Bone morphogenetic protein receptors and bone morphogenetic protein signaling are controlled by tumor necrosis factor-α in human bone cells

Bone morphogenetic proteins (BMP) stimulate osteoblast differentiation by signal transduction via three BMP receptors (BMPR-IA, -IB and -II), whereas the inflammatory cytokine tumor necrosis factor-α (TNF-α) has been shown to suppress osteoblast differentiation. Although the mechanisms which regulate the BMPR are not yet known, it is possible that they may be negatively controlled by TNF-α, thereby inhibiting BMP-induced osteoblast differentiation. To test this hypothesis, we have examined the effects of TNF-α on BMPR-IA, -IB and -II expression and the functional consequences of this cytokine on BMPR-mediated functions in human bone cells. The results showed that although TNF-α down-regulated BMPR-IA and -II transcripts, it increased the level of BMPR-IB mRNA via a MAPK-dependent pathway. In marked contrast, however, TNF-α nevertheless caused marked down-regulation of the expression of the BMPR-IB surface antigen specifically. Moreover, the cytokine-induced decrease in BMPR-IB expression was found to be associated with the concurrent presence of a ‘soluble’ form of this antigen in supernatants of TNF-α-treated cultures. Furthermore, the TNF-α-induced loss of BMPR-IB was found to ablate BMP-2-stimulated bone cell functions, including phosphorylation of Smad1/5/8, alkaline phosphatase activity and osteocalcin expression. In conclusion, our study has provided evidence, for the first time, that BMPR can be differentially modulated by TNF-α at both the post-transcriptional and post-translational levels, with the TNF-α-induced shedding of the BMPR-IB antigen associated with a significantly diminished response to BMP-2 in vitro.