhibitor of RANKL-stimulated osteoclast differentiation, in the presence of TNF-a Furthermore, the current study provides some evidence that endogenous type I IFN is contributing substantially to the effects of TNF-a on osteoclast formation in the TNF-a -treated cultures. Taken together, the above results from this study give a better insight into the complex mechanisms of how cytokines may be linked to osteoclastogenesis in inflammatory conditions.

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