General and local osteoporosis are two major pathological symptoms of rheumatoid arthritis (RA) that are the consequence of osteoclast induction. Transforming growth factor-β (TGF-β) is an abundant growth factor in bone that its expression is highly up regulated in RA. The effects of TGF-β on bone are quite complex although usually found to be direct stimulatory for osteoclast differentiation. To gain better understanding of the role of TGF-β in osteoclastogenesis, we have investigated effects of this factor on osteoclast differentiation of M-CSF-derived macrophages and GM-CSF-derived macrophages in vitro. Unexpectedly, we observed that TGF-β potently suppressed M-CSF + RANKL-driven osteoclast differentiation from both cell populations. Also TGF-β significantly suppressed the proliferation of osteoclast precursors (p <0.01) and inhibited osteoclastogenesis in a dose dependent manner. Although, TGF-β did not affect expression of the RANK and c-fms genes, it suppressed the induction of the c-fos gene (an essential transcription factor for osteoclast differentiation) by M-CSF and RANKL. Using cells from the respective gene deficient mice, this inhibition by TGF-β appeared to be independent of endogenous interferon a/b, GM-CSF and IL-10 production. Our data suggests that the influence of TGF-β on osteoclastogenesis depends upon the maturation state of the osteoclast precursor and on the presence or otherwise of other stimuli such as RANKL and it may represent a potent tool for preventing loss of bone mass in chronic inflammatory disorders, especially in RA.

Keywords