Bone morphogenetic protein receptors and bone morphogenetic protein signaling are controlled by tumor necrosis factor-alpha 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-alpha (TNF-alpha) 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-alpha, thereby inhibiting BMP-induced osteoblast differentiation. To test this hypothesis, we have examined the effects of TNF-alpha 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-alpha 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-alpha 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-alpha-treated cultures. Furthermore, the TNF-alpha-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-alpha at both the post-transcriptional and post-translational levels, with the TNF-alpha-induced shedding of the BMPR-IB antigen associated with a significantly diminished response to BMP-2 in vitro.
Singhatanadgit
W
W
Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, University College London, 256 Gray's Inn Road, London WC1X 8LD, United Kingdom.
Salih
V
V
Olsen
I
I
D000941:Antigens / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D055396:Bone Morphogenetic Protein 2; D052004:Bone Morphogenetic Protein Receptors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010011:Osteocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000941:Antigens; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D052004:Bone Morphogenetic Protein Receptors; D020929:Mitogen-Activated Protein Kinase Kinases